0% found this document useful (0 votes)

11 views

Principles of Biochemistry - (Chapter 1 The Foundations of Biochemistry)

The document summarizes the key foundations of biochemistry. It discusses that (1) cells are the fundamental unit of life and use a small set of carbon-based molecules to carry out functions and reproduce; (2) living organisms exist in a dynamic steady state and extract energy from their surroundings to do work and maintain homeostasis; (3) cells have the capacity for precise self-replication and self-assembly using genetic information stored in their genome; and (4) living organisms change over time through Darwinian evolution.

Uploaded by

gabriel.balsys

Available Formats

Download as PDF, TXT or read online on Scribd

0% found this document useful (0 votes)

11 views

Principles of Biochemistry - (Chapter 1 The Foundations of Biochemistry)

Uploaded by

gabriel.balsys

Available Formats

Download as PDF, TXT or read online on Scribd

You are on page 1/ 40

Chapter 1

THE FOUNDATIONS
OF BIOCHEMISTRY
1.1 Cellular Foundations 2 In each chapter of this book, we organize our discus-
sion around central principles or issues in biochemistry. In
1.2 Chemical Foundations 10 this chapter, we consider the features that define a living
1.3 Physical Foundations 19 organism, and we develop these principles:
P1 Cells are the fundamental unit of life.
1.4 Genetic Foundations 27 Although they vary in complexity and can be
1.5 Evolutionary Foundations 30 highly specialized for their environment or
function within a multicellular organism, they
share remarkable similarities.

A
bout 14 billion years ago, the universe arose as P2 Cells use a relatively small set of carbon-
a cataclysmic explosion of hot, energy-rich sub- based metabolites to create polymeric
atomic particles. Within seconds, the simplest machines, supramolecular structures,
elements (hydrogen and helium) were formed. As the and information repositories. The
universe expanded and cooled, material condensed chemical structure of these components
under the influence of gravity to form stars. Some stars defines their cellular function. The collection
became enormous and then exploded as supernovae, of molecules carries out a program, the end
releasing the energy needed to fuse simpler atomic result of which is reproduction of the program
nuclei into the more complex elements. Atoms and mole- and self-perpetuation of that collection of
cules formed swirling masses of dust particles, and their molecules — in short, life.
accumulation led eventually to the formation of rocks, P3 Living organisms exist in a dynamic
planetoids, and planets. Thus were produced, over bil- steady state, never at equilibrium with
lions of years, Earth itself and the chemical elements their surroundings. Following the laws of
found on Earth today. About 4 billion years ago, life arose thermodynamics, living organisms extract energy
on Earth — simple microorganisms with the ability to from their surroundings and employ it to maintain
extract energy from chemical compounds and, later, from homeostasis and do useful work. Essentially all of
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

sunlight, which they used to make a vast array of more the energy obtained by a cell comes from the flow
complex biomolecules from the simple elements and of electrons, driven by sunlight or by metabolic
compounds on the Earth’s surface. We and all other living redox reactions.
organisms are made of stardust. P4 Cells have the capacity for precise self-
Biochemistry asks how the remarkable properties of replication and self-assembly using chemical
living organisms arise from thousands of different biomol- information stored in the genome. A single
ecules. When these molecules are isolated and examined bacterial cell placed in a sterile nutrient medium
individually, they conform to all the physical and chemical can give rise to a billion identical “daughter”
laws that describe the behavior of inanimate matter — as cells in 24 hours. Each cell is a faithful copy of
do all the processes occurring in living organisms. The the original, its construction directed entirely by
study of biochemistry shows how the collections of inan- information contained in the genetic material of
imate molecules that constitute living organisms interact the original cell. On a larger scale, the progeny of
to maintain and perpetuate life governed solely by the vertebrate animals share a striking resemblance to
same physical and chemical laws that govern the nonliv- their parents, also the result of their inheritance of
ing universe. parental genes.

1
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
2 The Foundations of Biochemistry

P5 Living organisms change over time by

gradual evolution. The result of eons of
evolution is an enormous diversity of life forms, Cytoplasm
Plasma membrane
fundamentally related through their shared Ribosomes
ancestry, which can be seen at the molecular level 20–50 mm
1 mm Nucleus
in the similarity of gene sequences and protein Nucleoid
structures. Nuclear membrane
Membrane-bounded
Despite these common properties and the funda- organelles
mental unity of life they reveal, it is difficult to make Bacterial cell Animal cell
generalizations about living organisms. Earth has an
enormous diversity of organisms living in a wide range FIGURE 1-1 The universal features of living cells. All cells have a
nucleus or nucleoid containing their DNA, a plasma membrane, and cyto-
of habitats, from hot springs to Arctic tundra, from ani-
plasm. Eukaryotic cells contain a variety of membrane-bounded organelles
mal intestines to college dormitories. These habitats are (including mitochondria and chloroplasts) and large particles (ribosomes, for
matched by a correspondingly wide range of specific bio- example).
chemical adaptations, achieved within a common chem-
ical framework. For the sake of clarity, in this book we
sometimes risk certain generalizations, which, though Transport proteins in the plasma membrane allow the
not perfect, remain useful; we also frequently point out passage of certain ions and molecules, receptor proteins
the exceptions to these generalizations, which can prove transmit signals into the cell, and membrane enzymes
illuminating. participate in some reaction pathways. Because the indi-
Biochemistry describes in molecular terms the vidual lipids and proteins of the plasma membrane are
structures, mechanisms, and chemical processes shared not covalently linked, the entire structure is remarkably
by all organisms and provides organizing principles that flexible, allowing changes in the shape and size of the
underlie life in all its diverse forms. Although biochemis- cell. As a cell grows, newly made lipid and protein mole-
try provides important insights and practical applications cules are inserted into its plasma membrane; cell division
in medicine, agriculture, nutrition, and industry, its ulti- produces two cells, each with its own membrane. This
mate concern is with the wonder of life itself. growth and cell division (fission) occurs without loss of
In this introductory chapter we give an overview membrane integrity.
of the cellular, chemical, physical, and genetic back- The internal volume enclosed by the plasma mem-
grounds of biochemistry and the overarching principle of brane, the cytoplasm (Fig. 1-1), is composed of an
evolution — how life emerged and evolved into the diver- aqueous solution, the cytosol, and a variety of suspended
sity of organisms we see today. As you read through the particles with specific functions. These particulate com-
book, you may find it helpful to refer back to this chapter ponents (membranous organelles such as mitochondria
at intervals to refresh your memory of this background and chloroplasts; supramolecular structures such as
material. ribosomes and proteasomes, the sites of protein syn-
thesis and degradation) sediment when cytoplasm is
centrifuged at 150,000 g (g is the gravitational force of
1.1 Cellular Foundations Earth). What remains as the supernatant fluid is defined
The unity and diversity of organisms become apparent as the cytosol, a highly concentrated solution containing
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

even at the cellular level. The smallest organisms consist enzymes and the RNA (ribonucleic acid) molecules that
of single cells and are microscopic. Larger, multicellular encode them; the components (amino acids and nucleo-
organisms contain many different types of cells, which tides) from which these macromolecules are assembled;
vary in size, shape, and specialized function. Despite hundreds of small organic molecules called metabolites,
these obvious differences, all cells of the simplest and intermediates in biosynthetic and degradative pathways;
most complex organisms share certain fundamental prop- coenzymes, compounds essential to many enzyme-
erties, which can be seen at the biochemical level. catalyzed reactions; and inorganic ions (K + , Na + , Mg 2+ ,
and Ca 2+, for example).
All cells have, for at least some part of their life, either
Cells Are the Structural and Functional Units a nucleoid or a nucleus, in which the genome — the
of All Living Organisms complete set of genes, composed of DNA (deoxyribo-
Cells of all kinds share certain structural features nucleic acid) — is replicated and stored, with its asso-
(Fig. 1-1). The plasma membrane defines the periphery ciated proteins. The nucleoid, in bacteria and archaea,
of the cell, separating its contents from the surroundings. is not separated from the cytoplasm by a membrane;
It is composed of lipid and protein molecules that form a the nucleus, in eukaryotes, is enclosed within a dou-
thin, tough, pliable, hydrophobic barrier around the cell. ble membrane, the nuclear envelope. Cells with nuclear
The membrane is a barrier to the free passage of inor- envelopes make up the large domain Eukarya (Greek eu,
ganic ions and most other charged or polar molecules. “true,” and karyon, “nucleus”). Microorganisms without

Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
1.1 Cellular Foundations 3

nuclear membranes, formerly grouped together as pro-

karyotes (Greek pro, “before”), are now recognized as
comprising two very distinct groups: the domains Bacte-
ria and Archaea, described below.

Cellular Dimensions Are Limited by Diffusion

Most cells are microscopic, invisible to the unaided eye.
Animal and plant cells are typically 5 to 100 µ m in diam-
eter, and many unicellular microorganisms are only 1 to
2 µ m long (see the end of the book for information on
units and their abbreviations). What limits the dimen-
sions of a cell? The lower limit is probably set by the
minimum number of each type of biomolecule required
by the cell. The smallest cells, certain bacteria known as
mycoplasmas, are 300 nm in diameter and have a volume
of about 10−14 mL . A single bacterial ribosome is about 20
nm in its longest dimension, so a few ribosomes take up a
substantial fraction of the volume in a mycoplasmal cell.
The upper limit of cell size is probably set by the rate
of transport of nutrients into the cell and waste products
out. As the size of a cell increases, its surface-to-volume
ratio decreases. For a spherical cell, the surface area is
a function of the square of the radius (r 2 ), whereas its
volume is a function of r 3 . A bacterial cell the size of
Eschericia coli is so small, and the ratio of its surface
area to its volume is so large, that every part of its cyto-
plasm is easily reached by nutrients moving across the
membrane and into the cell. With increasing cell size,
surface-to-v olume ratio decreases, until metabolism
consumes nutrients faster than transmembrane carri- FIGURE 1-2 Most animal cells have intricately folded surfaces.
ers can supply them. Many types of animal cells have a The human lymphocytes in this artificially colored scanning electron
highly folded or convoluted surface that increases their micrograph are about 10–12 μm in diameter. Their convoluted surfaces
give them a much larger surface area than a sphere of the same diameter.
surface-to-volume ratio and allows higher rates of uptake
[Steve Gschmeissner/Science Source.]
of materials from their surroundings (Fig. 1-2).

Organisms Belong to Three Distinct Domains of Life

branch that gave rise to the Archaea; eukaryotes are
The development of techniques for determining DNA therefore more closely related to archaea than to bacteria.
sequences quickly and inexpensively has greatly Within the domains of Archaea and Bacteria are sub-
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

improved our ability to deduce evolutionary relationships groups distinguished by their habitats. In aerobic habitats
among organisms. Similarities between gene sequences with a plentiful supply of oxygen, some resident organ-
in various organisms provide deep insight into the course isms derive energy from the transfer of electrons from fuel
of evolution. In one interpretation of sequence similari- molecules to oxygen within the cell. Other environments
ties, all living organisms fall into one of three large groups are anaerobic, devoid of oxygen, and microorganisms
(domains) that define three branches of the evolution- adapted to these environments obtain energy by trans-
ary tree of life originating from a common progenitor ferring electrons to nitrate (forming N 2), sulfate (forming
(Fig. 1-3). Two large groups of single-celled microorgan- H2S ), or CO2 (forming CH4). Many organisms that have
isms can be distinguished on genetic and biochemical evolved in anaerobic environments are obligate anaer-
grounds: Bacteria and Archaea. Bacteria inhabit soils, obes: they die when exposed to oxygen. Others are facul-
surface waters, and the tissues of other living or decaying tative anaerobes, able to live with or without oxygen.
organisms. Many of the Archaea, recognized as a distinct
domain by the microbiologist Carl Woese in the 1980s,
inhabit extreme environments — salt lakes, hot springs,
Organisms Differ Widely in Their Sources of Energy
highly acidic bogs, and the ocean depths. The available and Biosynthetic Precursors
evidence suggests that the Archaea and Bacteria diverged We can classify organisms according to how they
early in evolution. All eukaryotic organisms, which make obtain the energy and carbon they need for synthesiz-
up the third domain, Eukarya, evolved from the same ing cellular material (as summarized in Fig. 1-4). There

Eukarya
Animals
Green Entamoebae Slime
Bacteria nonsulfur Archaea molds
bacteria Fungi
Gram-
Methanosarcina
positive Plants
Proteobacteria bacteria Methanobacterium
Halophiles Ciliates
(Purple bacteria) Thermoproteus Methanococcus
Cyanobacteria Pyrodictium Thermococcus Flagellates
Flavobacteria
Trichomonads

Thermotogales

Microsporidia
Diplomonads

Last universal common ancestor

FIGURE 1-3 Phylogeny of the three domains of life. Phylogenetic relationships are often illustrated by a “family tree” of this type. The basis for this tree is
the similarity in nucleotide sequences of the ribosomal RNAs of each group. [Information from C. R. Woese, Microbiol. Rev. 51:221, 1987, Fig. 4.]

All organisms

Energy source
Chemical Light

Chemotrophs Phototrophs

Carbon source Carbon source

CO2 Organic compounds CO2 Organic compounds

Chemoautotrophs Chemoheterotrophs Photoautotrophs Photoheterotrophs

Final electron acceptor Use H2O to reduce CO2?

O2 Yes No
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Hydrogen-, sulfur-, All animals; most fungi, Oxygenic Anoxygenic Green nonsulfur
iron-, nitrogen-, and protists, bacteria photosynthesis photosynthetic bacteria,
carbon monoxide– (plants, algae, bacteria (green and purple nonsulfur
oxidizing bacteria cyanobacteria) purple bacteria) bacteria

Not O2
Organic Inorganic
compounds compounds

Fermentative …and
bacteria such as Pseudomonas
Lactococcus lactis… denitrificans

FIGURE 1-4 All organisms can be classified according to their source of energy (sunlight or oxidizable chemical compounds) and their source of carbon for
the synthesis of cellular material.

are two broad categories based on energy sources: pho- Bacterial and Archaeal Cells Share Common Features
totrophs (Greek trophe, “nourishment”) trap and use but Differ in Important Ways
sunlight, and chemotrophs derive their energy from
oxidation of a chemical fuel. Some chemotrophs oxi- The best-studied bacterium, Escherichia coli, is a usu-
dize inorganic fuels — HS− to S0 (elemental sulfur), ally harmless inhabitant of the human intestinal tract.
S0 to SO−4 , NO−2 to NO−3 , or Fe2+ to Fe3+, for example. The E. coli cell (Fig. 1-5a) is an ovoid about 2 µ m long and
Phototrophs and chemotrophs may be further divided a little less than 1 µ m in diameter, but other bacteria may
into those that can synthesize all of their biomolecules be spherical or rod-shaped, and some are substantially
directly from CO2 (autotrophs) and those that require larger. E. coli has a protective outer membrane and an
some preformed organic nutrients made by other organ- inner plasma membrane that encloses the cytoplasm and
Nelson/Cox
isms (heterotrophs). We can describe an organism’s the nucleoid. Between the inner and outer Lehninger Biochemistry,
membranes is 8e
Figure #1.05a-d
mode of nutrition by combining these terms. For exam- a thin but strong layer of a high molecular weight poly-
ple, cyanobacteria are photoautotrophs; humans are mer (peptidoglycan) that gives the cell final its shape and
chemoheterotrophs. Even finer distinctions can be made, rigidity. The plasma membrane and the layers outside it
and many organisms can obtain energy and carbon from constitute the cell envelope. The plasma membranes of
more than one source under different environmental or bacteria consist of a thin bilayer of lipid molecules pen-
developmental conditions. etrated by proteins. Archaeal plasma membranes have

(a) (b) Gram-positive bacteria

Ribosomes Bacterial and archaeal ribosomes are smaller
than eukaryotic ribosomes, but serve the same function—
Polysaccharide
protein synthesis from an RNA message.
Solid layer
Cell envelope
Structures differ.
Glycoprotein
Nucleoid
Contains one Peptidoglycan
or several long,
circular DNA Lipoprotein
molecules. Plasma membrane
Cytoplasm
(c) Gram-negative bacteria (shown at left)
Pili Provide
points of LPS
adhesion to
surface of Outer membrane
other cells. Porin
Lipoprotein

Peptidoglycan
Lipoprotein Periplasm
Plasma membrane
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Cytoplasm

(d) Methanothermus, an extremely heat-tolerant archaeon

Solid layer

Flagella Glycoprotein
Propel cell Pseudo-
through its peptidoglycan
surroundings.
Plasma membrane
Cytoplasm Membrane protein

FIGURE 1-5 Some common structural features of bacterial and proteins, to diffuse through. The inner (plasma) membrane, made of phos-
archaeal cells. (a) This correct-scale drawing of E. coli serves to illustrate pholipids and proteins, is impermeable to both large and small molecules.
some common features. (b) The cell envelope of gram-positive bacteria is Between the inner and outer membranes, in the periplasm, is a thin layer of
a single membrane with a thick, rigid layer of peptidoglycan on its outside peptidoglycan, which gives the cell shape and rigidity, but does not retain
surface. A variety of polysaccharides and other complex polymers are inter- Gram’s stain. (d) Archaeal membranes vary in structure and composition, but
woven with the peptidoglycan, and surrounding the whole is a porous “solid all have a single membrane surrounded by an outer layer that includes either
layer” composed of glycoproteins. (c) E. coli is gram-negative and has a dou- a peptidoglycan-like structure or a porous protein shell (solid layer), or both.
ble membrane. Its outer membrane has a lipopolysaccharide (LPS) on the [(a) David S. Goodsell. (b, c, d) Information from S.-V. Albers and B. H. Meyer, Nature Rev. Microbiol. 9:414,
outer surface and phospholipids on the inner surface. This outer membrane 2011, Fig. 2.]
is studded with protein channels (porins) that allow small molecules, but not
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
6 The Foundations of Biochemistry

a similar architecture, but the lipids can be strikingly dif- These organelles include mitochondria, the site of
ferent from those of bacteria (see Fig. 10-6). most of the energy-extracting reactions of the cell; the
Bacteria and archaea have group-specific specializa- endoplasmic reticulum and Golgi complexes, which
tions of their cell envelopes (Fig. 1-5b–d). Some bacteria, play central roles in the synthesis and processing of lip-
called gram-positive because they are colored by Gram’s ids and membrane proteins; peroxisomes, in which
stain (introduced by Hans Christian Gram in 1884), have very-long-chain fatty acids are oxidized and reactive
a thick layer of peptidoglycan outside their plasma mem- oxygen species are detoxified; and lysosomes, filled
brane but lack an outer membrane. Gram-negative bacte- with digestive enzymes to degrade unneeded cellular
ria have an outer membrane composed of a lipid bilayer debris. In addition to these, plant cells contain vacu-
into which are inserted complex lipopolysaccharides oles (which store large quantities of organic acids) and
and proteins called porins that provide transmembrane chloroplasts (in which sunlight drives the synthesis of
channels for the diffusion of low molecular weight com- ATP (adenosine triphosphate) in the process of photo-
pounds and ions across this outer membrane. The struc- synthesis). Also present in the cytoplasm of many cells
tures outside the plasma membrane of archaea differ are granules or droplets containing stored nutrients
from organism to organism, but they, too, have a layer such as starch and fat.
of peptidoglycan or protein that confers rigidity on their In a major advance in biochemistry, Albert Claude,
cell envelopes. Christian de Duve, and George Palade developed meth-
The cytoplasm of E. coli contains about 15,000 ods for separating organelles from the cytosol and from
ribosomes, various numbers (from 10 to thousands) each other — an essential step in investigating their
of copies of each of 1,000 or so different enzymes, per- structures and functions. In a typical cell fractionation
haps 1,000 organic compounds of molecular weight less (Fig. 1-7), cells or tissues in solution are gently disrupted
than 1,000 (metabolites and cofactors), and a variety of by physical shear. This treatment ruptures the plasma
inorganic ions. The nucleoid contains a single, circular membrane but leaves most of the organelles intact.
molecule of DNA, and the cytoplasm (like that of most The homogenate is then centrifuged; organelles such as
bacteria) contains one or more smaller, circular segments nuclei, mitochondria, and lysosomes differ in size and
of DNA called plasmids. In nature, some plasmids confer therefore sediment at different rates.
resistance to toxins and antibiotics in the environment. These methods were used to establish, for example,
In the laboratory, these DNA segments are especially that lysosomes contain degradative enzymes, mitochon-
amenable to experimental manipulation and are powerful dria contain oxidative enzymes, and chloroplasts contain
tools for genetic engineering (see Chapter 9). photosynthetic pigments. The isolation of an organelle
Other species of bacteria, as well as archaea, contain enriched in a certain enzyme is often the first step in the
a similar collection of biomolecules, but each species has purification of that enzyme.
physical and metabolic specializations related to its envi-
ronmental niche and nutritional sources. Cyanobacteria, The Cytoplasm Is Organized by the Cytoskeleton
for example, have internal membranes specialized to trap and Is Highly Dynamic
energy from light (see Fig. 20-23). Many archaea live in
Fluorescence microscopy reveals several types of pro-
extreme environments and have biochemical adaptations
tein filaments crisscrossing the eukaryotic cell, forming
to survive in extremes of temperature, pressure, or salt
an interlocking three-dimensional meshwork, the cyto-
concentration. Differences in ribosomal structure gave
skeleton. Eukaryotes have three general types of cyto-
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

the first hints that Bacteria and Archaea constituted sep-

plasmic filaments — actin filaments, microtubules, and
arate domains. Most bacteria (including E. coli) exist as
intermediate filaments (Fig. 1-8) — differing in width
individual cells, but often associate in biofilms or mats, in
(from about 6 nm to 22 nm), composition, and specific
which large numbers of cells adhere to each other and to
function. All types provide structure and organization to
some solid substrate beneath or at an aqueous surface.
the cytoplasm and shape to the cell. Actin filaments and
Cells of some bacterial species (the myxobacteria, for
microtubules also help to produce the motion of organ-
example) show simple social behavior, forming many-
elles or of the whole cell.
celled aggregates in response to signals between neigh-
Each type of cytoskeletal component consists of sim-
boring cells.
ple protein subunits that associate noncovalently to form
filaments of uniform thickness. These filaments are not
Eukaryotic Cells Have a Variety of Membranous permanent structures; they undergo constant disassem-
Organelles, Which Can Be Isolated for Study bly into their protein subunits and reassembly into fila-
Typical eukaryotic cells (Fig. 1-6) are much larger ments. Their locations in cells are not rigidly fixed but
than bacteria — commonly 5 to 100 µ m in diameter, may change dramatically with mitosis, cytokinesis, amoe-
with cell volumes a thousand to a million times larger boid motion, or other changes in cell shape. The assem-
than those of bacteria. The distinguishing character- bly, disassembly, and location of all types of filaments are
istics of eukaryotes are the nucleus and a variety of regulated by other proteins, which serve to link or bun-
membrane-enclosed organelles with specific functions. dle the filaments or to move cytoplasmic organelles along
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
Permanent figure # 111
3rd pass

1.1 Cellular Foundations 7

(a) Animal cell

Ribosomes are protein-
synthesizing machines.
Peroxisome oxidizes fatty acids.

Cytoskeleton supports cell, aids

in movement of organelles.

Lysosome degrades intracellular

debris.
Transport vesicle shuttles lipids
and proteins between ER, Golgi,
and plasma membrane.
Golgi complex processes,
packages, and targets proteins to
other organelles or for export.

Smooth endoplasmic reticulum

(SER) is site of lipid synthesis
and drug metabolism.

Nuclear envelope segregates Nucleolus is site of ribosomal

chromatin (DNA 1 protein) RNA synthesis.
from cytoplasm. Nucleus contains the
Rough endoplasmic reticulum
(RER) is site of much protein genes (chromatin).
Plasma membrane separates cell synthesis.
from environment, regulates Nuclear
movement of materials into and envelope Ribosomes Cytoskeleton
out of cell.
Mitochondrion oxidizes fuels to
produce ATP.

Chloroplast harvests sunlight,

produces ATP and carbohydrates. Golgi complex

Starch granule temporarily stores

carbohydrate products of
photosynthesis.

Thylakoids are site of light-

driven ATP synthesis.

Cell wall provides shape and

rigidity; protects cell from

osmotic swelling.

Vacuole degrades and recycles

macromolecules, stores
metabolites. Cell wall of adjacent cell
Plasmodesma provides path
between two plant cells.
Glyoxysome contains enzymes of
the glyoxylate cycle.

(b) Plant cell

FIGURE 1-6 Eukaryotic cell structure. Schematic illustrations of two in red are unique to animal cells; those labeled in green are unique to plant
major types of eukaryotic cell: (a) a representative animal cell and (b) a repre- cells. Eukaryotic microorganisms (such as protists and fungi) have structures
sentative plant cell. Plant cells are usually 10 to 100 µm in diameter — larger similar to those in plant and animal cells, but many also contain specialized
than animal cells, which typically range from 5 to 30 µm. Structures labeled organelles not illustrated here.

the filaments. (Bacteria contain actinlike proteins that fuse with another. Organelles move through the cyto-
serve similar roles in those cells.) plasm along protein filaments, their motion powered by
The filaments disassemble and then reassemble else- energy-dependent motor proteins. The endomembrane
where. Membranous vesicles bud from one organelle and system (see Fig. 11-4) segregates specific metabolic
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
8 The Foundations of Biochemistry

Differential
centrifugation

Tissue
homogenization
(a) (b)

Low-speed centrifugation Liver tissue FIGURE 1-8 The three types of cytoskeletal filaments: actin
(1,000 g, 10 min) filaments, microtubules, and intermediate filaments. Cellular struc-
❚

▲
tures can be labeled with an antibody (that recognizes a characteristic pro-
▲

▲
▲

▲❚ tein) covalently attached to a fluorescent compound. The stained structures

▲
❚

❚
❚

Supernatant subjected to are visible when the cell is viewed with a fluorescence microscope. (a) In this
▲
❚ ▲

❚▲ ▲

▲
▲❚

medium-speed centrifugation cultured fibroblast cell, bundles of actin filaments are stained red; microtu-
▲

❚
❚ ❚ (20,000 g, 20 min) bules, radiating from the cell center, are stained green; and chromosomes
▲

❚
❚

▲
▲
(in the nucleus) are stained blue. (b) A newt lung cell undergoing mitosis.
▲
▲

▲ ▲ ❚▲ ❚
▲ Supernatant subjected M icrotubules (green), attached to structures called kinetochores (yellow)
❚

❚ ❚
▲ to high-speed
❚

Tissue ▲ on the condensed chromosomes (blue), pull the chromosomes to opposite

❚ ❚
▲

homogenate
❚
centrifugation
▲ ❚▲ poles, or centrosomes (magenta), of the cell. Intermediate filaments, made of
❚

▲
❚ (80,000 g, 1 h)
keratin (red), maintain the structure of the cell. [(a) James J. Faust and David G. Capco.
❚ ❚
▲
❚
▲
▲
▲❚

(b) Dr. Alexey Khodjakov, Wadsworth Center, New York State Department of Health.]
▲

❚
▲
▲
▲

▲ ❚
▲
❚
Supernatant
❚

Pellet ❚ subjected to
❚

contains very high-speed

❚

❚
whole cells, ❚
centrifugation
This structural organization of the cytoplasm is far
❚

nuclei, (150,000 g, 3 h)
❚

cytoskeletons, ▲
▲

from random. The motion and positioning of organelles

▲

▲▲
▲

▲ ▲
plasma
▲

membranes Pellet
and cytoskeletal elements are under tight regulation, and
contains at certain stages in its life, a eukaryotic cell undergoes
mitochondria, dramatic, finely orchestrated reorganizations, such as the
lysosomes, ❚ ❚
❚❚❚❚

❚
events of mitosis. The interactions between the cytoskel-
❚
❚❚

peroxisomes
❚

Pellet eton and organelles are noncovalent, reversible, and sub-

contains Supernatant
contains ject to regulation in response to various intracellular and
microsomes
(fragments soluble extracellular signals.
of ER), proteins
small vesicles
Cells Build Supramolecular Structures
Pellet contains Macromolecules and their monomeric subunits dif-
ribosomes, large fer greatly in size. An alanine molecule is less than
macromolecules
0.5 nm long. A molecule of hemoglobin, the
FIGURE 1-7 Subcellular fractionation of tissue. A tissue such o xygen-carrying protein of erythrocytes (red blood
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

as liver is first mechanically homogenized to break cells and disperse their cells), consists of nearly 600 amino acid subunits in four
contents in an aqueous buffer. The sucrose medium has an osmotic pressure
long chains, folded into globular shapes and associated in
similar to that in organelles, thus balancing diffusion of water into and out
of the organelles, which would swell and burst in a solution of lower osmo- a structure 5.5 nm in diameter. In turn, proteins are much
larity (see Fig. 2-12). The large and small particles in the suspension can be smaller than ribosomes (about 20 nm in diameter), which
separated by centrifugation at different speeds. Larger particles sediment are much smaller than organelles such as mitochondria,
more rapidly than small particles, and soluble material does not sediment. By typically 1 µ m in diameter. It is a long jump from simple
careful choice of the conditions of centrifugation, subcellular fractions can be
biomolecules to cellular structures that can be seen with
separated for biochemical characterization. [Information from B. Alberts et al., Molecular
Biology of the Cell, 2nd edn, p. 165, Garland Publishing, 1989.]
the light microscope. Figure 1-9 illustrates the structural
hierarchy in cellular organization.
The monomeric subunits of proteins, nucleic acids,
processes and provides surfaces on which certain and polysaccharides are joined by covalent bonds. In
enzyme-catalyzed reactions occur. Exocytosis and supramolecular complexes, however, macromolecules are
endocytosis, mechanisms of transport (out of and into held together largely by noncovalent interactions — much
cells, respectively) that involve membrane fusion and weaker, individually, than covalent bonds. Among these
fission, provide paths between the cytoplasm and the noncovalent interactions are hydrogen bonds; ionic
surrounding medium, allowing the secretion of sub- interactions (between charged groups); and aggrega-
stances produced in the cell and uptake of extracellular tions of nonpolar groups in aqueous solution, brought
materials. about by van der Waals interactions (also called London

The cell Supramolecular

Macromolecules Monomeric units
and its organelles complexes
NH2
Nucleotides
DNA N
O 2
O N
2
O P O CH2 O
O
H H
H H

Chromatin OH H

COO2
1
H3N C H
CH3
Protein
Amino acids
Plasma membrane
Cellulose OH
CH 2 O
H
H H OH
OH
HO OH
H

Sugars CH2O
H
Cell wall H O

FIGURE 1-9 Structural hierarchy in the molecular organization that consists of DNA and basic proteins (histones). DNA is made up of simple
of cells. The organelles and other relatively large components of cells are monomeric subunits (nucleotides), as are proteins (amino acids). [Information
composed of supramolecular complexes, which in turn are composed of from W. M. Becker and D. W. Deamer, The World of the Cell, 2nd edn, Fig. 2-15, Benjamin/Cummings
smaller macromolecules and even smaller molecular subunits. For example, Publishing Company, 1991.]
the nucleus of this plant cell contains chromatin, a supramolecular complex

forces) and by the hydrophobic effect — all of which have must be slowed by collisions with other large structures.
energies much smaller than those of covalent bonds. In short, a given molecule may behave quite differently in
(These noncovalent interactions are described in Chap- the cell than it behaves in vitro. A central challenge of bio-
ter 2.) The large numbers of weak interactions between chemistry is to understand the influences of cellular orga-
macromolecules in supramolecular complexes stabilize nization and macromolecular associations on the function
these assemblies, producing their unique structures. of individual enzymes and other biomolecules — to
understand function in vivo as well as in vitro.
In Vitro Studies May Overlook Important Interactions
among Molecules
One approach to understanding a biological process is to
study purified molecules in vitro (from the Latin, meaning
“in glass” — in the test tube), without interference from
other molecules present in the intact cell — that is, in vivo
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

(from the Latin, meaning “in the living”). Although this Cell Flagellum
envelope
approach has been remarkably revealing, we must keep in
mind that the inside of a cell is quite different from the
inside of a test tube. The “interfering” components elimi-
nated by purification may be critical to the biological func-
tion or regulation of the molecule that is being purified. For Outer
membrane
example, in vitro studies of pure enzymes are commonly
done at very low enzyme concentrations in thoroughly Inner
stirred aqueous solutions. In the cell, an enzyme is dis- membrane
solved or suspended in the gel-like cytosol with thousands Ribosome
of other proteins, some of which bind to that enzyme and DNA
(nucleoid)
influence its activity. Some enzymes are components of
multienzyme complexes in which reactants are channeled
from one enzyme to another, never entering the bulk sol-
vent. When all of the known macromolecules in a cell are
represented in their known dimensions and concentra- FIGURE 1-10 The crowded cell. This drawing is an accurate repre-
tions (Fig. 1-10), it is clear that the cytosol is very crowded sentation of the relative sizes and numbers of macromolecules in one small
and that diffusion of macromolecules within the cytosol region of an E. coli cell. [© David S. Goodsell 1999.]

SUMMARY 1.1 Cellular Foundations two apparently very different cell types; for example,
the breakdown of glucose in yeast and in muscle cells
All cells share certain fundamental properties: they are involved the same 10 chemical intermediates and the
bounded by a plasma membrane; have a cytosol contain- same 10 enzymes. Subsequent studies of many other
ing metabolites, coenzymes, inorganic ions, and enzymes; biochemical processes in many different organisms have
and have a set of genes contained within a nucleoid (bac- confirmed the generality of this observation, neatly
teria and archaea) or a nucleus (eukaryotes). summarized in 1954 by the biochemist Jacques Monod:
The size of cells is limited by the need to deliver oxy- “What is true of E. coli is true of the elephant.” The cur-
gen to all parts of the cell. rent understanding that all organisms share a common
By comparing their DNA sequences, researchers can evolutionary origin is based in part on this observed uni-
place organisms in three domains: Bacteria, Archaea, and versality of chemical intermediates and transformations,
Eukarya. Archaea and Eukarya are more closely related often termed “biochemical unity.”
to each other than either is to Bacteria. Fewer than 30 of the more than 90 naturally occur-
ring chemical elements are known to be essential to
All organisms require a source of energy to perform organisms. Most of the elements in living matter have a
cellular work. Phototrophs obtain energy from sunlight; relatively low atomic number; only three have an atomic
chemotrophs obtain energy from chemical fuels. number above that of selenium, 34 (Fig. 1-11). The four
Bacterial and archaeal cells contain cytosol, a nucle- most abundant elements in living organisms, in terms of
oid, and plasmids, all within a cell envelope. percentage of total number of atoms, are hydrogen, oxy-
Eukaryotes contain a nucleus and a variety of gen, nitrogen, and carbon, which together make up more
membrane-enclosed organelles with specialized func- than 99% of the mass of most cells. They are the lightest
tions, which can be studied in the isolated organelles. elements capable of efficiently forming one, two, three,
and four bonds, respectively; in general, the lightest ele-
Cytoskeletal proteins assemble into long filaments ments form the strongest bonds. The trace elements rep-
that give cells shape and rigidity and serve as rails along resent a miniscule fraction of the weight of the human
which cellular organelles move throughout the cell. The body, but all are essential to life, usually because they are
membrane-bounded compartments constitute an inter- essential to the function of specific proteins, including
connected and dynamic endomembrane system. many enzymes. The oxygen-transporting capacity of the
Supramolecular complexes held together by nonco- hemoglobin molecule, for example, is absolutely depen-
valent interactions are part of a hierarchy of structures, dent on four iron ions that make up only 0.3% of the mol-
some visible with the light microscope. ecule’s mass.
Studying isolated cellular components in vitro simpli-
fies the experimental system, but such study may over- Biomolecules Are Compounds of Carbon with
look important interactions that occur in the living cell.
a Variety of Functional Groups
1.2 Chemical Foundations The chemistry of living organisms is organized around car-
bon, which accounts for more than half of the dry weight
Biochemistry aims to explain biological form and func- of cells. Carbon can form single bonds with hydrogen
tion in chemical terms. During the first half of the twen- atoms and can form both single bonds and double bonds
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

tieth century, parallel biochemical investigations of with oxygen and nitrogen atoms (Fig. 1-12). Of greatest
glucose breakdown in yeast and in animal muscle cells significance in biology is the ability of carbon atoms to
revealed remarkable chemical similarities between these form very stable single bonds with up to four other carbon

FIGURE 1-11 Elements essential to animal 1 2

H He
life and health. Bulk elements (shaded light red) are
structural components of cells and tissues and are 3 4 Bulk elements 5 6 7 8 9 10

required in the diet in gram quantities daily. For trace Li Be Trace elements B C N O F Ne

elements (shaded yellow), the requirements are much 11 12 13 14 15 16 17 18

smaller: for humans, a few milligrams per day of Fe, Na Mg Al Si P S Cl Ar

Cu, and Zn, and even less of the others. The elemental 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
requirements for plants and microorganisms are similar K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr
to those shown here; the ways in which they acquire 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
these elements vary. Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe

55 56 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86
Cs Ba Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn

87 88 Lanthanides
Fr Ra
Actinides

. . A . . . G FIGURE 1-12 Versatility of carbon

. C . 1 .H . C :H . C . 1 . N: .

:
. . O C OH . . . C : :N D
C PNO bonding. Carbon can form covalent single, dou-
A
ble, and triple bonds (all bonds in red), particularly
. . . A . . . . A A with other carbon atoms. Triple bonds are rare in
.C . 1 .O: .C:O. .C . 1 .C . .C: C .

: :
. . O C OO O . . . . O C OC O biomolecules.
A A A
:

. . . : G . . . . G E
.C . 1 .O: .C . 1 .C .
. .C: :O D
C PO . . .C: :C. D
C PCH

:
:

. . . . A D . .
. C . 1 .N: . C : N: O C ON .C . 1 .C . .C: : :C. O C qCO
. . . . G . .
A

atoms. Two carbon atoms also can share two (or three) own chemical characteristics and reactions. The chem-
electron pairs, thus forming double (or triple) bonds. ical “personality” of a compound is determined by the
The four single bonds that can be formed by a car- chemistry of its functional groups and their disposition in
bon atom project from the nucleus to the four apices of three-dimensional space.
a tetrahedron (Fig. 1-13), with an angle of about 109.5°
between any two bonds and an average bond length of
0.154 nm. There is free rotation around each single bond, Cells Contain a Universal Set of Small Molecules
unless very large or highly charged groups are attached Dissolved in the aqueous phase (cytosol) of all cells is
to both carbon atoms, in which case rotation may be a collection of perhaps several thousand different small
restricted. A double bond is shorter (about 0.134 nm) organic molecules (M r ~100 to ~500), with intracellular
and rigid, and it allows only limited rotation about its axis. concentrations ranging from nanomolar to >10 mM (see
Covalently linked carbon atoms in biomolecules can Fig. 13-31). (See Box 1-1 for an explanation of the var-
form linear chains, branched chains, and cyclic struc- ious ways of referring to molecular weight.) These are
tures. It seems likely that the bonding versatility of car- the central metabolites in the major pathways occurring
bon, with itself and with other elements, was a major in nearly every cell — the metabolites and pathways that
factor in the selection of carbon compounds for the have been conserved throughout the course of evolu-
molecular machinery of cells during the origin and evo- tion. This collection of molecules includes the common
lution of living organisms. No other chemical element can amino acids, nucleotides, sugars and their phosphory-
form molecules of such widely different sizes, shapes, lated derivatives, and mono-, di-, and tricarboxylic acids.
and composition. The molecules may be polar or charged and most are
Most biomolecules can be regarded as derivatives of water-soluble. They are trapped in the cell because the
hydrocarbons, with hydrogen atoms replaced by a vari- plasma membrane is impermeable to them, although spe-
ety of functional groups that confer specific chemical cific membrane transporters can catalyze the movement
properties on the molecule, forming various families of of some molecules into and out of the cell or between
organic compounds. Typical of these are alcohols, which compartments in eukaryotic cells. The universal occur-
have one or more hydroxyl groups; amines, with amino rence of the same set of compounds in living cells reflects
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

groups; aldehydes and ketones, with carbonyl groups; the evolutionary conservation of metabolic pathways that
and carboxylic acids, with carboxyl groups (Fig. 1-14). developed in the earliest cells.
Many biomolecules are polyfunctional, containing two or There are other small biomolecules, specific to cer-
more types of functional groups (Fig. 1-15), each with its tain types of cells or organisms. For example, vascular

(a) (b) (c)

X
120°
A
109.5° C
C C
C
C Y
109.5° B

FIGURE 1-13 Geometry of carbon bonding. (a) Carbon atoms compound ethane (CH3O CH3 ). (c) Double bonds are shorter and do not
have a characteristic tetrahedral arrangement of their four single bonds. allow free rotation. The two doubly bonded carbons and the atoms desig-
(b) Carbon–carbon single bonds have freedom of rotation, as shown for the nated A, B, X, and Y all lie in the same rigid plane.

plants contain, in addition to the universal set, small Macromolecules Are the Major Constituents of Cells
molecules called secondary metabolites, which play
Many biological molecules are macromolecules, poly-
roles specific to plant life. These metabolites include
mers with molecular weights above ~5,000 that are
compounds that give plants their characteristic scents
assembled from relatively simple precursors (Fig. 1-16).
and colors, and compounds such as morphine, quinine,
Shorter polymers are called oligomers (Greek oligos,
nicotine, and caffeine that are valued for their physiolog-
“few”). Proteins, nucleic acids, and polysaccharides are
ical effects on humans but have other purposes in plants.
macromolecules composed of monomers with molecular
The entire collection of small molecules in a given
weights of 500 or less. Synthesis of macromolecules is
cell under a specific set of conditions has been called
a major energy-consuming activity of cells. Macromole-
the metabolome, in parallel with the term “genome.”
cules themselves may be further assembled into supra-
Metabolomics is the systematic characterization of
molecular complexes, forming functional units such as
the metabolome under very specific conditions (such as
ribosomes. Table 1-1 shows the major classes of biomole-
following administration of a drug, or a biological signal
cules in an E. coli cell.
such as insulin).

H H H
A A E
Methyl R O C OH Ether R1 O O OR2 Guanidinium R O NO C ON
A B

E
H 1N H
D G
H H
H H
A A
Ethyl R O C O C OH Ester R1O C O O OR2 Imidazole R OO C P CH
A A B D G
H H O HN N:
GC J
A
H H H
C PC H
E G A
Phenyl R OC CH Acetyl R O O OC O C OH Sulfhydryl R O S OH
M J B A
COC O H
H H

Carbonyl R O C OH Anhydride R1 O C O O O C OR2 Disulfide R1 O S O S OR2

(aldehyde) B (two car- B B
O O O
boxylic acids)

H
A
Carbonyl R1 O C O R2 Amino R O N1OH Thioester R1 O C O S OR2
(ketone) B (protonated) A B
O H O

H O2
A
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

D
Carboxyl R O C O O2 Amido R O C ON Phosphoryl R O O OP O OH
B B G B
O H O
O

H
A
N O2 O2
B A A
Hydroxyl R OO OH Imine R1 O C OR2 Phosphoanhydride R1 O O OP O O OP O O OR2
(alcohol) B B
O O

O OH H O2
A D R3 A
Enol R OCPC N-Substituted A Mixed anhydride R O C O O OP O OH
G imine (Schiff N (carboxylic acid and B B
H B O O
base) R1 O C OR2 phosphoric acid;
also called acyl
phosphate)

FIGURE 1-14 Some common functional groups of biomol- the book, we use R to represent “any substituent.” It may be as simple as a
ecules. Functional groups are screened with a color typically used to hydrogen atom, but typically it is a carbon-containing group. When two
represent the element that characterizes the group: gray for C, red for O, or more substituents are shown in a molecule, we designate them R1, R2 ,
blue for N, yellow for S, and orange for P. In this figure and throughout and so forth.
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
1.2 Chemical Foundations 13

amino
NH2
imidazole-like A
phosphoanhydride C
N E N
H CH3 O2 O2 C N
thioester amido amido A A A A HC B A
CH3 O C O SOCH2 OCH2 ONHOC OCH2 OCH2 ONHOC OC OO C O CH2 OO OP OOOP OOOCH2 C CH
N H K
B B B A A B B N
O O O OH CH3 O O O
HC CH
hydroxyl
HC CH

O OH
A
2OOP PO
A phosphoryl
OH

Acetyl-coenzyme A

FIGURE 1-15 Several common functional groups in a single C is black, P is orange, O is red, and H is white. The yellow atom at the left
biomolecule. Acetyl-coenzyme A (often abbreviated as acetyl-CoA) is a is the sulfur of the critical thioester bond between the acetyl moiety and
carrier of acetyl groups in some enzymatic reactions. Its functional groups coenzyme A. [Acetyl-CoA structure data from PDB ID 1DM3, Y. Modis and R. K. Wierenga, J. Mol.
are screened in the structural formula. In the space-filling model, N is blue, Biol. 297:1171, 2000.]

Proteins, long polymers of amino acids, constitute roles in supramolecular complexes. The genome is the
the largest mass fraction (besides water) of a cell. Some entire sequence of a cell’s DNA (or in the case of RNA
proteins have catalytic activity and function as enzymes; viruses, its RNA), and genomics is the characteriza-
others serve as structural elements, signal receptors, or tion of the structure, function, evolution, and mapping
transporters that carry specific substances into or out of genomes.
of cells. Proteins are perhaps the most versatile of all The polysaccharides, polymers of simple sugars
biomolecules; a catalog of their many functions would such as glucose, have three major functions: as energy-
be very long. The sum of all the proteins functioning rich fuel stores, as rigid structural components of cell
in a given cell is the cell’s proteome , and proteo- walls (in plants and bacteria), and as extracellular
mics is the systematic characterization of this protein recognition elements that bind to proteins on other cells.
complement under a specific set of conditions. The Shorter polymers of sugars (oligosaccharides) attached
nucleic acids, DNA and RNA, are polymers of nucle- to proteins or lipids at the cell surface serve as specific
otides. They store and transmit genetic information, cellular signals. A cell’s glycome is its entire comple-
and some RNA molecules have structural and catalytic ment of carbohydrate-containing molecules. The lipids,
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

BOX 1-1

Molecular Weight, Molecular Mass, and Their Correct Units

There are two common (and equivalent) ways to describe Consider, for example, a molecule with a mass 1,000 times
molecular mass; both are used in this text. The first is molecular that of water. We can say of this molecule either Mr = 18,000 or
weight, or relative molecular mass, denoted Mr. The molecular m = 18,000 daltons . We can also describe it as an “18 kDa mole-
weight of a substance is defined as the ratio of the mass of a cule.” However, the expression Mr = 18,000 daltons is incorrect.
molecule of that substance to one-twelfth the mass of an atom Another convenient unit for describing the mass of a sin-
of carbon-12 (12 C). Since Mr is a ratio, it is dimensionless — it gle atom or molecule is the atomic mass unit (formerly amu,
has no associated units. The second is molecular mass, denoted now commonly denoted u). One atomic mass unit (1 u) is
m. This is simply the mass of one molecule, or the molar mass defined as one-twelfth the mass of an atom of carbon-12. Since
divided by Avogadro’s number. The molecular mass, m, is the experimentally measured mass of an atom of carbon-12 is
expressed in daltons (abbreviated Da). One dalton is equivalent 1.9926 × 10 − 23 g, 1u = 1.6606 × 10− 24 g . The atomic mass unit
to one-twelfth the mass of an atom of carbon-12; a kilodalton is convenient for describing the mass of a peak observed by
(kDa) is 1,000 daltons; a megadalton (MDa) is 1 million daltons. mass spectrometry (see Chapter 3, p. 93).

(a) Some of the amino acids of proteins

COO2 COO2 COO2 COO2

A1 A
1 A
1 A
1
H3NOC OH H3NOC OH H3NOC OH H3NOC OH (c) Some components of lipids
A A A A
CH3 CH2OH CH2 CH2 COO2 CH2OH
A A A A
Alanine Serine NH
COO2 C CH2 CHOH
Aspartate CH A A
HC 1 CH2 CH2OH
NH A
Histidine Glycerol
CH2
A
(b) Some components of nucleic acids CH2
A CH3
A
CH2 1
O NH2 O A CH3 O N O CH2CH2OH
A
CH2 CH3
C C N C N O2 A
HN CH N C HN C A Choline
CH CH 2O
O P O OH CH2
A
C CH HC C C C B
O N N N H2N N N O CH2
H H H A
Phosphate CH2
Uracil Adenine Guanine A (d) The parent sugar
Nitrogenous bases CH2
A
CH2
HOCH2 O A CH2OH
H HOCH2 O CH2
A A A H A
A A A A O
A H H A AA H H
H H A CH2 A H A
H A A OH
H A A OH A
A A A OH H A
A A CH2 HO A A OH
OH OH OH H A A A
a-D-Ribose 2-Deoxy-a-D-ribose CH3 H OH
Five-carbon sugars Palmitate a-D-Glucose

FIGURE 1-16 The organic compounds from which most cel- two 5-carbon sugars, and the phosphate ion from which all nucleic acids
lular materials are constructed: the ABCs of biochemistry. Shown are built; (c) 4 components of membrane lipids (including phosphate);
here are (a) 4 of the 20 amino acids from which all proteins are built (the and (d) d -glucose, the simple sugar from which most carbohydrates
side chains are shaded light red); (b) 3 of the 5 nitrogenous bases, the are derived.

TABLE 1-1 Molecular Components of an E. coli Cell Proteins, polynucleotides, and polysaccharides have
large numbers of monomeric subunits and thus high
Percentage of total Approximate number of molecular weights — in the range of 5,000 to more than
weight of cell different molecular species
1 million for proteins, up to several billion for DNA,
Water 70 1 and in the millions for polysaccharides such as starch.
Proteins 15 3,000 Individual lipid molecules are much smaller (M r 750 to
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Nucleic acids 1,500) and are not classified as macromolecules, but they
DNA 1 1–4 can associate noncovalently into very large structures.
RNA 6 >3,000
Cellular membranes are built of enormous noncovalent
aggregates of lipid and protein molecules.
Polysaccharides 3 20
Given their characteristic information-rich subunit
Lipids 2 50a
sequences, proteins and nucleic acids are often referred
Monomeric subunits 2 2,600 to as informational macromolecules. Some oligosac-
and intermediates
charides, as noted above, also serve as informational
Inorganic ions 1 20 molecules.
Source: A. C. Guo et al., Nucleic Acids Res. 41:D625, 2013.
a
If all permutations and combinations of fatty acid substituents are considered,
this number is much larger.
Three-Dimensional Structure Is Described by
Configuration and Conformation
The covalent bonds and functional groups of a bio-
water-insoluble hydrocarbon derivatives, serve as struc- molecule are, of course, central to its function, but so
tural components of membranes, energy-rich fuel stores, also is the arrangement of the molecule’s constituent
pigments, and intracellular signals. The lipid-containing atoms in three-dimensional space — its stereochemis-
molecules in a cell constitute its lipidome. try. Carbon-containing compounds commonly exist as

stereoisomers, molecules with the same chemical These compounds are geometric isomers, or cis-trans
bonds and same chemical formula but different config- isomers; they differ in the arrangement of their substit-
uration, the fixed spatial arrangement of atoms. Interac- uent groups with respect to the nonrotating double bond
tions between biomolecules are typically stereospecific, (Latin cis, “on this side” — groups on the same side of the
requiring specific configurations in the interacting double bond; trans, “across” — groups on opposite sides).
molecules.
Figure 1-17 shows three ways to illustrate the ste-
reochemistry, or configuration, of simple molecules. The
perspective diagram specifies stereochemistry unam- O O
M D
biguously, but bond angles and center-to-center bond C
´
lengths are better represented with ball-and-stick mod- H3N #C ! H
els. In space-filling models, the radius of each “atom” is ≥
HOC OH
proportional to its van der Waals radius, and the contours A
of the model define the space occupied by the molecule H
(the volume of space from which atoms of other mole-
cules are excluded).
(a) (b) (c)
Configuration is conferred by the presence of either
(1) double bonds, around which there is little or no free- FIGURE 1-17 Representations of molecules. Three ways to repre-
dom of rotation, or (2) chiral centers, around which sub- sent the structure of the amino acid alanine (shown here in the ionic form
stituent groups are arranged in a specific orientation. The found at neutral pH). (a) Structural formula in perspective form: a solid wedge
(!) represents a bond in which the atom at the wide end projects out of
identifying characteristic of stereoisomers is that they
the plane of the paper, toward the reader; a dashed wedge (`) represents
cannot be interconverted without the temporary break- a bond extending behind the plane of the paper. (b) Ball-and-stick model,
ing of one or more covalent bonds. Figure 1-18a shows the showing bond angles and relative bond lengths. (c) Space-filling model, in
configurations of maleic acid and its isomer, fumaric acid. which each atom is shown with its correct relative van der Waals radius.

FIGURE 1-18 Configurations of geometric isomers. (a) Isomers

such as maleic acid (maleate at pH 7) and fumaric acid (fumarate) cannot be
interconverted without breaking covalent bonds, which requires the input
of much more energy than the average kinetic energy of molecules at phys-
iological temperatures. (b) In the vertebrate retina, the initial event in light
detection is the absorption of visible light by 11-cis-retinal. The energy of the
absorbed light (about 250 kJ/mol) converts 11-cis-retinal to all-trans-retinal,
triggering electrical changes in the retinal cell that lead to a nerve impulse.
H H HOOC H (Note that the hydrogen atoms are omitted from the ball-and-stick models
G D G D
C PC C PC of the retinals.)
D G D G
HOOC COOH H COOH
Maleic acid (cis) Fumaric acid (trans)
(a)
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

CH3 CH3 CH3 O

CH3 CH3 11 CH3 CH3 11 J
GD 9 light GD 9 C
12 G
10 10 12 H
CH3 CH3 CH3
C
J G
O H
11-cis-Retinal All-trans-Retinal
(b)

Chiral Achiral
Mirror molecule: Mirror molecule:
image of A Rotated image of A Rotated
original molecule original molecule
molecule cannot be molecule can be
superposed superposed
A C on its mirror A C on its mirror
Y image X image
Original B Original B
molecule molecule
X A X A
C C
Y X X X

B C B C
X B X B

(a) Y (b) X

FIGURE 1-19 Molecular asymmetry: chiral and achiral mole- issimilar groups (that is, the same group occurs twice), only one configu-
d
cules. (a) When a carbon atom has four different substituent groups (A, B, X, ration is possible and the molecule is symmetric, or achiral. In this case, the
Y), they can be arranged in two ways that represent nonsuperposable mirror molecule is superposable on its mirror image: the molecule on the left can be
images of each other (enantiomers). This asymmetric carbon atom is called rotated counterclockwise (when looking down the vertical bond from A to C)
a chiral atom or chiral center. (b) When a tetrahedral carbon has only three to create the molecule in the mirror.

Maleic acid (maleate at the neutral pH of cytoplasm) is have similar or identical chemical properties but differ in
the cis isomer, and fumaric acid (fumarate) is the trans certain physical and biological properties. A carbon atom
isomer; each is a well-defined compound that can be sep- with four different substituents is said to be asymmetric,
arated from the other, and each has its own unique chemi- and asymmetric carbons are called chiral centers (Greek
cal properties. A binding site (on an enzyme, for example) chiros, “hand”; some stereoisomers are related structur-
that is complementary to one of these molecules would ally as the right hand is to the left hand). A molecule with
not be complementary to the other, which explains why only one chiral carbon can have two stereoisomers; when
the two compounds have distinct biological roles despite two or more (n) chiral carbons are present, there can be
their similar chemical makeup. The visual pigment in the 2n stereoisomers. Stereoisomers that are mirror images
vertebrate eye, rhodopsin, contains retinal, a vitamin A– of each other are called enantiomers (Fig. 1-19). Pairs
derived lipid (Fig. 1-18b). In the primary event of vision, of stereoisomers that are not mirror images of each other
light converts one isomer of retinal to another, triggering are called diastereomers (Fig. 1-20).
a neuronal signal to the brain (see Fig. 12-19). As the biologist, microbiologist, and chemist Louis
In the second type of stereoisomer, four different Pasteur first observed in 1843 (Box 1-2), enantiomers
substituents bonded to a tetrahedral carbon atom may have nearly identical chemical reactivities but differ
be arranged in two different ways in space — that is, have in a characteristic physical property: optical activ-
two configurations — yielding two stereoisomers that ity. In separate solutions, two enantiomers rotate the
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Enantiomers (mirror images) Enantiomers (mirror images)

CH3 CH3 CH3 CH3

´ ´ ´ ´
X # C !H H# C ! X X #C! H H #C! X
A A A A
Y # C !H H# C ! Y H #C! Y Y #C! H
≥ ≥ ≥ ≥
CH3 CH3 CH3 CH3

FIGURE 1-20 Enantiomers and diastereomers. There are four dif- Two pairs of stereoisomers are mirror images of each other, or enantiomers.
ferent stereoisomers of 2,3-disubstituted butane (n = 2 asymmetric carbons, All other possible pairs are not mirror images, and so are diastereomers.
hence 2n = 4 stereoisomers). Each is shown in a box as a perspective formula [Information from F. Carroll, Perspectives on Structure and Mechanism in Organic Chemistry, p. 63, Brooks/
and a ball-and-stick model, which has been rotated to show all of the groups. Cole Publishing Co., 1998.]

Louis Pasteur and Optical Activity: In Vino, Veritas

Louis Pasteur encountered the phenomenon of In isomeric bodies, the elements and the pro-
optical activity in 1843, during his investigation portions in which they are combined are the
of the crystalline sediment that accumulated in same, only the arrangement of the atoms is dif-
wine casks (a form of tartaric acid called paratar- ferent . . . We know, on the one hand, that the
taric acid — also called racemic acid, from Latin molecular arrangements of the two tartaric
racemus, “bunch of grapes”). He used fine for- acids are asymmetric, and, on the other hand,
ceps to separate two types of crystals identical that these arrangements are absolutely identi-
in shape but mirror images of each other. Both cal, excepting that they exhibit asymmetry in
types proved to have all the chemical properties opposite directions. Are the atoms of the dextro
of tartaric acid, but in solution one type rotated acid grouped in the form of a right-handed spi-
plane-polarized light to the left (levorotatory), ral, or are they placed at the apex of an irregu-
whereas the other rotated it to the right (dextro- lar tetrahedron, or are they disposed according
rotatory). Pasteur later described the experiment Louis Pasteur 1822–1895
to this or that asymmetric arrangement? We do
and its interpretation: [Granger, NYC — All rights reserved.] not know.*

Now we do know. In 1951, x-ray crystallo-

graphic studies confirmed that the levorota-
tory and dextrorotatory forms of tartaric acid
are mirror images of each other at the molecular level and
HOOC1 4COOH HOOC1 4COOH
established the absolute configuration of each (Fig. 1). The
H2 3 E H2 3 E
{ C OC ¨ { C C(¨ H
O same approach has been used to demonstrate that although
H & ( OH HO &
OH H H OH the amino acid alanine has two stereoisomeric forms (desig-
(2R,3R)-Tartaric acid (2S,3S)-Tartaric acid nated D and L), alanine in proteins exists exclusively in one form
(dextrorotatory) (levorotatory) (the L isomer; see Chapter 3).
FIGURE 1 Pasteur separated crystals of two stereoisomers of tar-
taric acid and showed that solutions of the separated forms rotated
plane-polarized light to the same extent but in opposite directions.
These dextrorotatory and levorotatory forms were later shown to be * From Pasteur’s lecture to the Société Chimique de Paris in 1883, quoted
the (R,R) and (S,S) isomers represented here. in R. DuBos, Louis Pasteur: Free Lance of Science, p. 95. New York: Charles
Scribner’s Sons, 1976.

plane of plane-polarized light in opposite directions, “right”); if counterclockwise, the configuration is (S) (Latin sinister,
but an equimolar solution of the two enantiomers (a “left”). In this way, each chiral carbon is designated either (R) or (S),
racemic mixture ) shows no optical rotation. Com- and the inclusion of these designations in the name of the com-
pounds without chiral centers do not rotate the plane of pound provides an unambiguous description of the stereochemis-
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

plane-polarized light. try at each chiral center.

KEY CONVENTION Given the importance of stereochem-

1 1
istry in reactions between biomolecules (see below), biochemists 4 4
must name and represent the structure of each biomolecule so that
its stereochemistry is unambiguous. For compounds with more than
one chiral center, the most useful system of nomenclature is the RS 2 3
3 2
system. In this system, each group attached to a chiral carbon is
assigned a priority. The priorities of some common substituents are
OOCH3 > OOH > ONH2 > OCOOH > Clockwise Counterclockwise
OCHO > OCH2 OH > OCH3 > OH (R) (S)

For naming in the RS system, the chiral atom is viewed with the Another naming system for stereoisomers, the D and l system, is
group of lowest priority (4 in the following diagram) pointing away described in Chapter 3. A molecule with a single chiral center can
from the viewer. If the priority of the other three groups (1 to 3) be named unambiguously by either system, as shown here. The
decreases in clockwise order, the configuration is (R) (Latin rectus, two naming systems are based on different criteria, so no general

17
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
18 The Foundations of Biochemistry

correlation can be made between, say, the l isomer and the (S) iso- large and small — the combination of configuration and
mer seen in this example. conformation — is of the utmost importance in their bio-
logical interactions: reactant with its enzyme, hormone
CHO(2) with its receptor, antigen with its specific antibody, for
CHO *

≡
´ example (Fig. 1-22). The study of biomolecular stereo-
HO # C ! H H(4) ! OH(1)
≥ chemistry, with precise physical methods, is an important
CH2OH &
CH2OH(3) part of modern research on cell structure and biochemi-
L-Glyceraldehyde (S)-Glyceraldehyde cal function.
In living organisms, chiral molecules are usually
present in only one of their chiral forms. For example,
Distinct from configuration is molecular conforma-
the amino acids in proteins occur only as their l isomers;
tion, the spatial arrangement of substituent groups that,
glucose occurs only as its d isomer. (The conventions for
without breaking any bonds, are free to assume differ-
naming stereoisomers of the amino acids are described in
ent positions in space because of the freedom of rotation
Chapter 3; those for sugars, in Chapter 7. The RS system,
about single bonds. In the simple hydrocarbon ethane,
described on p. 17, is the most useful for some biomole-
for example, there is nearly complete freedom of rotation
cules.) In contrast, when a compound with an asymmetric
around the COC bond. Many different, interconvertible
carbon atom is chemically synthesized in the laboratory,
conformations of ethane are possible, depending on the
the reaction usually produces both possible chiral forms:
degree of rotation (Fig. 1-21). Two conformations are of
a mixture of the d and l forms, for example. Living cells
special interest: the staggered, which is more stable than
produce only one chiral form of a biomolecule because
all others and thus predominates, and the eclipsed, which
the enzymes that synthesize that molecule are also chiral.
is the least stable. We cannot isolate either of these con-
Stereospecificity, the ability to distinguish between
formational forms, because they are freely interconvert-
stereoisomers, is a property of enzymes and other pro-
ible. However, when one or more of the hydrogen atoms
teins and a characteristic feature of biochemical interac-
on each carbon is replaced by a functional group that is
tions. If the binding site on a protein is complementary to
either very large or electrically charged, freedom of rota-
one isomer of a chiral compound, it will not be comple-
tion around the COC bond is hindered. This limits the
mentary to the other isomer, for the same reason that a
number of stable conformations of the ethane derivative.
left-handed glove does not fit a right hand. Two striking
examples of the ability of biological systems to distin-
Interactions between Biomolecules Are Stereospecific guish stereoisomers are shown in Figure 1-23.
When biomolecules interact, the “fit” between them The common classes of chemical reactions encoun-
is often stereochemically correct; they are complemen- tered in biochemistry are described in Chapter 13, as an
tary. The three-dimensional structure of biomolecules introduction to the reactions of metabolism.

Fully eclipsed
conformation
Potential energy (kJ/mol)
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

12
8 12.1
4 kJ/mol
0

Fully staggered
conformation
0 60 120 180 240 300 360
Torsion angle (degrees)

FIGURE 1-21 Conformations. Many conformations of ethane are

possible because of freedom of rotation around the COC bond. In the ball-
and-stick model, when the front carbon atom (as viewed by the reader) with FIGURE 1-22 Complementary fit between a macromolecule and
its three attached hydrogens is rotated relative to the rear carbon atom, the a small molecule. A glucose molecule fits into a pocket on the surface of the
potential energy of the molecule rises to a maximum in the fully eclipsed con- enzyme hexokinase and is held in this orientation by several noncovalent inter-
formation (torsion angle 0°, 120°, and so on), then falls to a minimum in the actions between the protein and the sugar. This representation of the hexokinase
fully staggered conformation (torsion angle 60°, 180°, and so on). Because the molecule is produced with software that can calculate the shape of the outer
energy differences are small enough to allow rapid interconversion of the two surface of a macromolecule, defined either by the van der Waals radii of all the
forms (millions of times per second), the eclipsed and staggered forms can- atoms in the molecule or by the “solvent exclusion volume,” the volume that a
not be separately isolated. water molecule cannot penetrate. [Data from PDB ID 3B8A, P. Kuser et al., Proteins 72:731, 2008.]

1NH 1NH
3 3
2OOC
´ H H
! KO 2OOC
´ H H
! KO
H EC H EN H EC H H EC H EN H EC H
CH2 C }C! OCH3 CH2 C C! OCH3
B H B H{
O A 2CH O CH 2
A
C C
E N E N
HC CH HC CH
B A B A
HC CH HC CH
H K H K
C C
H H
L-Aspartyl-L-phenylalanine methyl ester L-Aspartyl-D-phenylalanine methyl ester
(aspartame) (sweet) (bitter)
(a)

F F

FIGURE 1-23 Stereoisomers have different effects in humans.

N N (a) Aspartame, the artificial sweetener sold under the trade name Nutra-
µ$ Sweet, is easily distinguishable by taste receptors from its bitter-tasting ste-

µ
$
O O reoisomer, although the two differ only in the configuration at one of the
two chiral carbon atoms. (b) The antidepressant medication citalopram (trade
C C name Celexa), a selective serotonin reuptake inhibitor, is a racemic mixture of
V V
N N these two stereoisomers, but only (S)-citalopram has the therapeutic effect.
(S)-Citalopram (R)-Citalopram A stereochemically pure preparation of (S)-citalopram (escitalopram oxalate)
(therapeutically active) (therapeutically inactive) is sold under the trade name Lexapro. As you might predict, the effective
(b) dose of Lexapro is one-half the effective dose of Celexa.

SUMMARY 1.2 Chemical Foundations in any factory, require the input of energy. Energy input
is also needed in the motion of a bacterium or an Olym-
Because of its bonding versatility, carbon can produce pic sprinter, in the flashing of a firefly or the electrical
a broad array of carbon–carbon skeletons with a variety discharge of an eel. And the storage and expression of
of functional groups; these groups give biomolecules information require energy, without which structures
their biological and chemical personalities. that are rich in information inevitably become disordered
A nearly universal set of several thousand small mole- and meaningless.
cules is found in living cells; the interconversions of these In the course of evolution, cells have developed
molecules in the central metabolic pathways have been highly efficient mechanisms for coupling the energy
conserved in evolution. obtained from sunlight or chemical fuels to the many
Proteins and nucleic acids are macromolecules — long, energy-requiring processes they must carry out. One
linear polymers of simple monomeric subunits; their goal of biochemistry is to understand, in quantitative and
sequences contain the information that gives each molecule chemical terms, the means by which energy is extracted,
its three-dimensional structure and its biological functions. stored, and channeled into useful work in living cells. We
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

can consider cellular energy conversions — like all other

Molecular configuration can be changed only by breaking energy conversions — in the context of the laws of ther-
and re-forming covalent bonds. For a carbon atom with four modynamics. For a more extensive discussion of cellular
different substituents (a chiral carbon), the substituent thermodynamics, see Chapter 13.
groups can be arranged in two different ways, generating
stereoisomers with distinct properties. Only one stereo-
isomer is biologically active. Molecular conformation is the Living Organisms Exist in a Dynamic Steady State,
position of atoms in space that can be changed by rotation Never at Equilibrium with Their Surroundings
about single bonds, without covalent bonds being broken. The molecules and ions contained within a living organ-
Interactions between biological molecules are often ism differ in kind and in concentration from those in
stereospecific: there is a close fit between complemen- the organism’s surroundings. A paramecium in a pond,
tary structures in the interacting molecules. a shark in the ocean, a bacterium in the soil, an apple
tree in an orchard — all are different in composition from
1.3 Physical Foundations their surroundings and, once they have reached maturity,
maintain a more or less constant composition in the face
Living cells and organisms must perform work to stay of a constantly changing environment.
alive and to reproduce themselves. The synthetic reac- Although the characteristic composition of an
tions that occur within cells, like the synthetic processes organism changes little through time, the population of

molecules within the organism is far from static. Small (a)

• Nutrients in environment
molecules, macromolecules, and supramolecular com- (complex molecules such as
Potential energy
plexes are continuously synthesized and broken down in sugars, fats)
chemical reactions that involve a constant flux of mass • Sunlight
and energy through the system. The hemoglobin mole-
cules carrying oxygen from your lungs to your brain at
this moment were synthesized within the past month; by Energy (b) Chemical transformations
next month they will have been degraded and entirely transductions within cells
accomplish
replaced by new hemoglobin molecules. The glucose you work
ingested with your most recent meal is now circulating in Cellular work:
your bloodstream; before the day is over these particular • chemical synthesis
• mechanical work
glucose molecules will have been converted into some- • osmotic and electrical
thing else — carbon dioxide or fat, perhaps — and will gradients
have been replaced with a fresh supply of glucose, so that • light production
• genetic information transfer
your blood glucose concentration is more or less constant
over the whole day. The amounts of hemoglobin and glu-
cose in the blood remain nearly constant because the rate (c)
Heat
of synthesis or intake of each just balances the rate of its
breakdown, consumption, or conversion into some other
product. The constancy of concentration is the result of
a dynamic steady state, a steady state that is far from Increased randomness
(entropy) in the surroundings
equilibrium. Maintaining this steady state requires the
(d)
constant investment of energy; when a cell can no longer Metabolism produces
obtain energy, it dies and begins to decay toward equi- compounds simpler than the
initial fuel molecules: CO2,
librium with its surroundings. We consider below exactly NH3, H2O, HPO42
what is meant by “steady state” and “equilibrium.”

Organisms Transform Energy and Matter from Decreased randomness

Their Surroundings (entropy) in the system
(e)
For chemical reactions occurring in solution, we can Simple compounds polymerize
define a system as all the constituent reactants and to form information-rich
macromolecules: DNA, RNA,
products, the solvent that contains them, and the imme- proteins
diate atmosphere — in short, everything within a defined
region of space. The system and its surroundings together
FIGURE 1-24 Some energy transformations in living organisms.
constitute the universe. If the system exchanges nei- As metabolic energy is spent to do cellular work, the randomness of the sys-
ther matter nor energy with its surroundings, it is said tem plus surroundings (expressed quantitatively as entropy) increases as the
to be isolated. If the system exchanges energy but not potential energy of complex nutrient molecules decreases. (a) Living organ-
matter with its surroundings, it is a closed system; if it isms extract energy from their surroundings; (b) convert some of it into useful
forms of energy to produce work; (c) return some energy to the surroundings
exchanges both energy and matter with its surroundings,
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

as heat; and (d) release end-product molecules that are less well organized
it is an open system. than the starting fuel, increasing the entropy of the universe. One effect of all
A living organism is an open system; it exchanges these transformations is (e) increased order (decreased randomness) in the
both matter and energy with its surroundings. Organ- system in the form of complex macromolecules.
isms obtain energy from their surroundings in two ways:
(1) they take up chemical fuels (such as glucose) from the
environment and extract energy by oxidizing them (see Nearly all living organisms derive their energy,
Box 1-3, Case 2); or (2) they absorb energy from sunlight. directly or indirectly, from the radiant energy of sunlight.
The first law of thermodynamics describes the prin- In the photoautotrophs, light-driven splitting of water
ciple of the conservation of energy: in any physical or during photosynthesis releases its electrons for the reduc-
chemical change, the total amount of energy in the tion of CO2 and the release of O2 into the atmosphere:
universe remains constant, although the form of the
energy may change. This means that while energy is light
“used” by a system, it is not “used up”; rather, it is con-
verted from one form into another — from potential energy 6CO2 6H2O 888n C6H12O6 6O2
in chemical bonds, say, into kinetic energy of heat and (light-driven reduction of CO2)
motion. Cells are consummate transducers of energy, capa-
ble of interconverting chemical, electromagnetic, mechan- Nonphotosynthetic organisms (chemotrophs) obtain the
ical, and osmotic energy with great efficiency (Fig. 1-24). energy they need by oxidizing the energy-rich products
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
1.3 Physical Foundations 21

of photosynthesis stored in plants, then passing the elec- constant temperature, the free-energy change, ∆G , is
trons thus acquired to atmospheric O2 to form water, determined by the enthalpy change, ∆H, reflecting the
CO2 , and other end products, which are recycled in the kinds and numbers of chemical bonds and noncovalent
environment: interactions broken and formed, and the entropy change,
∆S, describing the change in the system’s randomness:
C6H12O6 6O2 888n 6CO2 6H2O energy
(energy-yielding oxidation of glucose) ∆G = ∆ H − T∆ S
Thus autotrophs and heterotrophs participate in global where, by definition, ∆H is negative for a reaction that
cycles of O2 and CO2 , driven ultimately by sunlight, mak- releases heat, and ∆S is positive for a reaction that
ing these two large groups of organisms interdependent. increases the system’s randomness.
Virtually all energy transductions in cells can be traced A process tends to occur spontaneously only if ∆G
to this flow of electrons from one molecule to another, is negative (if free energy is released in the process).
in a “downhill” flow from higher to lower electrochemical Yet cell function depends largely on molecules, such as
potential; as such, this is formally analogous to the flow proteins and nucleic acids, for which the free energy of
of electrons in a battery-driven electric circuit. All formation is positive: the molecules are less stable and
these reactions involved in electron flow are oxidation- more highly ordered than a mixture of their monomeric
reduction reactions: one reactant is oxidized (loses components. To carry out these thermodynamically unfa-
electrons) as another is reduced (gains electrons). vorable, energy-requiring (endergonic) reactions, cells
couple them to other reactions that liberate free energy
Creating and Maintaining Order Requires (exergonic reactions), so that the overall process is
Work and Energy exergonic: the sum of the free-energy changes is nega-
tive. The exergonic reaction most commonly employed in
As we’ve noted, DNA, RNA, and proteins are informational this way involves adenosine triphosphate (ATP; Fig. 1-25)
macromolecules; the precise sequence of their mono- in which two phosphoanhydride bonds are capable of
meric subunits contains information, just as the letters in supplying the free energy to make a coupled endergonic
this sentence do. In addition to using chemical energy to reaction possible. In Section 13.3 we discuss in more
form the covalent bonds between these subunits, the cell detail this role of ATP.
must invest energy to order the subunits in their correct
sequence. It is extremely improbable that amino acids in a
mixture would spontaneously condense into a single type
of protein, with a unique sequence. This would represent NH2
increased order in a population of molecules; but accord-
N
ing to the second law of thermodynamics, the tendency O2 O2 O2
C N
HC
in nature is toward ever-greater disorder in the universe: 2O P
A A A
C CH
O O O O P O O OP O O O CH2 N
randomness in the universe is constantly increasing. B B B A O A N
To bring about the synthesis of macromolecules from their O O O A
A H H A
A
monomeric units, free energy must be supplied to the sys- H A A H
tem (in this case, the cell). We discuss the quantitative A A
OH OH
energetics of oxidation-reduction reactions in Chapter 13.
P O P O P OAdenosine (Adenosine triphosphate, ATP)
The randomness or disorder of the components of a
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

chemical system is expressed as entropy, S (Box 1-3). O2

Any change in randomness of the system is expressed A
2O P
O O OH 1 P O P OAdenosine
as entropy change, ∆S, which by convention has a pos- B (Adenosine diphosphate, ADP)
itive value when randomness O
increases. J. Willard Gibbs, the Inorganic phosphate (Pi)
scientist who developed the OH O2
theory of energy changes during A A
2O O P O
O OP O OH 1 P OAdenosine
chemical reactions, showed B B (Adenosine monophosphate, AMP)
that the free energy, G, of any O O
closed system can be defined Inorganic pyrophosphate (PPi)
in terms of three quantities: FIGURE 1-25 Adenosine triphosphate (ATP) provides energy.
enthalpy, H, or heat content, Here, each P represents a phosphoryl group. The removal of the terminal
roughly reflecting the number phosphoryl group (shaded light red) of ATP, by breakage of a phosphoanhy-
and kinds of bonds; entropy, S; dride bond to generate adenosine diphosphate (ADP) and inorganic phos-
phate ion (HPO24− ), is highly exergonic, and this reaction is coupled to many
and the absolute temperature,
endergonic reactions in the cell (as in the example in Worked Example 1-2).
T (in Kelvin). The definition of ATP also provides energy for many cellular processes by undergoing cleav-
J. Willard Gibbs, 1839–1903 free energy is G = H − TS. When age that releases the two terminal phosphates as inorganic pyrophosphate
[Science Source.] a chemical reaction occurs at (H2P2O72− ) , often abbreviated PPi .
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
BOX 1-3

Entropy: Things Fall Apart

The term “entropy,” which literally means “a change within,” within the kitchen. Moreover, the increase in entropy of the
was first used in 1851 by Rudolf Clausius, one of the formula- kitchen (the surroundings) is irreversible. We know from every-
tors of the second law of thermodynamics. It refers to the ran- day experience that heat never spontaneously passes back
domness or disorder of the components of a chemical system. from the kitchen into the teakettle to raise the temperature of
Entropy is a central concept in biochemistry; life requires con- the water to 100 °C again.
tinual maintenance of order in the face of nature’s tendency
to increase randomness. A rigorous quantitative definition of Case 2: The Oxidation of Glucose
entropy involves statistical and probability considerations.
Entropy is a state not only of energy but of matter. Aerobic
However, its nature can be illustrated qualitatively by three
(heterotrophic) organisms extract free energy from glucose
simple examples, each demonstrating one aspect of entropy.
obtained from their surroundings by oxidizing the glucose
The key descriptors of entropy are randomness and disorder,
with O2 , also obtained from the surroundings. The end prod-
manifested in different ways.
ucts of this oxidative metabolism, CO2 and H2 O, are returned
to the surroundings. In this process the surroundings undergo
Case 1: The Teakettle and the Randomization an increase in entropy, whereas the organism itself remains in
of Heat a steady state and undergoes no change in its internal order.
We know that steam generated from boiling water can do Although some entropy arises from the dissipation of heat,
useful work. But suppose we turn off the burner under a tea- entropy also arises from another kind of disorder, illustrated by
kettle full of water at 100 °C (the “system”) in the kitchen (the the equation for the oxidation of glucose:
“surroundings”) and allow the teakettle to cool. As it cools, no
C6H12 O 6 + 6O2 
→ 6CO2 + 6H2 O
work is done, but heat passes from the teakettle to the sur-
roundings, raising the temperature of the surroundings (the We can represent this schematically as
kitchen) by an infinitesimally small amount until complete
equilibrium is attained. At this point all parts of the teakettle
7 molecules 12 molecules
and the kitchen are at precisely the same temperature. The
free energy that was once concentrated in the teakettle of CO2
hot water at 100 °C, potentially capable of doing work, has dis- O2 (a gas)
(a gas)
appeared. Its equivalent in heat energy is still present in the
teakettle + kitchen (that is, the “universe”) but has become com- Glucose H2O
(a solid) (a liquid)
pletely randomized throughout. This energy is no longer avail-
able to do work because there is no temperature differential

Energy Coupling Links Reactions in Biology the object slides downward and the greater the amount
The central issue in bioenergetics (the study of energy of work that can be accomplished. The larger object
transformations in living systems) is the means by which can lift the smaller one only because, at the outset,
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

energy from fuel metabolism or light capture is cou- the larger object was far from its equilibrium posi-
pled to a cell’s energy-requiring reactions. With regard tion: it had at some earlier point been elevated above
to energy coupling, it is useful to consider a simple the ground, in a process that itself required the input of
mechanical example, as shown in Figure 1-26a. An object energy.
at the top of an inclined plane has a certain amount of How does this apply in chemical reactions? In closed
potential energy as a result of its elevation. It tends to systems, chemical reactions proceed spontaneously until
slide down the plane, losing its potential energy of posi- equilibrium is reached. When a system is at equilibrium,
tion as it approaches the ground. When an appropri- the rate of product formation exactly equals the rate at
ate string-and-pulley device couples the falling object which product is converted to reactant. Thus there is no
to another, smaller object, the spontaneous downward net change in the concentration of reactants and prod-
motion of the larger can lift the smaller, accomplishing ucts. The energy change as the system moves from its
a certain amount of work. The amount of energy avail- initial state to equilibrium, with no changes in tempera-
able to do work is the free-energy change , ∆G ; this ture or pressure, is given by the free-energy change, ∆G.
is always somewhat less than the theoretical amount The magnitude of ∆G depends on the particular chemical
of energy released, because some energy is dissipated reaction and on how far from equilibrium the system
as the heat of friction. The greater the elevation of the is initially. Each compound involved in a chemical reac-
larger object, the greater the energy released (∆G ) as tion contains a certain amount of potential energy, related

22
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
The atoms contained in 1 molecule of glucose plus 6 mole-
cules of oxygen, a total of 7 molecules, are more randomly dis- n o

t
f a
persed by the oxidation reaction and are now present in a total t s
h

h
of 12 molecules (6CO2 + 6H2 O). l e s

e a d
I
r t r
t
Whenever a chemical reaction results in an increase in the

W
l a
number of molecules — or when a solid substance is converted f s i

f
e t o f i n
e c
i
into liquid or gaseous products, which allow more freedom of e m ad
o
s

i
m a

i e

k
molecular movement than solids — molecular disorder, and
d
b n

r
n
a gh o

i
thus entropy, increases. l

o
T

n
t

t
n
n a
t l

n
o
e
s e l a

o
h

y
f
t
Case 3: Information and Entropy
h

s
s
i

e
oi e i
r
l

e
h

if
a
The following short passage from Shakespeare’s Julius Caesar, m h
w h e

d
v n

s
d
e t
e
Act IV, Scene 3, is spoken by Brutus, when he realizes that he O u r u f
t

o
e

e
must face Mark Antony’s army. It is an information-rich non-
random arrangement of 125 letters of the English alphabet:
There is a tide in the affairs of men, shown in the following box, they would have no meaning
Which, taken at the flood, leads on to fortune; whatsoever.
Omitted, all the voyage of their life In this form, the 125 letters contain little or no information,
Is bound in shallows and in miseries. but they are very rich in entropy. Such considerations have led
to the conclusion that information is a form of energy; infor-
In addition to what this passage says overtly, it has many
mation has been called “negative entropy.” In fact, the branch
hidden meanings. It not only reflects a complex sequence of
of mathematics called information theory, which is basic to
events in the play, but also echoes the play’s ideas on conflict,
the programming logic of computers, is closely related to ther-
ambition, and the demands of leadership. Permeated with
modynamic theory. Living organisms are highly ordered, non-
Shakespeare’s understanding of human nature, it is very rich
random structures, immensely rich in information and thus
in information.
entropy-poor.
However, if the 125 letters making up this quotation were
allowed to fall into a completely random, chaotic pattern, as

to the kind and number of its bonds. In reactions that reaction in which a moles of A react with b moles of B to
occur spontaneously, the products have less free energy give c moles of C and d moles of D,
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

than the reactants and thus the reaction releases free

aA + bB → cC + dD
energy, which is then available to do work. Such reactions
are exergonic; the decline in free energy from reactants the equilibrium constant, K eq , is given by
to products is expressed as a negative value. Endergonic
c d
reactions require an input of energy, and their ∆G values [C] eq [D] eq
K eq = a
are positive. This coupling of an exergonic reaction to an [A] eq [B] beq
endergonic reaction is illustrated in Figure 1-26b. As in
where [A]eq is the concentration of A, [B]eq the concen-
mechanical processes, only part of the energy released in
tration of B, and so on, when the system has reached
exergonic chemical reactions can be used to accomplish
equilibrium. K eq is dimensionless (that is, has no units
work. In living systems, some energy is dissipated as heat
of measurement), but, as we explain on page 54 , we
or is lost to increasing entropy.
will include molar units in our calculations to reinforce
the point that molar concentrations (represented by
K eq and ∆G ° Are Measures of a Reaction’s Tendency the square brackets) must be used in the calculation of
to Proceed Spontaneously equilibrium constants. A large value of K eq means the
The tendency of a chemical reaction to go to completion reaction tends to proceed until the reactants are almost
can be expressed as an equilibrium constant. For the completely converted into the products.

23
Nelson, David L., and Michael M. Cox. Principles of Biochemistry, W. H. Freeman & Company, 2021. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/csuau/detail.action?docID=6643897.
Created from csuau on 2024-02-18 09:08:43.
24 The Foundations of Biochemistry

(a) Mechanical example Q = [ADP][Pi ] / [ATP] = (0.5 mM )(5 mM ) / 5 mM

= 0.5 mM = 5 × 10−4 M
DG > 0 DG < 0
This value is far from the equilibrium constant for the reaction
Work Loss of
(2 × 105 M), so the reaction is very far from equilibrium in cells.
done potential [ATP] is far higher, and [ADP] is far lower, than is expected at
raising energy of
object position equilibrium. How can a cell hold its [ATP]/[ADP] ratio so far from
equilibrium? It does so by continuously extracting energy (from
nutrients such as glucose) and using it to make ATP from ADP
and Pi.

Endergonic Exergonic
Gibbs showed that ∆G (the actual free-energy change)
for any chemical reaction is a function of the standard
(b) Chemical example
free-energy change, ∆G° — a constant that is character-
Reaction 2:
ATP → ADP 1 Pi istic of each specific reaction — and a term that expresses
Reaction 3:
Glucose 1 ATP → the initial concentrations of reactants and products:
glucose 6-phosphate 1 ADP
[C] ci [D] di
∆G = ∆G° + RT ln (1-1)
Free energy, G

Reaction 1:
Glucose 1 Pi → [A] ai [B] bi
glucose 6-phosphate
DG2 DG3 where [A] i is the initial concentration of A, and so forth;
R is the gas constant; and T is the absolute temperature.
DG1 ∆G is a measure of the distance of a system from its
DG3 = DG1 1 DG2 equilibrium position. When a reaction has reached equi-
librium, no driving force remains and it can do no work:
∆G = 0 . For this special case, [A] i = [A]eq , and so on, for
Reaction coordinate
all reactants and products, and
FIGURE 1-26 Energy coupling in mechanical and chemical pro- c d
cesses. (a) The downward motion of an object releases potential energy [C] ci [D] di [C] eq [D] eq
a b = a d
that can do mechanical work. The potential energy made available by spon- [A] i [B] i [A] eq [B] eq
taneous downward motion, an exergonic process (red), can be coupled to
the endergonic upward movement of another object (blue). (b) In reaction Substituting 0 for ∆G and K eq for [C] ci [D] di /[ A ] ai [B]bi in
1, the formation of glucose 6-phosphate from glucose and inorganic phos- Equation 1-1, we obtain the relationship
phate (Pi ) yields a product of higher energy than the two reactants. For this
endergonic reaction, ∆G is positive. In reaction 2, the exergonic break- ∆G° = − RT ln K eq
down of adenosine triphosphate (ATP) has a large, negative free- energy
change (∆G2 ) . The third reaction is the sum of reactions 1 and 2, and the from which we see that ∆G° is simply a second way
free-energy change, ∆G3 , is the arithmetic sum of ∆G1 and ∆G2. Because (besides K eq) of expressing the driving force on a reac-
∆G3 is negative and relatively large, the overall reaction is exergonic and tion. Because K eq is experimentally measurable, we have
proceeds spontaneously. a way of determining ∆G°, the thermodynamic constant
characteristic of each reaction.
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

The units of ∆G° and ∆G are joules per mole (or calo-
ries per mole). When K eq >> 1, ∆G° is large and negative;
WORKED EXAMPLE 1-1 Are ATP and ADP at Equilibrium
in Cells? when K eq << 1, ∆G° is large and positive. From a table of
experimentally determined values of either K eq or ∆G°,
ATP breakdown yields adenosine diphosphate (ADP) and inorganic we can see at a glance which reactions tend to go to com-
phosphate (Pi ). The equilibrium constant, K eq , for the reaction is pletion and which do not.
2 × 105 M: One caution about the interpretation of ∆G°: ther-
→ ADP + HPO24−
ATP  modynamic constants such as this show where the final
equilibrium for a reaction lies but tell us nothing about
If the measured cellular concentrations are [ATP] = 5 mM, how fast that equilibrium will be achieved. The rates of
[ADP] = 0.5 mM, and [Pi ] = 5 mM, is this reaction at equilibrium in reactions are governed by the parameters of kinetics, a
living cells? topic we consider in detail in Chapter 6.
SOLUTION: The definition of the equilibrium constant for this In living organisms, just as in the mechanical
reaction is example in Figure 1-26a, an exergonic reaction can be
coupled to an endergonic reaction to drive otherwise
K eq = [ADP] [Pi ]/[ATP]
unfavorable reactions. Figure 1-26b, a reaction coordi-
From the measured cellular concentrations given above, we can cal- nate diagram, illustrates this principle for the conver-
culate the mass-action ratio, Q: sion of glucose to glucose 6-phosphate, the first step in

the pathway for oxidation of glucose. The most direct chemical energy in all cells. As we describe in detail
way to produce glucose 6-phosphate would be in Chapter 13, it is not the mere breakdown of ATP that
provides energy to drive endergonic reactions; rather, it is
Reaction 1: Glucose + Pi → glucose 6-phosphate
the transfer of a phosphoryl group from ATP to another
(endergonic;
small molecule (glucose in the case above) that conserves
∆G1 is positive)
some of the chemical potential originally in ATP.
This reaction does not occur spontaneously; ∆G1 is posi-
tive. A second, highly exergonic reaction can occur in all
WORKED EXAMPLE 1-3 Energetic Cost of ATP Synthesis
cells:
If the equilibrium constant, K eq , for the reaction
Reaction 2: ATP → ADP + Pi (exergonic;
∆G2 is negative) ATP 
→ ADP + Pi

These two chemical reactions share a common interme- is 2.22 × 105 M, calculate the standard free-energy change, ∆G°, for
diate, Pi , which is consumed in reaction 1 and produced the synthesis of ATP from ADP and Pi at 25 °C .
in reaction 2. The two reactions can therefore be coupled SOLUTION: First calculate ∆G° for the reaction above:
in the form of a third reaction, which we can write as the
sum of reactions 1 and 2, with the common intermediate, ∆G ° = − RT ln K eq
Pi , omitted from both sides of the equation: = −(8.315 J/mol i K)(298 K)(ln 2.22 × 105 )
= −30.5 kJ/mol
Reaction 3: Glucose + ATP → glucose 6-phosphate
+ ADP This is the standard free-energy change for the breakdown of ATP
to ADP and Pi. The standard free-energy change for the reverse of
Because more energy is released in reaction 2 than is
a reaction has the same absolute value but the opposite sign. The
consumed in reaction 1, the free-energy change for reac-
standard free-energy change for the reverse of the above reaction is
tion 3, ∆G3 , is negative, and the synthesis of glucose
therefore 30.5 kJ/mol. So, to synthesize 1 mol of ATP under standard
6-phosphate can therefore occur by reaction 3.
conditions (25 °C, 1 M concentrations of ATP, ADP, and Pi), at least 30.5
kJ of energy must be supplied. The actual free-energy change in
WORKED EXAMPLE 1-2 Standard Free-Energy Changes cells — approximately 50 kJ/mol — is greater than this because the
Are Additive concentrations of ATP, ADP, and Pi in cells are not the standard 1 M
Given that the standard free-energy change for the reaction (see Worked Example 13-2).
glucose + Pi →
 glucose 6-phosphate is 13.8 kJ/mol, and the stan-
dard free-energy change for the reaction ATP →  ADP + Pi is
−30.5 kJ/mol, what is the free-energy change for the reaction Enzymes Promote Sequences of Chemical Reactions
glucose + ATP →
 glucose 6-phosphate + ADP? All biological macromolecules are much less thermo-
SOLUTION: We can write the equation for this reaction as the sum
dynamically stable than their monomeric subunits, yet
of two other reactions: they are kinetically stable: their uncatalyzed break-
down occurs so slowly (over years rather than seconds)
(1) Glucose + Pi →
 glucose 6-phosphate ∆G°1 = 13.8 kJ/mol that, on a time scale that matters for the organism, these
(2) ATP → ADP + Pi ∆G °2 = −30.5 kJ/mol molecules are stable. Virtually every chemical reaction
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Sum: Glucose + ATP →  glucose 6-phosphate + ADP in a cell occurs at a significant rate only because of the
∆G °Sum = −16.7 kJ/mol presence of enzymes — biocatalysts that, like all other
catalysts, greatly enhance the rate of specific chemical
The standard free-energy change for two reactions that sum to a reactions without being consumed in the process.
third is simply the sum of the two individual reactions. A negative The path from reactant(s) to product(s) almost invari-
value for ∆G°( − 16.7 kJ/mol) indicates that the reaction will tend to ably involves an energy barrier, called the activation bar-
occur spontaneously. rier (Fig. 1-27), that must be surmounted for any reaction
to proceed. The breaking of existing bonds and formation
of new ones generally requires, first, a distortion of the
The coupling of exergonic and endergonic reactions existing bonds to create a transition state of higher free
through a shared intermediate is central to the energy energy than either the reactant or the product (see Section
exchanges in living systems. As we shall see, reactions 6.2). The highest point in the reaction coordinate diagram
that break down ATP (such as reaction 2 in Fig. 1-26b) represents the transition state, and the difference in energy
release energy that drives many endergonic processes between the reactant in its ground state and in its transition
in cells. ATP breakdown in cells is exergonic because state is the activation energy, ∆G‡ . An enzyme catalyzes
all living cells maintain a concentration of ATP far a reaction by providing a more comfortable fit for the tran-
above its equilibrium concentration. It is this disequi- sition state: a surface that complements the transition state
librium that allows ATP to serve as the major carrier of in stereochemistry, polarity, and charge. The binding of

reactions drives the synthesis of ATP. As a result, the cel-

lular concentration of ATP is held far above its equilibrium
Activation barrier
(transition state, ‡)
concentration, so that ∆G for ATP breakdown is large and
negative. Similarly, catabolism results in the production of
Free energy, G

the reduced electron carriers NADH (nicotinamide ade-

G ‡uncat
Reactants (A) ‡
nine dinucleotide) and NADPH ( nicotinamide a denine
G cat dinucleotide phosphate hydrogen), both of which can
donate electrons in processes that generate ATP or drive
G reductive steps in biosynthetic pathways. They are often
Products (B) referred to collectively as NAD(P)H.
Other pathways start with small precursor mole-
Reaction coordinate (A B) cules and convert them to progressively larger and more
complex molecules, including proteins and nucleic acids.
FIGURE 1-27 Energy changes during a chemical reaction. An Such synthetic pathways, which invariably require the
activation barrier, representing the transition state, must be overcome in the input of energy, are collectively designated anabolism.
conversion of reactants (A) into products (B), even though the products are
more stable than the reactants, as indicated by a large, negative free-energy
change (∆G ) . The energy required to overcome the activation barrier is the
activation energy (∆G ‡ ). Enzymes catalyze reactions by lowering the activa- Stored Other
tion barrier. They bind the transition-state intermediates tightly, and the bind- nutrients cellular work
ing energy of this interaction effectively reduces the activation energy from
‡
∆Guncat (blue curve) to ∆Gcat‡
(red curve). (Note that activation energy is not Ingested Complex
related to free-energy change, ∆G.) foods biomolecules

Solar Mechanical
photons work
enzyme to the transition state is exergonic, and the energy
released by this binding reduces the activation energy for Osmotic
the reaction and greatly increases the reaction rate. work
A further contribution to catalysis occurs when two
or more reactants bind to the enzyme’s surface close to
each other and with stereospecific orientations that favor
NAD(P)
their reaction. This increases by orders of magnitude the
probability of productive collisions between reactants. As
a result of these factors and several others, discussed in ADP
Chapter 6, many enzyme-catalyzed reactions proceed at Catabolic Anabolic
rates 106 times faster than the uncatalyzed reactions. reaction reaction
Cellular catalysts are, with some notable exceptions, pathways pathways
(exergonic) (endergonic)
proteins. (Some RNA molecules have enzymatic activity,
ATP
as discussed in Chapters 26 and 27.) Again with a few
exceptions, each enzyme catalyzes a specific reaction,
and each reaction in a cell is catalyzed by a different
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

NAD(P)H
enzyme. Thousands of different enzymes are therefore
required by each cell. The multiplicity of enzymes, their
specificity (the ability to discriminate between reactants),
and their susceptibility to regulation give cells the capac-
ity to lower activation barriers selectively. This selectivity
is crucial for the effective regulation of cellular processes. CO2
By allowing specific reactions to proceed at significant NH3
rates at particular times, enzymes determine how matter H2O
Sim
and energy are channeled into cellular activities. ple prod sors
ucts, precur
The thousands of enzyme-catalyzed chemical reac-
tions in cells are functionally organized into many FIGURE 1-28 The central roles of ATP and NAD(P)H in metabo-
sequences of consecutive reactions, called pathways, in lism. ATP is the shared chemical intermediate linking energy-releasing and
which the product of one reaction becomes the reactant in energy-consuming cellular processes. Its role in the cell is analogous to that
the next. Some pathways degrade organic nutrients into of money in an economy: it is “earned/produced” in exergonic reactions and
“spent/consumed” in endergonic ones. NADH is an electron-carrying cofactor
simple end products in order to extract chemical energy that collects electrons from oxidative reactions. The closely related NADPH
and convert it into a form useful to the cell; together, carries electrons in a wide variety of reduction reactions in biosynthesis. Pres-
these degradative, free-energy-yielding reactions are des- ent in relatively low concentrations, these cofactors essential to anabolic reac-
ignated catabolism. The energy released by catabolic tions must be constantly regenerated by catabolic reactions.

The overall network of enzyme-catalyzed pathways, is daunting, but systems biology, discussed in Chap-
both catabolic and anabolic, constitutes cellular metab- ter 9, has begun to offer important insights into the over-
olism. ATP (as well as other energetically equivalent all regulation of metabolism.
nucleoside triphosphates) is the connecting link between Cells also regulate the synthesis of their own
the catabolic and anabolic components of this network catalysts, the enzymes, in response to increased or
(shown schematically in Fig. 1-28). The pathways diminished need for a metabolic product; this is the sub-
of enzyme-catalyzed reactions that act on the main con- stance of Chapter 28. The regulated expression of genes
stituents of cells — proteins, fats, sugars, and nucleic (the translation from information in DNA to active pro-
acids — are nearly identical in all living organisms. This tein in the cell) and the synthesis of enzymes are other
remarkable unity of life is part of the evidence for a layers of metabolic control in the cell. All layers must be
common evolutionary precursor for all living things. taken into account when the overall control of cellular
metabolism is described.

Metabolism Is Regulated to Achieve Balance

SUMMARY 1.3 Physical Foundations
and Economy
Not only do living cells simultaneously synthesize thou- Living cells extract and channel energy to main-
sands of different kinds of carbohydrate, fat, protein, and tain themselves in a dynamic steady state distant from
nucleic acid molecules and their simpler subunits, but they equilibrium.
do so in the precise proportions required by the cell under Living cells are open systems, exchanging matter and
any given circumstance. For example, during rapid cell energy with their surroundings. Energy is obtained from
growth the precursors of proteins and nucleic acids must sunlight or chemical fuels when the energy from electron
be made in large quantities, whereas in nongrowing cells flow is converted into the chemical bonds of ATP.
the requirement for these precursors is much reduced. Key The tendency for a chemical reaction to proceed
enzymes in each metabolic pathway are regulated so that toward equilibrium can be expressed as the free-energy
each type of precursor molecule is produced in a quantity change, ∆G. When ∆G of a reaction is negative, the reac-
appropriate to the current requirements of the cell. tion is exergonic and tends to go toward completion;
Consider the pathway in E. coli that leads to the when ∆G is positive, the reaction is endergonic and tends
synthesis of the amino acid isoleucine, a constituent of to go in the reverse direction. When two reactions can be
proteins. The pathway has five steps catalyzed by five summed to yield a third reaction, the ∆G for this overall
different enzymes (A through F represent the intermedi- reaction is the sum of the ∆G values for the two separate
ates in the pathway): reactions.
The reactions converting ATP to Pi and ADP are highly
exergonic (large negative ∆G). Many endergonic cellular
enzyme 1
reactions are driven by coupling them, through a com-
A B C D E F mon intermediate, to these highly exergonic reactions.
Threonine Isoleucine
The standard free-energy change for a reaction, ∆G°,
is a physical constant that is related to the equilibrium
If a cell begins to produce more isoleucine than it needs constant by the equation ∆G° = − RT ln K eq.
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

for protein synthesis, the unused isoleucine accumulates,

and the increased concentration inhibits the catalytic Most cellular reactions proceed at useful rates only
activity of the first enzyme in the pathway, immediately because enzymes are present to catalyze them. Enzymes
slowing the production of isoleucine. Such feedback act in part by stabilizing the transition state, reducing the
inhibition keeps the production and utilization of each activation energy, ∆G‡, and increasing the reaction rate
metabolic intermediate in balance. (Throughout the book, by many orders of magnitude. The catalytic activity of
we use ⊗ to indicate inhibition of an enzymatic reaction.) enzymes in cells is regulated.
Although the concept of discrete pathways is an Metabolism is the sum of many interconnected reac-
important tool for organizing our understanding of tion sequences that interconvert cellular metabolites.
metabolism, it is an oversimplification. There are thou- Each sequence is regulated to provide what the cell
sands of metabolic intermediates in a cell, many of which needs at a given time and to expend energy only when
are part of more than one pathway. Metabolism necessary.
would be better represented as a web of interconnected
and interdependent pathways. A change in the concen-
tration of any one metabolite would start a ripple effect,
1.4 Genetic Foundations
influencing the flow of materials through other pathways. Perhaps the most remarkable property of living cells
The task of understanding these complex interactions and organisms is their ability to reproduce themselves
among intermediates and pathways in quantitative terms for countless generations with nearly perfect fidelity.

sperm or egg, carrying the accumulated hereditary infor-

mation of billions of years of evolution, transmits this
inheritance in the form of DNA molecules, in which the
linear sequence of covalently linked nucleotide subunits
encodes the genetic message.
Usually when we describe the properties of a chem-
ical species, we describe the average behavior of a very
large number of identical molecules. While it is difficult to
predict the behavior of any single molecule in a collection
of, say, a picomole (about 6 × 1011 molecules ) of a com-
pound, the average behavior of the molecules is predict-
able because so many molecules enter into the average.
Cellular DNA is a remarkable exception. The DNA
that is the entire genetic material of an E. coli cell is a
single molecule containing 4.64 million nucleotide pairs.
(a) (b) That single molecule must be replicated perfectly in every
FIGURE 1-29 Two ancient scripts. (a) The Prism of Sennacherib, detail if an E. coli cell is to give rise to identical progeny by
inscribed in about 700 BCE, describes in characters of the Assyrian language cell division; there is no room for averaging in this process!
some historical events during the reign of King Sennacherib. The Prism con- The same is true for all cells. A human sperm brings to the
tains about 20,000 characters, weighs about 50 kg, and has survived almost egg that it fertilizes just one molecule of DNA in each of its
intact for about 2,700 years. (b) The single DNA molecule of the bacterium
E. coli, leaking out of a disrupted cell, is hundreds of times longer than the cell
23 different chromosomes, to combine with just one DNA
itself and contains all the encoded information necessary to specify the cell’s molecule in each corresponding chromosome in the egg.
structure and functions. The bacterial DNA contains about 4.6 million charac- The result of this union is highly predictable: an embryo
ters (nucleotides), weighs less than 10 −10 g, and has undergone only relatively with all of its ~20,000 genes, constructed of 3 billion nucle-
minor changes during the past several million years. (The yellow spots and otide pairs, intact. An amazing chemical feat!
dark specks in this colorized electron micrograph are artifacts of the prepara-
tion.) [(a) Erich Lessing/Art Resource, New York. (b) Dr. Gopal Murti/Science Source.]
WORKED EXAMPLE 1-4 Fidelity of DNA Replication
Calculate the number of times the DNA of a modern E. coli cell has
This continuity of inherited traits implies constancy, been copied accurately since its earliest bacterial precursor cell
over millions of years, in the structure of the molecules arose about 3.5 billion years ago. Assume for simplicity that over
that contain the genetic information. Very few histori- this time period, E. coli has undergone, on average, one cell division
cal records of civilization, even those etched in copper every 12 hours (this is an overestimate for modern bacteria, but
or carved in stone (Fig. 1-29), have survived for a thou- probably an underestimate for ancient bacteria).
sand years. But there is good evidence that the genetic
instructions in living organisms have remained nearly SOLUTION:
unchanged over very much longer periods; many bacteria (1generation/12 h)(24 h/ day)(365 days/yr)(3.5 × 109 yr)
have nearly the same size, shape, and internal structure = 2.6 × 1012 generations
as bacteria that lived almost four billion years ago. This
continuity of structure and composition is the result of
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

continuity in the structure of the genetic material. A single page of this book contains about 5,000 charac-
Among the seminal discoveries in biology in the ters, so the entire book contains about 5 million characters.
twentieth century were the chemical nature and the The chromosome of E. coli also contains about 5 million
three-dimensional structure of the genetic material, characters (nucleotide pairs). Imagine making a handwrit-
deoxyribonucleic acid , DNA . The sequence ten copy of this book and passing on the copy to a class-
of the monomeric subunits, the nucleotides (strictly, mate, who copies it by hand and passes this second copy to
deoxyribonucleotides, as discussed below), in this linear a third classmate, who makes a third copy, and so on. How
polymer encodes the instructions for forming all other closely would each successive copy of the book resemble
cellular components and provides a template for the pro- the original? Now, imagine the textbook that would result
duction of identical DNA molecules to be distributed to from hand-copying this one a few trillion times!
progeny when a cell divides.
The Structure of DNA Allows Its Replication
Genetic Continuity Is Vested in Single DNA Molecules and Repair with Near-Perfect Fidelity
DNA is a long, thin, organic polymer, the rare molecule The capacity of living cells to preserve their genetic
that is constructed on the atomic scale in one dimension material and to duplicate it for the next generation
(width) and the human scale in another (length: a mol- results from the structural complementarity between the
ecule of DNA can be many centimeters long). A human two strands of the DNA molecule (Fig. 1-30). The basic

1.4 Genetic Foundations 29

The Linear Sequence in DNA Encodes Proteins

A
T with Three-Dimensional Structures
G C
The information in DNA is encoded in its linear
(one-dimensional) sequence of deoxyribonucleotide sub-
T A units, but the expression of this information results in
Strand 1
A a three-dimensional cell. This change from one to three
T
G dimensions occurs in two phases. A linear sequence of
deoxyribonucleotides in DNA codes (through an inter-
Strand 2 mediary, RNA) for the production of a protein with a
T A
A corresponding linear sequence of amino acids (Fig. 1-31).
T
The protein folds into a particular three-dimensional
T A
G
C
shape, determined by its amino acid sequence and stabi-
C
A T A T lized primarily by noncovalent interactions. Although the
final shape of the folded protein is dictated by its amino
acid sequence, the folding of many proteins is aided by
C G C G
A A
“molecular chaperones” (see Fig. 4-28). The precise
T T three-dimensional structure, or native conformation,
G G
of the protein is crucial to its function.
Once in its native conformation, a protein may asso-
T A T A
ciate noncovalently with other macromolecules (other
A
T
A
T proteins, nucleic acids, or lipids) to form supramolecular
G C G C

Hexokinase gene
T A T A
DNA
A T A T

Old New New Old transcription of DNA

strand 1 strand 2 strand 1 strand 2 into complementary RNA

FIGURE 1-30 Complementarity between the two strands of

DNA. DNA is a linear polymer of covalently joined deoxyribonucleotides of Messenger RNA
four types: deoxyadenylate (A), deoxyguanylate (G), deoxycytidylate (C), and
deoxythymidylate (T). Each nucleotide, with its unique three-dimensional translation of RNA on
structure, can associate very specifically but noncovalently with one other ribosome to polypeptide chain
nucleotide in the complementary chain: A always associates with T, and G
with C. Thus, in the double-stranded DNA molecule, the entire sequence of
nucleotides in one strand is complementary to the sequence in the other. The Unfolded
two strands, held together by hydrogen bonds (represented here by verti- hexokinase
cal light blue lines) between each pair of complementary nucleotides, twist
about each other to form the DNA double helix. In DNA replication, the two folding of polypeptide chain
strands (blue) separate and two new strands (pink) are synthesized, each with into native structure
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

a sequence complementary to one of the original strands. The result is two of hexokinase
double-helical molecules, each identical to the original DNA.

unit of DNA is a linear polymer of four different mono- ATP + glucose

meric subunits, deoxyribonucleotides, arranged in a ADP + glucose
Catalytically
precise linear sequence. It is this linear sequence that 6-phosphate
active hexokinase
encodes the genetic information. Two of these polymeric
strands are twisted about each other to form the DNA
double helix, in which each deoxyribonucleotide in one
strand pairs specifically with a complementary deoxyri-
bonucleotide in the opposite strand. Before a cell FIGURE 1-31 DNA to RNA to protein to enzyme (hexokinase).
divides, the two DNA strands separate locally and each The linear sequence of deoxyribonucleotides in the DNA (the gene) that
serves as a template for the synthesis of a new, comple- encodes the protein hexokinase is first transcribed into a ribonucleic acid
mentary strand, generating two identical double-helical (RNA) molecule with the complementary ribonucleotide sequence. The RNA
sequence (messenger RNA) is then translated into the linear protein chain of
molecules, one for each daughter cell. If either strand is
hexokinase, which folds into its native three-dimensional shape, most likely
damaged at any time, continuity of information is assured aided by molecular chaperones. Once in its native form, hexokinase acquires
by the information present in the other strand, which can its catalytic activity: it can catalyze the phosphorylation of glucose, using ATP
act as a template for repair of the damage. as the phosphoryl group donor.

complexes such as chromosomes, ribosomes, and mem- Incorrectly repaired damage to one of the DNA strands
branes. The individual molecules of these complexes has the same effect. Mutations in the DNA handed down
have specific, high-affinity binding sites for each other, to offspring — that is, mutations carried in the reproduc-
and within the cell they spontaneously self-assemble into tive cells — may be harmful or even lethal to the new
functional complexes. organism or cell; they may, for example, cause the syn-
Although the amino acid sequences of proteins carry thesis of a defective enzyme that is not able to catalyze
all necessary information for achieving the proteins’ an essential metabolic reaction. Occasionally, however,
native conformation, accurate folding and self-assembly a mutation better equips an organism or cell to survive
also require the right cellular environment — pH, ionic in its environment (Fig. 1-32). The mutant enzyme might
strength, metal ion concentrations, and so forth. Thus, have acquired a slightly different specificity, for exam-
DNA sequence alone is not enough to form and maintain ple, so that it is now able to use some compound that the
a fully functioning cell. cell was previously unable to metabolize. If a population
of cells were to find itself in an environment where that
compound was the only or the most abundant available
SUMMARY 1.4 Genetic Foundations
source of fuel, the mutant cell would have a selective
Genetic information is encoded in the linear sequence advantage over the other, unmutated (wild-type) cells
of four types of deoxyribonucleotides in DNA. in the population. The mutant cell and its progeny would
Despite the enormous size of DNA, the sequence of survive and prosper in the new environment, whereas
its nucleotides is very precise, and the maintenance of wild-type cells would starve and be eliminated. This is
this precise sequence over very long times is the basis for what Charles Darwin meant by natural selection — what
genetic continuity in organisms. is sometimes summarized as “survival of the fittest.”
Occasionally, a second copy of a whole gene is intro-
The double-helical DNA molecule contains an internal duced into the chromosome as a result of defective
template for its own replication and repair. replication of the chromosome. The second copy is super-
The linear sequence of amino acids in a protein, which fluous, and mutations in this gene will not be deleterious;
is encoded in the DNA of the gene for that protein, pro- it becomes a means by which the cell may evolve, by pro-
duces a protein’s unique three-dimensional structure — a ducing a new gene with a new function while retaining
process that is also dependent on environmental the original gene and gene function. Seen in this light,
conditions. the DNA molecules of modern organisms are historical
Individual macromolecules with specific affinity for documents, records of the long journey from the earli-
other macromolecules self-assemble into supramolecular est cells to modern organisms. The historical accounts in
complexes. DNA are not complete, however; in the course of evolu-
tion, many mutations must have been erased or written
over. But DNA molecules are the best source of biolog-
1.5 Evolutionary Foundations ical history we have. The frequency of errors in
DNA replication represents a balance between too many
Nothing in biology makes sense except in the light of
errors, which would yield nonviable daughter cells, and
evolution.
too few errors, which would prevent the genetic varia-
— Theodosius Dobzhansky, in The American Biology
tion that allows survival of mutant cells in new ecological
Teacher, March 1973
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

niches.
Great progress in biochemistry and molecular biology in Several billion years of natural selection have refined
recent decades has amply confirmed the validity of Dob- cellular systems to take maximum advantage of the
zhansky’s striking generalization. The remarkable chemical and physical properties of available raw mate-
similarity of metabolic pathways and gene sequences rials. Chance genetic mutations occurring in individ-
across the three domains of life argues strongly that all uals in a population, combined with natural selection,
modern organisms are derived from a common evolution- have resulted in the evolution of the enormous variety
ary progenitor by a series of small changes (mutations), of species we see today, each adapted to its particular
each of which conferred a selective advantage to some ecological niche.
organism in some ecological niche.

Biomolecules First Arose by Chemical Evolution

Changes in the Hereditary Instructions Allow Evolution In our account thus far, we have passed over the first
Despite the near-perfect fidelity of genetic replica- chapter of the story of evolution: the appearance of
tion, infrequent unrepaired mistakes in the DNA rep- the first living cell. Apart from their occurrence in liv-
lication process lead to changes in the nucleotide ing organisms, organic compounds, including the basic
sequence of DNA, producing a genetic mutation and biomolecules such as amino acids and carbohydrates,
changing the instructions for a cellular component. are found in only trace amounts in the Earth’s crust,

Hexokinase gene FIGURE 1-32 Gene duplication and mutation: one

DNA path to generate new enzymatic activities. In this example,
the single hexokinase gene in a hypothetical organism might
A rare mistake during
occasionally, by accident, be copied twice during DNA repli-
DNA replication duplicates
cation, such that the organism has two full copies of the gene,
the hexokinase gene.
one of which is superfluous. Over many generations, as the DNA
Original gene Duplicate gene with two hexokinase genes is repeatedly duplicated, rare mis-
takes occur, leading to changes in the nucleotide sequence of
the superfluous gene and thus of the protein that it encodes.
A second rare mistake results In a few very rare cases, the altered protein produced from this
in a mutation in the second mutant gene can bind a new substrate — galactose in our hypo-
hexokinase gene. thetical case. The cell containing the mutant gene has acquired
Mutation a new capability (metabolism of galactose), which may allow the
cell to survive in an ecological niche that provides galactose but
not glucose. If no gene duplication precedes mutation, the origi-
nal function of the gene product is lost.
expression
expression of of mutated
original gene duplicate gene

ATP + glucose ATP + galactose

ADP + glucose ADP + galactose

6-phosphate 6-phosphate

Original hexokinase Mutant hexokinase with

(galactose not a substrate) new substrate specificity
for galactose

the sea, and the atmosphere. How did the first living s pectrometry), his original observations were confirmed
organisms acquire their characteristic organic building and greatly broadened. Previously unpublished exper-
blocks? According to one hypothesis, these compounds iments by Miller that included H2S in the gas mixture
were created by the effects of powerful environmen- (mimicking the “smoking” volcanic plumes at the sea bot-
tal forces — ultraviolet irradiation, lightning, or volcanic tom; Fig. 1-34) showed the formation of 23 amino acids
eruptions — on the gases in the prebiotic Earth’s atmo- and 7 organosulfur compounds, as well as a large num-
sphere and on inorganic solutes in superheated thermal ber of other simple compounds that might have served as
vents deep in the ocean. building blocks in prebiotic evolution.
This hypothesis was tested in a classic experiment More-refined laboratory experiments have provided
on the abiotic (nonbiological) origin of organic bio- good evidence that many of the chemical components of
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

molecules carried out in 1953 by biochemist Stanley living cells can form under these conditions. Polymers of
Miller in the laboratory of the physical chemist Harold the nucleic acid RNA (ribonucleic acid) can act as cat-
Urey. Miller subjected gaseous mixtures such as those alysts in biologically significant reactions (see Chapters
presumed to exist on the prebiotic Earth, including 26 and 27), and RNA probably played a crucial role in
NH3 , CH4 , H2O, and H2 , to electrical sparks produced prebiotic evolution, both as catalyst and as information
across a pair of electrodes (to simulate lightning) for repository.
periods of a week or more, then analyzed the contents
of the closed reaction vessel (Fig. 1-33). The gas phase
of the resulting mixture contained CO and CO2 as well as RNA or Related Precursors May Have Been
the starting materials. The water phase contained a vari- the First Genes and Catalysts
ety of organic compounds, including some amino acids, In modern organisms, nucleic acids encode the genetic
hydroxy acids, aldehydes, and hydrogen cyanide (HCN). information that specifies the structure of enzymes, and
This experiment established the possibility of abiotic pro- enzymes catalyze the replication and repair of nucleic
duction of b iomolecules in relatively short times under acids. The mutual dependence of these two classes of
relatively mild conditions. When Miller’s carefully stored biomolecules brings up the perplexing question: Which
samples were rediscovered in 2010 and examined with came first, DNA or protein?
much more sensitive and discriminating techniques The answer may be that they appeared about
(high-p erformance liquid chromatography and mass the same time, and RNA preceded them both.

Electrodes

Spark
gap

NH3
HCN,
CH4
amino
H2
acids
H2O
H2S
80 C

Condenser

FIGURE 1-34 Black smokers. Hydrothermal vents in the sea floor

emit superheated water rich in dissolved minerals. Black “smoke” is formed
when the vented solution meets cold seawater and dissolved sulfides precip-
itate. Diverse life forms, including a variety of archaea and some remarkably
complex multicellular organisms, are found in the immediate vicinity of such
vents, which may have been the sites of early biogenesis. [NOAA/Science Source]

(a)
The concentration of a self-replicating RNA molecule
would increase exponentially, as one molecule formed
several, several formed many, and so on. The fidelity
of self-replication was presumably less than perfect, so
the process would generate variants of the RNA, some
of which might be even better able to self-replicate. In
the competition for nucleotides, the most efficient of the
self-replicating sequences would win, and less efficient
replicators would fade from the population.
The division of function between DNA (genetic infor-
mation storage) and protein (catalysis) was, according to
the “RNA world” hypothesis, a later development. New
variants of self-replicating RNA molecules developed that
had the additional ability to catalyze the condensation of
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

(b) amino acids into peptides. Occasionally, the peptide(s)

thus formed would reinforce the self-replicating ability
FIGURE 1-33 Abiotic production of biomolecules. (a) Spark- of the RNA, and the pair — RNA molecule and helping
discharge apparatus of the type used by Miller and Urey in experiments
demonstrating abiotic formation of organic compounds under primitive
peptide — could undergo further modifications in sequence,
atmospheric conditions. After subjection of the gaseous contents of the sys- generating increasingly efficient self-replicating systems.
tem to electrical sparks, products were collected by condensation. Biomol- The remarkable discovery that in the protein-synthesizing
ecules such as amino acids were among the products. (b) Stanley L. Miller machinery of modern cells (ribosomes), RNA molecules,
(1930–2007) using his spark-discharge apparatus. [(b) Bettmann/Getty Images.] not proteins, catalyze the formation of peptide bonds is
consistent with the RNA world hypothesis.
Some time after the evolution of this primi-
The discovery that RNA molecules can act as catalysts tive protein-synthesizing system, there was a further
in their own formation suggests that RNA or a simi- development: DNA molecules with sequences comple-
lar molecule may have been the first gene and the first mentary to the self-replicating RNA molecules took over
catalyst. According to this scenario (Fig. 1-35), one the function of conserving the “genetic” information, and
of the earliest stages of biological evolution was the RNA molecules evolved to play roles in protein synthesis.
chance formation of an RNA molecule that could cata- (We explain in Chapter 8 why DNA is a more stable mole-
lyze the formation of other RNA molecules of the same cule than RNA and thus a better repository of inheritable
sequence — a self-replicating, self-perpetuating RNA. information.) Proteins proved to be versatile catalysts

0
Prebiotic formation of simple compounds,
including nucleotides, from components of Earth’s primitive
atmosphere or gases in undersea volcanic vents
Diversification of multicellular eukaryotes
500 (plants, fungi, animals)

Production of short RNA molecules

Appearance of red and green algae
with random sequences 1,000
Appearance of endosymbionts
(mitochondria, chloroplasts)

Selective replication of self-duplicating 1,500 Appearance of protists, the first eukaryotes

catalytic RNA segments

Millions of years ago

2,000
Synthesis of specific peptides,
catalyzed by RNA

2,500 Appearance of aerobic bacteria

Development of O2-rich atmosphere
Increasing role of peptides in RNA replication;
coevolution of RNA and protein
3,000
Appearance of photosynthetic O2-producing
cyanobacteria
Primitive translation system develops, Appearance of photosynthetic sulfur bacteria
3,500
with RNA genome and RNA-protein catalysts Appearance of methanogens

4,000 Formation of oceans and continents

Genomic RNA begins to be copied into DNA

4,500 Formation of Earth

DNA genome, translated on RNA-protein complex

(ribosome) with RNA and protein catalysts FIGURE 1-36 Landmarks in the evolution of life on Earth.

FIGURE 1-35 A possible “RNA world” scenario.

ago (see the timeline in Figure 1-36). In 1996, scien-
tists working in Greenland found chemical evidence
and, over time, took over most of that function. Lipidlike
of life (“fossil molecules”) from as far back as 3.85 bil-
compounds in the primordial mixture formed relatively
lion years ago, forms of carbon embedded in rock that
impermeable layers around self-replicating collections
seem to have a distinctly biological origin. Somewhere on
of molecules. The concentration of proteins and nucleic
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Earth during its first billion years the first simple organ-
acids within these lipid enclosures favored the molecular
ism arose, capable of replicating its own structure from
interactions required in self-replication.
a template (RNA?) that was the first genetic material.
The RNA world scenario is intellectually satisfying,
Because the terrestrial atmosphere at the dawn of life
but it leaves unanswered a vexing question: Where did
was nearly devoid of oxygen, and because there were few
the nucleotides needed to make the initial RNA mole-
microorganisms to scavenge organic compounds formed
cules come from? An alternative to this scenario supposes
by natural processes, these compounds were relatively
that simple metabolic pathways evolved first, perhaps at
stable. Given this stability and eons of time, the improb-
the hot vents in the ocean floor. A set of linked chemical
able became inevitable: lipid vesicles containing organic
reactions there might have produced precursors, includ-
compounds and self-replicating RNA gave rise to the first
ing nucleotides, before the advent of lipid membranes or
cells, or protocells, and those protocells with the greatest
RNA. Without more experimental evidence, neither of
capacity for self-replication became more numerous. The
these hypotheses can be disproved.
process of biological evolution had begun.
Biological Evolution Began More Than Three
and a Half Billion Years Ago The First Cell Probably Used Inorganic Fuels
Earth was formed about 4.6 billion years ago, and the The earliest cells arose in a reducing atmosphere (there
first evidence of life dates to more than 3.5 billion years was no oxygen) and probably obtained energy from

inorganic fuels such as ferrous sulfide and ferrous car- Modern bacteria and archaea inhabit almost every
bonate, both abundant on the early Earth. For example, ecological niche in the biosphere, and there are organ-
the reaction isms capable of using virtually every type of organic com-
pound as a source of carbon and energy. Photosynthetic
FeS + H2S → FeS2 + H2
microbes in both fresh and marine waters trap solar
yields enough energy to drive the synthesis of ATP or sim- energy and use it to generate carbohydrates and all other
ilar compounds. The organic compounds these early cells cell constituents, which are in turn used as food by other
required may have arisen by the nonbiological actions forms of life. The process of evolution continues — and,
of lightning or of heat from volcanoes or thermal vents in rapidly reproducing bacterial cells, on a time scale that
in the sea on components of the early atmosphere such allows us to witness it in the laboratory.
as CO, CO2 , N 2 , NH3 , and CH4. An alternative source of
organic compounds has been proposed: extraterrestrial
space. Space missions in 2006 (the NASA Stardust space Eukaryotic Cells Evolved from Simpler Precursors
probe) and 2014 (the European Space Agency lander in Several Stages
Philae) found particles of comet dust containing the sim- Starting about 1.5 billion years ago, the fossil record
ple amino acid glycine and 20 other organic compounds begins to show evidence of larger and more complex
capable of reacting to form biomolecules. organisms, probably the earliest eukaryotic cells (see
Early unicellular organisms gradually acquired the Fig. 1-37). Details of the evolutionary path from non-
ability to derive energy from compounds in their envi- nucleated to nucleated cells cannot be deduced from
ronment and to use that energy to synthesize more of the fossil record alone, but morphological and biochem-
their own precursor molecules, thereby becoming less ical comparisons of modern organisms have suggested a
dependent on outside sources. A very significant evolu- sequence of events consistent with the fossil evidence.
tionary event was the development of pigments capable Three major changes must have occurred. First, as
of capturing the energy of light from the sun, which could cells acquired more DNA, the mechanisms required to
be used to reduce, or “fix,” CO2 to form more complex, fold it compactly into discrete complexes with specific
organic compounds. The original electron donor for these proteins and to divide it equally between daughter cells
photosynthetic processes was probably H2S, yield- at cell division became more elaborate. Specialized pro-
ing elemental sulfur or sulfate (SO24− ) as the byproduct. teins were required to stabilize folded DNA and to pull
Some hydrothermal vents in the sea bottom (black smok- the resulting DNA-protein complexes (chromosomes)
ers; Fig. 1-36) emit significant amounts of H2 , which is apart during cell division. This was the evolution of the
another possible electron donor in the metabolism of the chromosome. Second, as cells became larger, a system of
earliest organisms. Later cells developed the enzymatic intracellular membranes developed, including a double
capacity to use H2O as the electron donor in photosyn- membrane surrounding the DNA. This membrane seg-
thetic reactions, producing O2 as waste. Cyanobacteria regated the nuclear process of RNA synthesis on a DNA
are the modern descendants of these early photosyn- template from the cytoplasmic process of protein synthe-
thetic oxygen-producers. sis on ribosomes. This was the evolution of the nucleus,
Because the atmosphere of Earth in the earliest a defining feature of eukaryotes. Third, early eukaryotic
stages of biological evolution was nearly devoid of oxy- cells, which were incapable of photosynthesis or aero-
gen, the earliest cells were anaerobic. Under these condi- bic metabolism, enveloped aerobic bacteria or photo-
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

tions, chemotrophs could oxidize organic compounds to synthetic bacteria to form endosymbiotic associations
CO2 by passing electrons not to O2 but to acceptors such that eventually became permanent (Fig. 1-37). Some
as SO24− , in this case yielding H2S as the product. With the aerobic bacteria evolved into the mitochondria of mod-
rise of O2 -producing photosynthetic bacteria, the atmo- ern eukaryotes, and some photosynthetic cyanobacteria
sphere became progressively richer in oxygen — a power- became the plastids, such as the chloroplasts of green
ful oxidant and a deadly poison to anaerobes. Responding algae, the likely ancestors of modern plant cells.
to the evolutionary pressure of what evolutionary theorist At some later stage of evolution, unicellular organ-
and biologist Lynn Margulis and science writer Dorion isms found it advantageous to cluster together, thereby
Sagan called the “oxygen holocaust,” some lineages of acquiring greater motility, efficiency, or reproductive
microorganisms gave rise to aerobes that obtained energy success than their free-living single-celled competitors.
by passing electrons from fuel molecules to oxygen. Further evolution of such clustered organisms led to
Because the transfer of electrons from organic molecules permanent associations among individual cells and even-
to O2 releases a great deal of energy, aerobic organisms tually to specialization within the colony — to cellular
had an energetic advantage over their anaerobic counter- differentiation.
parts when both competed in an environment containing The advantages of cellular specialization led to the
oxygen. This advantage translated into the predominance evolution of increasingly complex and highly differen-
of aerobic organisms in O2 -rich environments. tiated organisms, in which some cells carried out the

Symbiotic system can Nonphotosynthetic

now carry out aerobic eukaryote
catabolism. Some
Anaerobic metabolism Bacterium is bacterial genes move
is inefficient because engulfed by ancestral to the nucleus, and the
fuel is not completely eukaryote, and bacterial endosymbionts
oxidized. multiplies within it. become mitochondria.

Nucleus

Photosynthetic
eukaryote
Mitochondrion Chloroplast

Ancestral anaerobic Aerobic eukaryote

eukaryote

Bacterial
genome Cyanobacterial
genome

Aerobic bacterium Photosynthetic

cyanobacterium
Aerobic metabolism Engulfed cyanobacterium In time, some
is efficient because Light energy is becomes an endosymbiont cyanobacterial genes
fuel is oxidized to CO2. used to synthesize and multiplies; new cell move to the nucleus, and
biomolecules can make ATP using endosymbionts become
from CO2. energy from sunlight. chloroplasts.

FIGURE 1-37 Evolution of eukaryotes through endosymbiosis. over time, mitochondria. When photosynthetic cyanobacteria subsequently
The earliest eukaryote, an anaerobe, acquired endosymbiotic purple bacteria, became endosymbionts of some aerobic eukaryotes, these cells became the
which carried with them their capacity for aerobic catabolism and became, photosynthetic precursors of modern green algae and plants.

s ensory functions; others the digestive, photosynthetic, simplest to the most complex organisms. These similari-
or reproductive functions; and so forth. Many modern ties are most easily seen at the level of sequences, either
multicellular organisms contain hundreds of different cell the DNA sequences that encode proteins or the protein
types, each specialized for a function that supports the sequences themselves.
entire organism. Fundamental mechanisms that evolved When two genes share readily detectable sequence
early have been further refined and embellished through similarities (nucleotide sequence in DNA or amino acid
evolution. The same basic structures and mechanisms sequence in the proteins they encode), their sequences
that underlie the beating motion of cilia in Paramecium are said to be homologous and the proteins they encode
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

and of flagella in Chlamydomonas are employed by the are homologs. In the course of evolution, new struc-
highly differentiated vertebrate sperm cell, for example. tures, processes, or regulatory mechanisms are acquired,
reflections of the changing genomes of the evolving
organisms. The genome of a simple eukaryote such
Molecular Anatomy Reveals Evolutionary Relationships as yeast should have genes related to formation of the
Now that genomes can be sequenced relatively quickly nuclear membrane, genes not present in bacteria or
and inexpensively, biochemists have an enormously rich, archaea. The genome of an insect should contain genes
ever-increasing treasury of information on the molecular that encode proteins involved in specifying a characteris-
anatomy of cells that they can use to analyze evolution- tic segmented body plan, genes not present in yeast. The
ary relationships and refine evolutionary theory. Thus far, genomes of all vertebrate animals should share genes
the molecular phylogeny derived from gene sequences that specify the development of a spinal column, and
is consistent with, but in many cases more precise than, those of mammals should have unique genes necessary
the classical phylogeny based on macroscopic structures. for the development of the placenta, a characteris-
Although organisms have continuously diverged tic of mammals — and so on. Comparisons of the whole
at the level of gross anatomy, at the molecular level the genomes of species in each phylum are leading to the
basic unity of life is readily apparent; molecular struc- identification of genes critical to fundamental evolution-
tures and mechanisms are remarkably similar from the ary changes in body plan and development.

Functional Genomics Shows the Allocations of Genes ecological niche, and their progeny come to dominate the
to Specific Cellular Processes population in that niche. This process of mutation and
selection is the basis for the Darwinian evolution that
When the sequence of a genome is fully determined and
led from the first cell to all modern organisms. The large
each gene is assigned a function, molecular geneticists
number of genes shared by all living organisms explains
can group genes according to the processes (DNA syn-
organisms’ fundamental similarities.
thesis, protein synthesis, generation of ATP, and so forth)
in which they function and thus find what fraction of the The components for the first cell may have been pro-
genome is allocated to each of a cell’s activities. The larg- duced near hydrothermal vents at the bottom of the sea
est category of genes in E. coli, A. thaliana, and H. sapi- or by the action of lightning and high temperature on
ens consists of those of (as yet) unknown function, which simple atmospheric molecules such as CO2 and NH3 .
make up more than 40% of the genes in each species. The earliest cells may have been formed by the
The genes encoding the transporters that move ions and enclosure of a self-replicating RNA molecule within a
small molecules across plasma membranes make up a sig- membrane-like lipid layer. The catalytic and genetic roles
nificant proportion of the genes in all three species, more played by the early RNA genome were, over time, taken
in the bacterium and plant than in the mammal (10% of over by proteins and DNA, respectively.
the ~4, 400 genes of E. coli, ~8% of the ~27,000 genes of
Hydrothermal vents may have provided the oxidizable
A. thaliana, and ~4% of the ~20,000 genes of H. sapi-
fuels (iron compounds) for the first organisms.
ens). Genes that encode the proteins and RNA required
for protein synthesis make up 3% to 4% of the E. coli Eukaryotic cells acquired the capacity for photosyn-
genome; but in the more complex cells of A. thaliana, thesis and oxidative phosphorylation from endosymbiotic
more genes are needed for targeting proteins to their bacteria. In multicellular organisms, differentiated cell
final location in the cell than are needed to synthesize types specialize in one or more of the functions essential
those proteins (about 6% and 2% of the genome, respec- to the organism’s survival.
tively). In general, the more complex the organism, the Detailed phylogenetic relationships can be determined
greater the proportion of its genome that encodes genes from gene or protein sequence similarities between
involved in the regulation of cellular processes and the organisms.
smaller the proportion dedicated to basic processes, or
From knowledge of the roles of proteins encoded in
“housekeeping” functions, such as ATP generation and
the genome, scientists can approximate the proportion
protein synthesis. The housekeeping genes typically
of the genome dedicated to a specific process, such as
are expressed under all conditions and are not subject to
membrane transport or protein synthesis.
much regulation.
Knowledge of the complete genomic sequences of
organisms from different branches of the phylogenetic
Genomic Comparisons Have Increasing Importance tree provides insights into evolution and offers great
in Medicine opportunities in medicine.
Large-scale studies in which the entire genomic
sequence has been determined for hundreds or
thousands of people with cancer, type 2 diabetes, schizo- KEY TERMS
phrenia, or other diseases or conditions have allowed the
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

identification of many genes in which mutations correlate All terms are defined in the glossary.
with a medical condition. Typically, sequence differences biochemistry 2 endergonic reaction 21
are found in a number of different genes, each of which metabolite 2 exergonic reaction 21
makes a partial contribution to the predisposition to a nucleus 2 equilibrium 22
given condition or disease. Each of those genes codes for genome 2 standard free-energy
a protein that, in principle, might become the target for eukaryotes 2 change, ∆G° 24
drugs to treat that condition. We may expect that for bacteria 3 activation energy,
some genetic diseases, palliatives will be replaced by archaea 3 ∆G ‡ 25
cures, and that for disease susceptibilities associated cytoskeleton 6 catabolism 26
with particular genetic markers, forewarning and perhaps stereoisomers 15 anabolism 26
increased preventive measures will prevail. Today’s “med- configuration 15 metabolism 27
ical history” may be replaced by a “medical forecast.” chiral center 16 systems biology 27
conformation 18 mutation 30
entropy, S 21 housekeeping
SUMMARY 1.5 Evolutionary Foundations
enthalpy, H 21 genes 36
Occasional inheritable mutations yield organisms that free-energy change,
are better suited for survival and reproduction in an ∆G 21

PROBLEMS (a) How does the surface-to-volume ratio affect the maximum
rate of metabolism?
For all numerical problems, keep in mind that answers should (b) Calculate the surface-to-volume ratio for the spherical
be expressed with the correct number of significant figures. (In bacterium Neisseria gonorrhoeae (diameter 0.5 µ m ),
solving end-of-chapter problems, you may wish to refer to the responsible for the disease gonorrhea. The surface area of a
tables on the inside of the back cover.) Brief solutions are pro- sphere is 4 π r 2.
vided in Appendix B; expanded solutions are published in the (c) How many times greater is the surface-to-volume ratio of
Absolute Ultimate Study Guide to Accompany Principles of Neisseria gonorrhoeae compared to that of a globular amoeba,
Biochemistry. a large eukaryotic cell (diameter 150 µ m )?
1. The Size of Cells and Their Components A typical 5. Fast Axonal Transport Neurons have long thin pro-
eukaryotic cell has a cellular diameter of 50 µ m . cesses called axons, structures specialized for conducting sig-
(a) If you used an electron microscope to magnify this cell nals throughout the organism’s nervous system. The axons that
10,000-fold, how big would the cell appear? originate in a person’s spinal cord and terminate in the muscles
(b) If this cell were a liver cell (hepatocyte) with the same of the toes can be as long as 2 m. Small membrane-enclosed
cellular diameter, how many mitochondria could the cell vesicles carrying materials essential to axonal function move
contain? Assume the cell is spherical; that the cell contains along microtubules of the cytoskeleton, from the cell body
no other cellular components; and that each mitochondrion is to the tips of the axons. If the average velocity of a vesicle is
spherical, with a diameter of 1.5 µ m . (The volume of a sphere is 1 µ m/s, how long does it take a vesicle to move from a cell body
4 π r 3.)
3
in the spinal cord to the axonal tip in the toes?
(c) Glucose is the major energy-yielding nutrient for most
6. Comparing Synthetic versus Natural Vitamin C Some
cells. Assuming a cellular concentration of 1 mM glucose (that
purveyors of health foods claim that vitamins obtained from nat-
is, 1 millimole/L ), calculate how many molecules of glucose
ural sources are more healthful than those obtained by chemi-
would be present in the spherical eukaryotic cell. (Avogadro’s
cal synthesis. For example, some claim that pure l-ascorbic
number, the number of molecules in 1 mol of a nonionized
acid (vitamin C) extracted from rose hips is better than pure
substance, is 6.02 × 1023 .)
l-ascorbic acid manufactured in a chemical plant. Are the vita-
2. Components of E. coli E. coli cells are rod-shaped, mins from the two sources different? Can the body distinguish a
about 2 µ m long, and 0.8 µ m in diameter. E. coli has a protec- vitamin’s source? Explain your answer.
tive envelope 10 nm thick. The volume of a cylinder is π r 2 h,
where h is the height of the cylinder. 7. Fischer Projections of L- and D-Threonine
(a) What percentage of the total volume of the bacterium does (a) Identify the functional groups in the Fischer projection of
l-threonine.
the cell envelope occupy?
(b) E. coli is capable of growing and multiplying rapidly COO
because it contains some 15,000 spherical ribosomes (diameter A
18 nm), which carry out protein synthesis. What percentage of H3NO C O H
A
the cell volume do the ribosomes occupy? HO C OOH
(c) The molecular weight of an E. coli DNA molecule is about A
CH3
3.1 × 109 g/mol . The average molecular weight of a nucleotide
L-Threonine
pair is 660 g/mol, and each nucleotide pair contributes 0.34
nm to the length of DNA. Calculate the length of an E. coli (b) Draw the Fischer projection structure of d-threonine.
DNA molecule. Compare the length of the DNA molecule (c) How many chiral centers does d-threonine have?
with the cell dimensions. Now, consider the photomicrograph
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

showing the single DNA molecule of the bacterium E. coli 8. Drug Activity and Stereochemistry The quanti-
leaking out of a disrupted cell ( Fig. 1-31b ). How does the tative differences in biological activity between the two
DNA molecule fit into the cell? enantiomers of a compound are sometimes quite large. For
example, the d isomer of the drug isoproterenol, used to treat
3. Isolating Ribosomes through Differential Centrifu- mild asthma, is 50 to 80 times more effective as a bronchodila-
gation Assume you have a crude lysate sample that you tor than the l isomer. Identify the chiral center in isoproterenol.
obtained from mechanically homogenizing E. coli cells. You Why do the two enantiomers have such radically different
centrifuged the supernatant from the sample at a medium bioactivity?
speed (20,000 g) for 20 min, collected the supernatant, and
then centrifuged the supernatant at high speed (80,000 g) for OH H H
A A A
1 h. What procedure should you follow to isolate the ribosomes HO C O CH2 O NO C O CH3
from this sample? A A
H CH3
4. The High Rate of Bacterial Metabolism Bacterial cells HO
Isoproterenol
have a much higher rate of metabolism than animal cells. Under
ideal conditions, some bacteria double in size and divide every
20 min, whereas most animal cells under rapid growth condi- 9. Separating Biomolecules In studying a particular bio-
tions require 24 hours. The high rate of bacterial metabolism molecule (a protein, nucleic acid, carbohydrate, or lipid) in
requires a high ratio of surface area to cell volume. the laboratory, the biochemist first needs to separate it from

other biomolecules in the sample — that is, to purify it. Specific (a) Guanosine triphosphate (GTP), an energy-rich nucleotide
purification techniques are described later in this book. How- that serves as a precursor to RNA:
ever, by looking at the monomeric subunits of a biomolecule,
you can determine the characteristics of the molecule that will O
B
allow you to separate it from other molecules. For example, N C
how would you separate (a) amino acids from fatty acids and O O O NH
B B B
(b) nucleotides from glucose? O OP O O OP O O OP O O O CH N
2 O N NH2
A A A A
A A
A
10. Possibility of Silicon-Based Life Carbon and silicon O O O A H H A
are in the same group on the periodic table, and both can form H A A H
up to four single bonds. As such, many science fiction stories A A
OH OH
have been based on the premise of silicon-based
Nelson/Coxlife. Consider
Lehninger Biochemistry,
what you know about carbon’s bonding versatility (refer to a8e (b) Methionine enkephalin, the brain’s own opiate:
beginning inorganic chemistry resource Figure #01_UN09
for silicon’s bonding
properties, if needed). What property of carbon makes it espe-
final
cially suitable for the chemistry of living organisms? What char-
acteristics of silicon make it less well adapted than carbon as
the central organizing element for life? H O H H H O CH2 H H
A B A A A B A A A
11. S t e r e o c h e m i s t r y a n d D r u g A c t i v i t y o f HO O O CH2 O CO C O N O C O CON O C O CONO CO C ONO CO COO
A A A B A A A B A
Ibuprofen Ibuprofen is an over-the-counter drug that NH2 H H O H H H O CH2
blocks the formation of a class of prostaglandins that cause A
CH2
inflammation and pain. A
S
H3C H A
CH3
COO
(c) Phosphatidylcholine, a component of many membranes:
Ibuprofen CH3 O
A A

Ibuprofen is available as a racemic mixture of (R)-ibuprofen CH3 ONO CH2 O CH2 O O OP O O O CH2 H H
Nelson/Cox A B A A A
and (S)-ibuprofen. In living organisms, an isomerase catalyzes CH3 O HC O C (CH2)7 C P C O (CH2)7 O CH3
O O O O
Lehninger Biochemistry, 8e A B
the chiral inversion of the (R)-enantiomer to the (S)-enantio-
Figure #01_UN20 A O
mer. The reverse reaction does not occur at an appreciable A
rate. The accompanying figure represents the two enantiomers
final CH2 O O O C O (CH2)14 O CH3
B
relative to the binding sites a, b, and c in the isomerase enzyme O
that converts the (R)-enantiomer to the (S)-enantiomer. All
three sites recognize the corresponding functional groups of 13. Experimental Determination of the Structure of a
the (R)-enantiomer of ibuprofen. However, sites a and c do not Biomolecule Researchers isolated an unknown substance, X,
recognize the corresponding functional groups of the (S)-enan- from rabbit muscle. They determined its structure from the
tiomer of ibuprofen. following observations and experiments. Qualitative analysis
(a) What substituents represent A, B, and C in the (R)- showed that X was composed entirely of C, H, and O. A weighed
enantiomer and in the (S)-enantiomer? sample of X was completely oxidized, and the H2 O and CO2 pro-
duced were measured; this quantitative analysis revealed that
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Mirror plane
X contained 40.00% C, 6.71% H, and 53.29% O by weight. The
(R)-Enantiomer (S)-Enantiomer
R R molecular mass of X, determined by mass spectrometry, was
90.00 u (atomic mass units; see Box 1-1). Infrared spectroscopy
A B C C B A showed that X contained one double bond. X dissolved read-
X X ily in water to give an acidic solution that demonstrated optical
b b activity when tested in a polarimeter.
a c a c
(a) Determine the empirical and molecular formula of X.
(b) Draw the possible structures of X that fit the molecular
The (S)-enantiomer of ibuprofen is 100 times more efficacious
formula and contain one double bond. Consider only linear or
for pain relief than is the (R)-enantiomer. Drug companies
branched structures and disregard cyclic structures. Note that
sometimes make enantiomerically pure versions of drugs that
oxygen makes very poor bonds to itself.
were previously sold as racemic mixes, such as esomeprazole
(c) What is the structural significance of the observed optical
(Nexium) and escitalopram (Lexapro).
activity? Which structures in (b) are consistent with the
(b) Given that (S)-ibuprofen is more effective, why do drug
observation?
companies not sell enantiomerically pure (S)-ibuprofen?
(d) What is the structural significance of the observation that a
12. Components of Complex Biomolecules Three impor solution of X was acidic? Which structures in (b) are consistent
tant biomolecules are depicted in their ionized forms at physio with the observation?
logical pH. Identify the chemical constituents that are part of (e) What is the structure of X? Is more than one structure
each molecule. consistent with all the data?

14. Naming Stereoisomers with One Chiral Carbon just one of the 500 amino acids is incorrect, the protein may
Using the RS System Propranolol is a chiral compound. lose all of its biological function. How can this small change in
(R)-Propranolol is used as a contraceptive; (S)-propranolol is a protein’s sequence inactivate it?
used to treat hypertension. The structure of one of the pro-
20. Gene Duplication and Evolution Suppose that a rare
pranolol isomers is shown.
DNA replication error results in the duplication of a single gene,
giving the daughter cell two copies of the same gene.
(a) How does this change favor the acquisition of a new
O 0 N function by the daughter cell?
H
OH (b) In the vascular plant Arabidopsis thaliana, 50% to 60%
of the genome consists of duplicate content. How might this
(a) Identify the chiral carbon in propranolol. confer a selective advantage?
(b) Does the structure show the (R) isomer or the (S) isomer? 21. Cryptobiotic Tardigrades and Life Tardigrades, also
(c) Draw the other isomer of propranolol. called water bears or moss piglets, are small animals that can
grow to about 0.5 mm in length. Terrestrial tardigrades (pictured
15. Naming Stereoisomers with Two Chiral Carbons here) typically live in the moist environments of mosses and
Using the RS System The (R,R) isomer of methylphenidate lichens. Some of these species are capable of surviving extreme
(Ritalin) is used to treat attention deficit hyperactivity disorder conditions. Some tardigrades can enter a reversible state called
(ADHD). The (S,S) isomer is an antidepressant. cryptobiosis, in which metabolism completely stops until con-
(a) Identify the two chiral carbons in the methylphenidate ditions become hospitable. In this state, various tardigrade spe-
structure shown here. cies have withstood dehydration, extreme temperatures from
−200 °C to +150° C, pressures from 6,000 atm to a vacuum,
O anoxic conditions, and the radiation of space. Do tardigrades in
HN ≥ cryptobiosis meet the definition of life? Why or why not?
O
H 0

(b) Does the structure show the (R,R) isomer or the (S,S)
isomer?
(c) Draw the other isomer of methylphenidate.
16. State of Bacterial Spores A bacterial spore is metaboli-
cally inert and may remain so for years. Spores contain no mea-
surable ATP, exclude water, and consume no oxygen. However,

Eye of Science/Science Source

when a spore is transferred into an appropriate liquid medium,
it germinates, makes ATP, and begins cell division within an
hour. Is the spore dead, or is it alive? Explain your answer.
17. Activation Energy of a Combustion Reaction Fire-
wood is chemically unstable compared with its oxidation prod-
ucts, CO2 and H2 O.
Copyright © 2021. W. H. Freeman & Company. All rights reserved.

Firewood + O2 → CO2 + H2O 22. Effects of Ionizing Radiation on Bacteria Treatment

of a bacterial culture (E. coli) with ionizing radiation resulted
(a) What can one say about the standard free-energy change
in the survival of only a tiny fraction of the cells. The survivors
for this reaction?
proved to be more resistant to radiation than the starting cells
(b) Why doesn’t firewood stacked beside the fireplace undergo
were. When exposed to even higher levels of radiation, a tiny
spontaneous combustion to its much more stable products?
fraction of these resistant cells survived with even greater resis-
(c) How can the activation energy be supplied to this reaction?
tance to radiation. Repetition of this protocol with progressively
(d) Suppose you have an enzyme (firewoodase) that
higher levels of radiation yielded a strain of E. coli that was
catalyzes the rapid conversion of firewood to CO2 and H2 O at
far more resistant to radiation than the starting strain. What
room temperature. How does the enzyme accomplish that in
changes might be occurring with each successive round of radi-
thermodynamic terms?
ation and selection?
18. Consequence of Nucleotide Substitutions Suppose
23. Data Analysis Problem In 1956, E. P. Kennedy and
deoxycytidine (C) in one strand of DNA is mistakenly replaced
S. B. Weiss published their study of membrane lipid phosphati-
with deoxythymidine (T) during cell division. What is the
dylcholine (lecithin) synthesis in rat liver. Their hypothesis was
consequence for the cell if the deoxynucleotide change is not
that phosphocholine joined with some cellular component to
repaired?
yield lecithin. In an earlier experiment, incubating [ 32 P]-labeled
19. Mutation and Protein Function Suppose that the gene phosphocholine at physiological temperature (37 °C) with bro-
for a protein 500 amino acids in length undergoes a mutation. If ken cells from rat liver yielded labeled lecithin. This became
the mutation causes the synthesis of a mutant protein in which their assay for the enzymes involved in lecithin synthesis.

Reactions with phosphorylated intermediatesfinal commonly

O
32
B require a divalent metal ion. The researchers tested Ca 2+ , Mn 2+ ,
O O P O O O CH2 O CH2 O N(CH3)3 Cell fraction ?
A and Mg 2+ to determine if a divalent metal ion was important in
O this reaction. The graph shows the results.
[32P]Phosphocholine
O
B
H2C O OO C OR1 Mg2+

[32P]Phosphocholine incorporated, nmol/L

10
O
B
HC O OO C OR2
O 8
32
B Mn2+
H2C O O O P O O O CH2 O CH2 O N(CH3)3
A
O 6
[32P]Phosphatidylcholine (lecithin)
4
The researchers centrifuged the broken cell preparation to sep-
arate the membranes from the soluble proteins. They tested
three preparations: whole extract, membranes, and soluble 2
proteins. Table 1 summarizes the results.
Ca2+
0
TABLE 1 Cell Fraction Requirement for Incorporation 0 5 10 15 20 25
of [32 P]-Phosphocholine into Lecithin Metal ion concentration (mM)

Tube [ 32 P]-Phosphocholine
(d) What is the metal ion dependence?
number Preparation incorporated into lecithin
The researchers reasoned that the reaction might require
1 Whole extract 6.3 µ mol
energy. To test the hypothesis, they incubated rat liver mem-
2 Membranes 18.5 µ mol
branes and [ 32 P]-phosphocholine with different nucleotides.
3 Soluble proteins 2.6 µ mol
Because the ATP sold in 1956 was not as highly purified as
(a) Was the enzyme responsible for this reaction a soluble modern commercial preparations, the researchers used two
protein from the cytoplasm or a membrane-bound
Nelson/Cox enzyme?
different ATP sources, lot 116 and lot 122. Table 2 gives the
Why? Lehninger Biochemistry, 8e results.
Figure #01_UN23
Having determined the location of the enzyme, the research- TABLE 2 Requirement of Nucleotides for Lecithin
ers investigated the effect of pH on enzyme final activity. They Synthesis from Phosphocholine
carried out their standard assay in solutions buffered at differ-
32
ent pH values between 6 and 9. The graph shows the results. Tube P incorporated
The enzyme activity is the amount, in nanomoles per liter, of number Nucleotide added into lecithin
[ 32 P]-phosphocholine incorporated into lecithin. 1 5 µ mol ATP from lot 116 5.1 µ mol
2 5 µ mol ATP from lot 122 0.2 µ mol
3 5 µ mol ATP from lot 0.4 µ mol
122 + 0.5 µ mol GDP
[32P]Phosphocholine incorporated, nmol/L

4 5 µ mol ATP from lot 15.0 µ mol

122 + 0.5 µ mol CTP
8 5 5 µ mol ATP from lot 10.0 µ mol
122 + 0.1 µ mol CTP
6 5 µ mol ATP from lot 0.4 µ mol
6
122 + 0.5 µ mol UTP
7 0.5 µ mol CTP with no ATP 8.0 µ mol
4
(e) What is your interpretation of the results in Table 2?
(f) Write the equation for the reaction the researchers studied.
2 Include all required components, including the cell fraction,
metal ion, and nucleotide cofactor.
0
4 5 6 7 8 9 10
pH Reference
Kennedy, E. P. and S. B. Weiss. 1956. The function of cyti-
(b) What is the optimal pH for this enzyme? dine coenzymes in the biosynthesis of phospholipids. J. Biol.
(c) How much more active is the enzyme at pH 8 than at pH 6? Chem. 193–214.

Biochemistry 9th Edition Campbell Solutions Manual 1
100% (63)
Biochemistry 9th Edition Campbell Solutions Manual 1
13 pages
Dermatology Secrets Plus. 5th Edition. ISBN 9780323310291, 978-0323310291
100% (29)
Dermatology Secrets Plus. 5th Edition. ISBN 9780323310291, 978-0323310291
23 pages
5e Ngss Lesson Planning Template 0 1
No ratings yet
5e Ngss Lesson Planning Template 0 1
2 pages
Environmental Microbiology Fundamentals and Applications 2015 PDF
100% (1)
Environmental Microbiology Fundamentals and Applications 2015 PDF
933 pages
Electronic Structure of Atoms: Chemistry for All
From Everand
Electronic Structure of Atoms: Chemistry for All
Amin Elsersawi
5/5 (1)
Biochemistry 9th Edition Campbell Solutions Manual 1
100% (56)
Biochemistry 9th Edition Campbell Solutions Manual 1
36 pages
04.01 Organization of Organisms Guided Notes: Objectives
No ratings yet
04.01 Organization of Organisms Guided Notes: Objectives
2 pages
Sample of Brief Lesson Plan
82% (67)
Sample of Brief Lesson Plan
2 pages
The Foundations of Biochemistry
100% (1)
The Foundations of Biochemistry
19 pages
Lehninger Principles of Biochemistry
No ratings yet
Lehninger Principles of Biochemistry
9 pages
Pages From Lehninger
100% (3)
Pages From Lehninger
3 pages
Biochemistry - Lehninger - 0003
No ratings yet
Biochemistry - Lehninger - 0003
1 page
Unit 1 - Foundations of Biochemistry - Copy
No ratings yet
Unit 1 - Foundations of Biochemistry - Copy
27 pages
Chapter 1 - Introduction - The Cell
No ratings yet
Chapter 1 - Introduction - The Cell
82 pages
Sinh Hóa Học
No ratings yet
Sinh Hóa Học
375 pages
2025-HY-BC-2W-0312-C1
No ratings yet
2025-HY-BC-2W-0312-C1
196 pages
240307-Introduction To Biology-MDC
No ratings yet
240307-Introduction To Biology-MDC
34 pages
Biochemistry: Major References
No ratings yet
Biochemistry: Major References
11 pages
Chapter 1. Foundations of Biochemistry (1)
No ratings yet
Chapter 1. Foundations of Biochemistry (1)
152 pages
Biochemistry (The Chemistry of Life)
No ratings yet
Biochemistry (The Chemistry of Life)
8 pages
Scope and History of Biochemistry PDF (1)
No ratings yet
Scope and History of Biochemistry PDF (1)
16 pages
Chapter 1: Biochemistry and The Organization of Cells
No ratings yet
Chapter 1: Biochemistry and The Organization of Cells
3 pages
Lecture For The Midterm Chem4 2nd Sem 2023-2024 Fin 03jan2024
No ratings yet
Lecture For The Midterm Chem4 2nd Sem 2023-2024 Fin 03jan2024
417 pages
Biochem Intro
No ratings yet
Biochem Intro
6 pages
Cell Reviewer
No ratings yet
Cell Reviewer
6 pages
Introduction To Biochemistry
No ratings yet
Introduction To Biochemistry
11 pages
Biochemistry (Powerpoint Presentation
100% (1)
Biochemistry (Powerpoint Presentation
39 pages
Shs Reviewer Biology
No ratings yet
Shs Reviewer Biology
43 pages
Intro to biochem presentation
No ratings yet
Intro to biochem presentation
47 pages
Chapter 1 - The Foundations of Biochemistry
No ratings yet
Chapter 1 - The Foundations of Biochemistry
35 pages
Biochemistry
No ratings yet
Biochemistry
22 pages
Biochem Lec Notes For Reading
No ratings yet
Biochem Lec Notes For Reading
51 pages
Introduction To Biochemistry USP
No ratings yet
Introduction To Biochemistry USP
22 pages
Chem14a Transcripts For Finals
No ratings yet
Chem14a Transcripts For Finals
12 pages
Lec 1 Intro Biochem
No ratings yet
Lec 1 Intro Biochem
17 pages
Chem413-Fall 2021-2022-Part 1-Introduction To Biochemistry 1 of 2
No ratings yet
Chem413-Fall 2021-2022-Part 1-Introduction To Biochemistry 1 of 2
21 pages
WEEK3 ModuleLec (BIO101)
No ratings yet
WEEK3 ModuleLec (BIO101)
10 pages
Biochemistry Reviewer
No ratings yet
Biochemistry Reviewer
20 pages
Lecture 2 BIO201
No ratings yet
Lecture 2 BIO201
30 pages
2024 BCH211 Chapter 1 Introduction To Biochemistry
No ratings yet
2024 BCH211 Chapter 1 Introduction To Biochemistry
14 pages
CH459 Winter 2024 Review Slides
No ratings yet
CH459 Winter 2024 Review Slides
120 pages
Layssa - Biochem Chapter 12
No ratings yet
Layssa - Biochem Chapter 12
8 pages
Biochem Prelim Compilation
No ratings yet
Biochem Prelim Compilation
22 pages
Lecture 2 BIO201-MALM(1)
No ratings yet
Lecture 2 BIO201-MALM(1)
33 pages
Introduction-to-Biochemistry 2
No ratings yet
Introduction-to-Biochemistry 2
7 pages
Principles and Foundations of Biochemistry_Student Copy
No ratings yet
Principles and Foundations of Biochemistry_Student Copy
34 pages
Introductory Biochemistry 1614727331. Print
No ratings yet
Introductory Biochemistry 1614727331. Print
477 pages
Chapter 1 by TG
No ratings yet
Chapter 1 by TG
61 pages
Handout 1 Lehninger
No ratings yet
Handout 1 Lehninger
9 pages
1 Biochemistry
No ratings yet
1 Biochemistry
22 pages
Get (Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett PDF ebook with Full Chapters Now
100% (7)
Get (Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett PDF ebook with Full Chapters Now
55 pages
(Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett - The latest ebook is available, download it today
100% (1)
(Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett - The latest ebook is available, download it today
50 pages
Astrobiology
No ratings yet
Astrobiology
12 pages
Lecture 1 For Ltho
No ratings yet
Lecture 1 For Ltho
44 pages
Biochemistry - Introduction
No ratings yet
Biochemistry - Introduction
2 pages
1-Foundations overview-26-07-2023
No ratings yet
1-Foundations overview-26-07-2023
13 pages
BIOCHEM
No ratings yet
BIOCHEM
6 pages
Molecular Logic of Life Student Notes
67% (3)
Molecular Logic of Life Student Notes
4 pages
Buy ebook (Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett cheap price
100% (7)
Buy ebook (Original PDF) Biochemistry Canadian Edition by Reginald H. Garrett cheap price
56 pages
Bio 100
No ratings yet
Bio 100
53 pages
Biochemistry and The Organization of Cells-Chap 1
0% (1)
Biochemistry and The Organization of Cells-Chap 1
33 pages
Thoughts on the Origin of Life
From Everand
Thoughts on the Origin of Life
RB Raikow
No ratings yet
The Miracle of the Cell
From Everand
The Miracle of the Cell
Michael Denton
5/5 (1)
Shungite Nanomatrixes: Origin of Life and Drug-Free Healing
From Everand
Shungite Nanomatrixes: Origin of Life and Drug-Free Healing
Eduard Vaganovich Osipov
No ratings yet
Biol1002 Unit Outline Usyd
No ratings yet
Biol1002 Unit Outline Usyd
20 pages
Cell Theory
No ratings yet
Cell Theory
18 pages
GenEd Science PART 1
No ratings yet
GenEd Science PART 1
5 pages
Unit 1 Module 1 Nature of Biology
No ratings yet
Unit 1 Module 1 Nature of Biology
40 pages
All Animals A-Z List - Animal Names - AZ Animals
No ratings yet
All Animals A-Z List - Animal Names - AZ Animals
2 pages
Science MCQ
No ratings yet
Science MCQ
29 pages
Devotional Biology Sample - Chapter 8
100% (3)
Devotional Biology Sample - Chapter 8
22 pages
SMILE L.P Q2 EARTH AND LIFE SCI WK 2
No ratings yet
SMILE L.P Q2 EARTH AND LIFE SCI WK 2
4 pages
Science Standards
No ratings yet
Science Standards
46 pages
The Animal Kingdom: Animals Cleary Dominate
No ratings yet
The Animal Kingdom: Animals Cleary Dominate
10 pages
Marine Life
No ratings yet
Marine Life
106 pages
Animal Cell Summary
No ratings yet
Animal Cell Summary
3 pages
Branches of Genetics
100% (4)
Branches of Genetics
3 pages
In Memoriam: Prof. Dr. Karsten Krohn, A Brilliant, Charming, Helpful and Dedicated Organic Chemist
No ratings yet
In Memoriam: Prof. Dr. Karsten Krohn, A Brilliant, Charming, Helpful and Dedicated Organic Chemist
16 pages
Introduction History and Development of Microbiology
No ratings yet
Introduction History and Development of Microbiology
17 pages
Cell (Biology) - Wikipedia, The Free Encyclopedia
100% (2)
Cell (Biology) - Wikipedia, The Free Encyclopedia
6 pages
Scope of Biotechnology
100% (1)
Scope of Biotechnology
21 pages
3RD Quarter Science 10 Curriculum Map
100% (2)
3RD Quarter Science 10 Curriculum Map
4 pages
BIO111 Principles of Biology Course Outline 2022
No ratings yet
BIO111 Principles of Biology Course Outline 2022
5 pages
Module 2
No ratings yet
Module 2
91 pages
SBI3U - Textbook Pages and Worksheets
No ratings yet
SBI3U - Textbook Pages and Worksheets
12 pages
Biotech Reviewer
No ratings yet
Biotech Reviewer
5 pages
ATG - Origin and Extinction of Species
No ratings yet
ATG - Origin and Extinction of Species
8 pages
Classification of Crops
No ratings yet
Classification of Crops
11 pages
Antibiotic Resistance in The Environment: A Link To The Clinic?
No ratings yet
Antibiotic Resistance in The Environment: A Link To The Clinic?
6 pages
Volume II C2 CaseTakingintheOrganon
0% (1)
Volume II C2 CaseTakingintheOrganon
60 pages