BIOCHEMISTRY REVIEWER (MIDTERMS)

LESSON 4: ENZYME - Catalyze isomerization reactions

• Enzymes are biological catalysts that speed up the rate - Structural change within a single molecule
of the biochemical reaction. - Intramolecular group transfer
• Enzymes are proteins that "catalyze" chemical reaction
• Enzymes speed up the reaction by lowering the
activation energy of the reaction
• Enzymes are sensitive to change in pH and
temperature
• They are highly specific in their action that is each
enzyme can catalyze one kind of substrate.
6. Ligase
Classification of Enzyme - Catalyze ligation reactions
1. Oxidoreductase - Chemically join two substrates at the expense of ATP
- Oxidation – Reduction Reaction hydrolysis
- electron transfer
- commonly called dehydrogenases

• Cofactors nonprotein parts of enzymes necessary for

catalytic function
2. Transferase • Coenzymes Organic molecules. frequently B vitamins,
- Transamination Reaction that act as confactors
- catalyze transfer o functional group • The compound on which the enzyme works, and whose
- many require the presence of coenzyme reaction it speeds up, is called the substrate.
- organic compound other than amino acids required for • The substrate binds to a specific portion of the enzyme
catalysis during the reaction, called the active site.
• Activation is a process that increases the action of an
enzyme
• Inhibition The process by which a compound binds to
an enzyme and lowers its activity

Factors that Influence Enzyme Activity

• Enzyme activity is a measure of how much reaction
rates are increased. In this section, we examine the
3. Hydrolase effects of concentration, temperature, and pH on
- Catalyze hydrolysis reactions enzyme activity.
- Transfer functional groups to water 1. Temperature - Each enzyme has an optimum
temperature at which it works best. A higher
temperature generally results in an increase in enzyme
activity.
2. pH - Each enzyme has an optimal pH that helps
maintain its three-dimensional shape. Changes in pH
may denature enzymes by altering the enzyme's
charge.
3. Concentration - Increasing the concentration of
4. Lyase substrate will increase the enzyme activity and will also
- Catalyze addition or removal of functional group to form increase the rate of reaction
a double bond
- Nonhydrolytic, nonoxidative, elimination reactions Mechanism of Enzyme Action
1. Lock – and – Key Model
• Was proposed by Emil Fischer in 1894
5. Isomerase
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• According to this model, shape of active site of enzyme Here Are Some Ways On How Enzymes Are Used In
is complementary to the shape of substrate molecules. Medicine:
le. the substrate is like a key whose shape is 1. ENZYMATIC ACTIVITY ASSAYS:
complementary to the enzyme which is supposed to be - Enzymatic activity assays are used to measure the
lock and they fit perfectly. activity levels of specific enzymes in a patient's blood
• Enzymes catalyze only those substrates which fit or tissues.
perfectly on the active site of that enzyme. - Changes in enzyme activity can indicate the presence
• Once the product is formed, they no longer fit into the of certain diseases or conditions.
active site and escape into surrounding medium - For example, liver function tests often measure the
activity of liver enzymes such as alanine transaminase
(ALT) and aspartate transaminase (AST) to assess
liver health.
2. ALANINE TRANSAMINASE:
- for example has a normal range of 4 to 36 U/L. (unit per
liter). An increased ALT level is often a sign of liver
disease.
- An increased ALT level may be due to any of the
following:
o Scarring of the liver
o (cirrhosis) Death of liver tissue
2. Induced Fit Model o Swollen and inflamed liver (hepatitis)
• In 1959, Koshland suggested a modification to the o Too much fat in the liver (fatty liver)
'Lock and Key' hypothesis which is known as 'Induced o Liver tumor or cancer
fit' hypothesis. 3. POLYMERASE CHAIN REACTION (PCR) :
• Working from evidence that suggested that some - PCR is a molecular biology technique that uses an
enzymes and their active site are more flexible. To this, enzyme called DNA polymerase to amplify a specific
he proposed that the active site can modify its shape as DNA sequence.
the substrate interact with the enzyme. - It is essential for detecting diseases caused by
• The amino acids which make up the active site are pathogens such as bacteria or viruses
molded into precise shape which enable the enzyme to - In diagnostic PCR, a small amount of DNA from a
perform its catalytic function most efficiently. patient's sample is mixed with DNA primers and
• For instance, a suitable analogy to describe Induced fit nucleotides, and DNA polymerase is added. The
model would be that of a hand changing the shape of mixture undergoes a series of temperature cycles that
the glove as the individual put on the glove. Therefore cause DNA replication, resulting in the exponential
amplification of the target DNA sequence if it is present.
in this case, glove is the active site of enzyme and the
- The presence or absence of the target DNA can be
hand is substrate.
determined through gel electrophoresis, fluorescent
probes, or other detection methods.

What Are Transition-State Analog And Designer Enzymes?

• TRANSITION STATE ANALOG::
o Molecules that mimic the transition state of a
chemical reaction and are used as enzyme
o PYRROLE-2-CARBOXYLATE (inhibitor and
transition-state analog)
o Abzyme: An antibody that has catalytic activity
because it was created using a transition state
analog as an immunogen.
How are Enzymes used in Medicine
• Enzymes are important tools in the field of medicine for How are enzymes regulated?
detecting and diagnosing various diseases. They are • enzymes are often regulated by environmental
commonly used in diagnostic tests to detect the conditions.
presence of specific biomarkers or substances • Feedback Control is an enzyme regulation process in
associated with certain medical conditions. which formation of a product inhibits an earlier reaction
in the sequence.
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• The reaction product of one enzyme may control the o Ha is allosterically inhibited by high levels of
activity of another, especially in a complex system in pyruvate while My is not.
which enzymes work cooperatively. o Ha in serum correlates with the severity of heart
• Feedback control: An enzyme-regulation process attack.
where the product of a series of enzyme-catalyzed • The isozymes of lactate dehydrogenase (LDH). The
reaction inhibits an earlier reaction in the sequence. electrophoresis gel depicts the relative isozyme types
• The inhibition may be or competitive or found in different. tissues.
noncompetitive
• Proenzyme (zymogen): An inactive form of an enzyme LESSON 5: CHEMICAL COMMUNICATIONS:
that must have part if its polypeptide chain hydrolyzed NEUROTRANSMITTERS AND HORMONES
and removed before it becomes active. Neuron or Nerve Cells - Colored scanning electron
• An example is trypsin, a digestive enzyme. It is micrograph (SEM) of neurons (nerve cells) from the cerebral
synthesized and stored as trypsinogen, which cortex (the outer, heavily folded gray matter of the brain).
has no enzyme activity. Neurons exist in varying sizes and shapes throughout the
• Removal of this small fragment changes not only nervous system, but all have a similar basic structure.
the primary structure but also the tertiary
structure, allowing the molecule to achieve its How do Cells Communicate?
active form. • Each cell in the body is an isolated entity enclosed in its
• Allosterism: Enzyme regulation based on an event own membrane. Furthermore, within each cell of higher
occurring at a place other than the active site but that organisms, organelles, such as the nucleus or the
creates a change in the active site. mitochondrion, are enclosed by membranes separating
• An enzyme regulated by this mechanism is them from the rest of the cell. If cells could not
called an allosteric enzyme communicate with one another, the thousands of
• Allosteric enzymes often have multiple reactions in each cell would be uncoordinated. The
polypeptide chains. same is true for organelles within a cell. Such
• Negative Modulation - Inhibition of an allosteric communication allows the activity of a cell in one part
enzyme. of the body to be coordinated with the activity of cells in
• Positive modulation - Stimulation of an allosteric a different part of the body.
enzyme.
• Regulator - A substance that binds to an There are three types of molecules for communication:
allosteric enzyme. 1. Receptors are protein molecules that bind to ligands
and effect some type of change. They may be on the
Enzyme Regulation surface of cells, embedded in the membrane of
• The allosteric effect. Binding of the regulator to a site subcellular organelles, or free in solution.
other than the active site changes the shape of the 2. Chemical messengers, also called ligands, interact with
active site. the receptors.
• Effects of binding activators and inhibitors to allosteric 3. Secondary messengers in many cases carry the
enzymes. The enzyme has an equilibrium between the message from the receptor to the inside of the cell and
T form and the R form. amplify the message.
• Protein modification: The process of affecting enzyme
activity by covalently modifying it.
o The best known examples of protein modification
involve phosphorylation/dephosphorylation.
o Example: Pyruvatekinase (PK) is the active form
of the enzyme; it is inactivated by phosphorylation
to pyruvatekinase phosphate (PKP).
• Isoenzyme (Isozymes): An enzyme that occurs in
multiple forms; each catalyzes the same reaction.
o Example: lactate dehydrogenase (LDH) catalyzes What Is the Difference Between a Neurotransmitter and a
the oxidation of lactate to pyruvate. Hormone?
o The enzyme is a tetramer of H and M chains. • As mentioned earlier, neurotransmitters are
o Ha is present predominately in heart muscle. compounds that communicate between two nerve cells
o M, is present predominantly in the liver and in or between a nerve cell and another cell (such as a
skeletal muscle. muscle cell). A nerve cell (Figure 5-1) consists of a main
o HM, H,M,, and HM also exist. cell body from which projects a long, fiber-like part
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called an axon. Coming off the other side of the main cell. The most universal yet most versatile signaling
body are hair-like structures called dendrites. agent is the cation.
• Typically, neurons do not touch each other. Between - Calcium ions control our heartbeats; our movements
the axon end of one neuron and the cell body or through the action of skeletal muscles; and through the
dendrite end of the next neuron is a space filled with an release of neurotransmitters in our neurons, learning
aqueous fluid, called a synapse. If the chemical signal and memory. They are also involved in signaling the
travels, say, from axon to dendrite, we call the nerve beginning of life at fertilization and its end at death.
ends on the axon the presynaptic site. The Calcium ion signaling controls these functions via two
neurotransmitters are stored at the presynaptic site in mechanisms: (1) increased concentration and (2) du-
vesicles, which are small, membrane-enclosed ration of the signals.
packages. Receptors are located on the postsynaptic - The source of calcium ions may be external (calcium
site of the cell body or the dendrite. influx caused by the electrical signal of nerve
• FIGURE 5-2 The pituitary gland is suspended from the transmission) or internal (calcium released from the
hypothalamus by a stalk of neural tissue. The endoplasmic reticulum stores). Upon receiving the
hormones secreted by the anterior and posterior lobes signal of increased calcium, the vesicles storing
of the pituitary gland and the target tissues they act on acetylcholine travel to the membrane of the presynaptic
are shown. cleft. They fuse with the membrane and empty their
o Hormones are diverse compounds secreted by contents into the synapse, as shown in Figure 5-4.
specific tissues (the endocrine glands), released - Calcium ions can also control signaling by controlling
into the bloodstream, and then adsorbed onto the duration of the signal. The signal in arterial smooth
specific receptor sites, usually relatively far from muscle lasts for 0.1 to 0.5 s. The wave of Ca in the liver
their source. Figure 5-2 shows the target organs of lasts 10 to 60 s. The calcium wave in the human egg
hormones secreted by the pituitary gland. lasts 1 to 35 min after fertilization. Thus, by combining
the concentration, localization, and duration of the
signal, calcium ions can deliver messages to perform a
variety of functions.
- The effects of Ca² are modulated through specific
calcium-binding proteins. In all nonmuscle cells and in
smooth muscles, calmodulin serves as the calcium-
binding protein. Calmodulin-bound calcium acti- vates
an enzyme, protein kinase II, which then
phosphorylates an ap- propriate protein substrate. In
this way, the signal is translated into metabolic activity.

A. Cholinergic Receptors
- We will look at the cholinergic receptor that exists on
the motor end plates of skeletal muscles. The nerve
cells that transmit messages contain stored
acetylcholine in the vesicles in their axons.

B. Storage of Messengers
- Events begin when a message is transmitted from one
neuron to the next by neurotransmitters. The message FIGURE 5-4 Calcium signaling releases acetylcholine from
is initiated by calcium ions. The messenger molecules the vesicles of a neuron. (a) In the resting state,
travel across the synapse and are adsorbed onto acetylcholine is sequestered inside vesicles in the
specific receptor sites. presynaptic site. (b) A nerve transmission depolarizes the
membrane causing the concentration of Ca2+ to increase,
C. Calcium as a Signaling Agent (Secondary Messenger) which causes the vesicles to fuse with the membrane. (c)
- The message delivered to the receptors on the cell Acetylcholine is released into the synaptic space and binds
membranes by neurotransmitters or hormones must be to receptors on the postsynaptic site.
delivered intracellularly to various locations within the
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D. The Action of Messengers open and propagate signals, this mode of action is
- Acetylcholine molecules at the postsynaptic receptor called ligand-gated channeling. The binding of the
site trigger a conformational change (Section 3-10) in ligand to its receptor is critical in signaling. Nicotine
the receptor protein. This opens the ion channel and given in low doses is a stimulant; it is an agonist
allows ions to cross membranes freely. Na" ions have because prolongs the receptor's biochemical response.
a higher concentration outside the neuron than do K When given in large doses, however, nicotine becomes
ions; thus, more Na enters the cell than K leaves. an antagonist and blocks the action of the receptor.
- Because it involves ions, which carry electric charges, - As such, it may cause convulsions and respiratory
this process is translated into an electrical signal. After paralysis. Succinylcholine, besides being a reversible
a few milliseconds, the channel closes again. The inhibitor of acetylcholinesterase, also has this
acetylcholine still occupies the receptor. For the concentration-dependent agonist/antagonist effect on
channel to reopen and transmit a new signal, the the receptor. A strong antagonist, which blocks the
acetylcholine must be removed and the neuron must be receptor completely, can interrupt the communication
reactivated. between neuron and muscle cell.
- The venom of a number of snakes, such as cobratoxin,
E. The Removal of Messengers exerts its deadly influence in this manner. The plant
- Acetylcholine is removed rapidly from the receptor site extract curare, which was used in poisoned arrows by
by the enzyme acetylcholinesterase, which hydrolyzes the Amazon Indians, works in the same way. In small
it. doses, curare is used as a muscle relaxant.
- Finally, the supply of the acetylcholine messenger can
influence the proper nerve transmission. If the
acetylcholine messenger is not released from its
- This rapid removal enables the nerves to transmit more storage, as in botulism, or if its synthesis is impaired,
than 100 signals per second. By this means, with as in Alzheimer's disease the concentration of
acetylcholine occupying a receptor, being removed, acetylcholine is reduced and the nerve transmission is
and then reactivation of the neuron with additional impaired.
acetylcholine, The message moves from neuron to
neuron until it is finally transmitted again by What Amino Acids Act as Neurotransmitters?
acetylcholine molecules, A. Messengers
- To the muscles or endocrine glands that are the - Amino acids are distributed throughout the neurons
ultimate target of the message. The action of the individually or as parts of peptides and proteins. They
acetylcholinesterase enzyme is essential to the entire can also act as neurotransmitters. Some of them, such
process. When this enzyme is inhibited, the removal of as glutamic acid, aspartic acid, and cysteine, act as
acetylcholine is complete and nerve transmission excitatory neurotransmitters similar to acetylcholine
ceases. and norepinephrine, Others, such as glycine, β-alanine,
taurine, and mainly γ-Aminobutyric acid (GABA), are
F. Control the Neurotransmission inhibitory neurotransmitters, they reduce
- Acetylcholinesterase is inhibited reversibly by neurotransmission.
succinylcholine and decamenthonium bromide. - β-alanine and γ-Aminobutyric acid (GABA) are not
found in proteins.

B. Receptors
- Succinylcholine and decamethonium bromide - Each of these amino acids has its own receptor; in fact,
resemble the choline end of acetylcholine and therefore glutamic acid has at least five subclasses of receptors.
act as competitive inhibitors of acetylcholinesterase. In The best known is the N-methyl D-aspartate (NMDA)
small doses, these reversible inhibitors relax the receptor. This ligand-gated ion channel is similar to the
muscles temporarily, making them useful as muscle nicotinic cholinergic receptor.
relaxants in surgery. In large doses, they are deadly.
The inhibition of acetylcholinesterase is but one way in
which cholinergic neurotransmission is controlled.
- Another way is to modulate the action of the receptor:
Because acetylcholine enables the ion channels to
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- In the example shown in Figure 5-5, the receptor has

an associated. A protein called G-protein. This protein
is the key to the cascade that produces many signals
inside the cell (amplification). The active G-protein has
an associated nucleotide, guanosine triphosphate
(GTP It is an analog of adenosine triphosphate)(ATP),
in which the aromatic base adenine is substituted by
guanine. The G-protein becomes inactive when its
associated nucleotide is hydrolyzed to guanosine
- When glutamic acid binds to this receptor, the ion
diphosphate (GDP). Signal transduction starts with the
channel opens, Na* and Ca2+ flow into the neuron, and
active G-protein, which activates the enzyme adenylate
K flows out of the neuron. The same thing happens
cyclase.
when NMDA, being an agonist, stimulates the receptor.
The gate of this channel is closed by a Mg2+ ion.
- Phencyclidine (PCP), an antagonist of this receptor,
induces hallug nation. PCP, known by the street name
"angel dust," is a controlled sub stance; it causes
bizarre psychotic behavior and long-term psychological
problems.

C. Removal of Messengers
- In contrast to acetylcholine, there is no enzyme that
would degrade glutamic acid and thereby remove it
from its receptor once the signaling ha occurred.
Glutamic acid is removed by transporter molecules,
which bring it back through the presynaptic membrane
into the neuron. This process is called reuptake

What are Adrenergic Messengers? FIGURE 5-5 The sequence of events in the postsynaptic
A. Monoamine Messengers membrane when the 108 norepinephrine is adsorbed onto
- The third class of neurotransmitters/hormones, the the receptor site.
adrenergic messenger includes such monoamines as - (a) The active G-protein hydrolyzes GTP The energy of
epinephrine, serotonin, dopamine, and hist mine. hydrolysis of GTP to GDP activates adenylate cyclase.
These monoamines transmit signals by mechanism A molecule of cAMP forms when adenylate cyclase
whose beginning is similar to the action of cleaves ATP into cAMP and pyrophosphate. (b) Cyclic
acetylcholine. That is, they are adsorbed on a receptor. AMP activates a protein kinase by dissociating the
regulatory (R) unit from the catalytic unit (C). A second
B. Signal Transduction molecule of ATP shown in (b), has phosphorylated the
- Once a hormone or neurotransmitter binds to a catalytic unit and been converted to ADP. (c) The
receptor, some mechanism must propagate the signal catalytic unit phosphorylates the ion-translocating
to the cell. The process by which the initial signal is protein that blocks the channel for ion flow. The
spread and amplified throughout the cell is called signal phosphorylated ion-translocating protein changes its
transduction. The process involves intermediate shape and position and opens the ion gate.
compounds that pass the signal on to the ultimate
targets. C. Secondary Messengers
- Eventually, enzymes are modified to alter their activity, - Adenylate cyclase produces a secondary messenger
or membrane channels are opened or closed The term inside the cell, cyclic AMP (CAMP). The manufacture of
"signal transduction" and much of the pioneering cAMP activates processes that result in the
research on this topic came from the work of Martin transmission of an electrical signal. The cAMP is
Rodbell (1925-1998) of the National Institutes of manufactured by adenylate cyclase from ATP:
Health, winner of the 1994 Nobel Prize in Physiology or
Medicine. The action of monoamine neurotransmitters
is a prime example: One the monoamine
neurotransmitter/hormone (for example,
norepinephrine is adsorbed onto the receptor site, the
signal will be amplified inside the cell.
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- The activation of adenylate cyclase accomplishes two acetylcholinesterase, most of the adrenergic
important goals: neurotransmitters are inactivated in different ways. The
o 1. It converts an event occurring at the outer body inactivates monoamines by monoamine oxidases
surface of the target cell to a change inside the (MAOs), which are very common in the body. For
target cell.n Thus, the primary messenger example, one MAO catalyzes the conversion of both
(neurotransmitter or hormone) epinephrine and norepinephrine to the corresponding
o 2. It amplifies the signal. One molecule adsorbed aldehyde:
on the receptor triggers does not have to cross the
membrane. the adenylate cyclase to make many
cAMP molecules. In this way, The signal is
amplified many thousands of times.

D. Removal of Signal
- How does this signal amplification stop? When the
neurotransmitter or hormone dissociates from the
receptor, the adenylate cyclase halts the many. facture
of cAMP. The cAMP already produced is destroyed by - Many drugs that are used as antidepressants or
the enzyme phosphodiesterase, which catalyzes the antihypertensive agents are MAO inhibitors example,
hydrolysis of the phosphoric ester bond, yielding AMP Marplan and Nardil. They prevent MAOS from
- The amplification through the secondary messenger converting monoamines to aldehydes, thereby
(CAMP) is a relatively slow process. It may take from increasing the concentration of the active adrenergic
0.1 s to a few minutes. There fore, in cases where the neurotransmitters. remove adrenergic
transmission of signals must be fast (milliseconds or neurotransmitters.
seconds), a neurotransmitter such as acetylcholine - There is also an alternative way to Shortly after
acts on mem brane permeability directly, without the adsorption onto the postsynaptic membrane, the
mediation of a secondary messenger. neurotransmitter comes off the receptor site and is
reabsorbed through the presynaptic membrane and
E. Control of Neurotransmission stored again in the vesicles.
- The G-protein-adenylate cyclase cascade in
transduction signaling is not limited to monoamine G. Histamines
messengers. A wide variety of peptide hormones and - The neurotransmitter histamine is present in
neurotransmitters use this signaling pathway. Included mammalian brains. It is synthesized from the amino
among them are glucagon, vasopressin, luteinizing acid histidine by decarboxylation:
hormone, enkephalins, and Substance P. Neither is the
opening of ion channels, depicted in Figure 5-4, the
only target of this signaling. A number of enzymes can
be phosphorylated by protein kinases, and the
phosphorylation controls whether these enzymes will
be active or inactive.
- The fine control of the G-protein-adenylate cyclase
cascade is essential for health. Consider the toxin of - The action of histamine as a neurotransmitter is very
the bacterium Vibrio cholerae, which permanently similar to that of other monoamines. There are two
activates G-protein. The result is the symptoms of kinds of receptors for histamine. One receptor, H₁, can
cholera- namely, severe dehydration as a result of be blocked by antihistamines such as dimenhydrinate
diarrhea. This problem arises because the activated G- (Dramamine) and diphenhydramine (Benadryl). The
proteins overproduce cAMP. This excess, in turn, other receptor, H₂, can be blocked by ranitidine
opens the ion channels, which leads to a large outflow (Zantac) and cimetidine (Tagamet).
of ions and accompanying water from the epithelial - H, receptors are found in the respiratory tract. They
cells to the intestines. Therefore, the first measure affect the vascular, muscular, and secretory changes
taken in treating cholera victims is to replace the lost associated with hay fever and asthma. Therefore,
water and salt. antihistamines that block H, receptors relieve these
symptoms. The H₂ receptors are found mainly in the
F. Removal of Neurotransmitters stomach and affect the secretion of HCI. Cimetidine
- The inactivation of the adrenergic neurotransmitters and ranitidine, both H₂ blockers, reduce acid secretion
differs somewhat from the inactivation of the cholinergic and, therefore, are effective drugs for ulcer patients.
transmitters. While acetylcholine is decomposed by
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The main culprit in the formation of most ulcers, - Glucagon is a peptide hormone that is critical for
however, is the bacterium Helicobacter pylori. maintaining blood glucose levels. When the pancreas
senses that blood glucose is dropping, it releases
What is the Role of Peptides in Chemical Communications? glucagon. When glucagon is released, it binds to
A. Messengers receptors on liver cells and acts through a series of
- Many of the most important hormones affecting reactions to raise blood glucose. The method of action
metabolism belong to the peptidergic messengers is far from simple, however. When glucagon binds to its
group. Among them are insulin (and glucagon, receptor and activates the G-protein cascade, the
hormones of the pancreatic islets, and vasopressin and second messenger, cAMP, activates protein kinase, an
oxytocin, products of the posterior pituitary gland. In the enzyme that phosphorylates many target enzymes. As
last few years, scientists have isolated a number of shown in Figure 5-7, protein kinase phosphorylates.
brain peptides that have an affinity for certain receptors - (a) Binding of a glucagon to its receptor sets off a chain
and, therefore, act as if they were neurotransmitters. of events that leads to the activation of a cAMP-
Some 25 or 30 such peptides are now known. dependent protein kinase The enzymes
- The first brain peptides isolated were the enkephalins. phosphorylated in this case are (bl
These pentapeptides are present in certain nerve cell phosphofructokinase-2, which is inactivated, and (c)
terminals. They bind to specific pain receptors and fructose-bisphosphatase-2, which is activated. The
seem to control pain perception. Because they bind to combined result of phosphorylating these two enzymes
the receptor site that also binds the pain-killing alkaloid is to (d) lower the concentration of fructose-2, 5-
morphine, it is assumed that the N-terminal end of the bisphosphate (F2.6P). A lower concentration of F2,6P
pentapeptide fits the receptor (Figure 5-6) Even though leads to a lack of allosteric activation of
morphine remains the most effective agent in reducing phosphofructokinase-1 and (e) lowered glycolysis while
pain, its clinical use is limited because of its side effects. also leading to (f) allosteric activation of fructose-
These include respiratory depression; constipation; bisphosphatase-1 and increased gluconeogenesis.
and, most significantly, addiction. - two key enzymes in carbohydrate metabolism, fructose
- The clinical use of enkephalins has yielded only modest bisphosphatase-2 (FBP-2) and phosphofructokinase-2
relief. The challenge is to develop analgesic drugs that (PFK-2). Phosphorylating these two enzymes has
do not involve the opiate receptors in the brain. Another opposite effects. The kinase is inactivated, and the
brain peptide, neuropeptide Y, affects the phosphatase uses it. is activated. This lowers the
hypothalamus, a region that integrates the body's intracellular concentration of fructose a key metabolic
hormonal and nervous systems. Neuropeptide Y is a regulator. The reduced level of the regulator increases
potent orexic (appetite-stimulating) agent. When its the activity of the pathway called gluconeogenesis 2,6-
receptors are blocked (for example, by leptin, the "thin" bisphosphate, (Chapter 10) and reduces the activity of
protein), appetite is suppressed. the pathway called glycolysis (Chapter 9).
- Leptin is an anorexic agent, Yet another peptidergic Gluconeogenesis produces glucose, and glycolysis u
neurotransmitter is substance P (P for "pain"). This 11- Thus, by turning on gluconeogenesis and turning off
amino-acid peptide is involved in the transmission of glycolysis, the liver produces more glucose for the
pain signals. In injury inflammation, sensory nerve blood.
fibers transmit pain signals from the peripherals - Insulin is another peptide hormone produced by the
nervous system (where the injury occurred) to the pancreas, but its overall effect is roughly the opposite
spinal cord, which processes the pain. The peripheral of glucagon's. Insulin binds to insulin receptors on liver
neurons synthesize and release substance P, which and muscle cells, as shown in Figure 5-8. The receptor
bonds to receptors on the surface of the spinal cord. is an example of a protein called a tyrosine kinase. A
Substance P then removes the magnesium block at the specific tyrosine residue becomes phosphorylated on
N-methyl-D-aspartate (NMDA) receptor. Glutamic acid, the receptor, initiating its kinase activity. A tar-get
an excitatory amino acid, can then bind to this receptor. protein called IRS (insulin receptor substrate) is then
In doing so, it amplifies the pain signal going to the phosphorylated
brain. - FIGURE 5-8 The insulin receptor has two types of
subunits, a and B. The a-subunit is on the extracellular
B. Secondary Messengers and Control Metabolism side of the membrane, and it binds to insulin. The B-
- All peptidergic messengers, hormones, and subunit spans the membrane. When insulin binds to the
neurotransmitters act through secondary messengers. a-subunit, the B-subunits auto-phosphorylate on
Glucagon, luteinizing hormone, antidiuretic hormone, tyrosine residues.
angiotensin, enkephalin, and substance P use the G- - These then phosphorylate target proteins called insulin
protein-adenylate cyclase cascade that we saw in the receptor substrates (RS), The IRSs act as the second
previous section. messengers in the cells. By the active tyrosine kinase.
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The phosphorylated IRS acts as the second There are several ways these drugs act in the body. A
messenger. It causes the phosphorylation of many drug may affect the messenger, the receptor, the
target enzymes in the cell. The effect is to reduce the secondary messenger, or any one of a host of enzymes
level of glucose in the blood by increasing the rate of that is activated or inhibited as part of a metabolic
pathways that use glucose and slowing the rate of pathway.
pathways that make glucose. 1. An antagonist drug blocks the receptor and
prevents its stimulation.
How Do Steroid Hormones Act as Messengers? 2. An agonist drug competes with the natural
- There is no need for special receptors embedded in the messenger for the receptor site. Once there, it
membrane for these hormones. It has been shown, stimulates the receptor.
however, that steroid hormones interact inside the cell 3. Other drugs decrease the concentration of the
with protein receptors. Most of these receptors are messenger by controlling the release of
localized in the nucleus of the cell, but small amounts messengers from their storage.
also exist in the cytoplasm. When they interact with 4. Other drugs increase the concentration of the
steroids, they facilitate their migration through the messenger by inhibiting its removal from the
aqueous cytoplasm, since the protein receptors receptors.
themselves are hydrophilic. 5. Still others act to inhibit or activate specific
- Once inside the nucleus, the steroid-receptor complex enzymes inside the cells.
can either bind directly to the DNA or combine with a
transcription factor, a protein that binds to DNA and LESSON 6: NUCLEOTIDES, NUCLEIC ACIDS, AND
alters the expression of a gene, influencing the HEREDITY
synthesis of a certain key protein. Thyroid hormones What are the Molecules of Heredity?
also have large hydrophobic domains as well as protein • Heredity is the transfer of characteristic, anatomical as
receptors, which facilitate their transport through well as biochemical, from generation to generation.
hydrophobic cell membranes. • Heredity based on genes located in the chromosomes.
- The steroid hormonal response through protein • Genes are sections of DNA that encode specific RNA
synthesis is not fast. In fact, it takes hours to occur. molecules.
Steroids can also act at the cell membrane, influencing • From about the end of the nineteenth century,
ligand-gated ion channels. Such a response would take biologists suspected that the transmission of hereditary
only seconds. An example of such a fast response information from one generation to another took place
occurs in fertilization. The sperm head contains in the nucleus of the cell. More precisely, the believed
proteolytic enzymes, which act on the egg to facilitate that the structures within the nucleus, called
its penetration. These enzymes are stored in chromosomes, had something to do with heredity.
acrosomes, organelles found on the sperm head. • The information that determines external
During fertilization, progesterone originating from the characteristics ( red hair, blue eyes) and internal
follicle cells surrounding the egg acts on the acrosome characteristics ( blood group, hereditary diseases) was
outer membrane, which disintegrates within seconds thought to reside in genes located inside the
and releases the proteolytic enzymes. chromosomes.
- The same steroid hormones depicted in Figure 2-7 act • Chemical analysis of nuclei showed that they are
as neurotransmitters, too. These neurosteroids are largely made up of special basic proteins called
synthesized in the brain cells in both neurons and glia, histones and a type of compound called nucleic acids.
and they affect receptors-mainly the NMDA and GABA What are Nucleic Acids Made Of?
receptors (Section 5-4). For both sexes, progesterone • Nucleic acids are composed of sugars, phosphates,
and progesterone metabolites in brain cells can induce and organic bases.
sleep, have analgesic and anticonvulsive effects, and
• Two kinds of nucleic acids are found in cells: ribonucleic
can even serve as natural anesthetics.
acid (RNA) and deoxyribonucleic acid (DNA).
• In DNA, the sugar is the monosaccharide 2- deoxy – D-
How Do Drugs Affect Chemical Communication?
ribose, in RNA, it is D- ribose.
- The chemical communications between different cells
and different organs play a role in the proper functioning • In DNA, the hetero cyclic amine bases are adenine (A),
of our bodies. Its significance is illustrated by the fact guanine (G), cytosine (C), thymine (T)
that a large percentage of the drugs we encounter in • In RNA, they are A, G, C, and uracil (U)
medical practice try to influence this communication.
The scope of these drugs covers all fields of Structure of DNA and RNA
prescriptions to treat hypertension, and heart disease, Two Kinds in Cells:
to antidepressants, to painkillers, just to mention a few. u Ribonucleic Acids (RNA)
 BIOCHEMISTRY REVIEWER (MIDTERMS)

u Deoxyribonucleic Acids (DNA) u The double helix model was proposed by James
Watson and Francis Crick in 1953.
Three Simpler Units of Nucleic Acids: u Double Helix- the arrangement in which two strands of
A. Base DNA are coiled around each other in a screw-like
Two of these bases adenine (A) and guanine (G) are purines fashion.
the other three cytosine (C), thymine (T), and uracil (U) are
pyrimidines. The two purines (A&G) and one of the C. Higher Order Structure of DNA
pyrimidines (C) are found in both DNA and RNA, uracil is u DNA is coiled around proteins called histones.
found only in RNA and thymine is found only in DNA. u The acidic DNA and the basic histones attract each
other by electrostatic forces, combining to form units
called nucleosomes.
u Chromatin- the DNA complexed with histone and
nonhistone proteins that exists in eukaryotic cells
between cells division.
u Somatin- A coil wound in the form of a helix.
B. Sugars
What are the different Classes of RNA?
u The sugar component of RNA is D- ribose, in DNA, it is
1. Messenger RNA (mRNA) mRNA molecules are
2- deoxy- D- ribose.
produced in the process called transcription, and they
carry the genetic information from the DNA in the
nucleus directly to the cytoplasm, where most of the
protein is synthesized.
2. Transfer RNA (tRNA) the RNA that transport amino
acids to the site of protein systhesis in ribosomes.
3. Ribosomal RNA (rRNA) the RNA complexed with
protein in ribosomes.
• Ribosomes- small spherical bodies in the cell
u The combination of sugar and base is known as a
nucleoside. The purine bases are linked to C-1 of the made of protein and RNA ; the site of protein
monosaccharide through N-9 by a B-N glycosidic bond. synthesis.
u Nucleoside- a compound composed of ribose or 4. Small Nuclear RNA (snRNA) is involved in splicing
deoxyribose and a base. reactions and has been found in some cases to have
catalytic activity. RNA with catalytic activity is called a
u The nucleoside made of guanine and ribose is called
guanosine. ribozyme.
5. Micro RNA (miRNA) they play important roles in cancer,
stress responses, and viral infections.
C. Phosphate
This group forms a phosphate ester bond with a nucleoside, 6. Small Interfering RNA (siRNA) have been found to have
an enormous control over gene expression.
the result is compound known as a nucleotide.
Nucleotide- a nucleoside bonded to one, two, or three 7. Long non-coding RNA (lncRNA) these are RNA
phosphate groups. molecules greater than 100 nucleotides in length that
do not fit into any of the other categories.
What is the Structure of DNA and RNA? 8. Piwi-Associated RNA (piRNA) - these so called “
jumping genes” can disrupt the normal cellular process
A. Primary Structure
and even lead to cancer.
u Their primary structure is the sequence of the
nucleotides. It can be divided into two parts: (1) the 9. Circular RNA most recent RNA discovery. Created by
backbone of the molecule and (2) the bases that are alternative splicing of introns during eukaryotic mRNA
the side chain group. transcription.
u The backbone in DNA consists of alternating
deoxyribose and phosphate groups. Each phosphate What are Genes?
group linked to the 3 carbon of one deoxyribose unit • Genes- is a segment of a DNA molecule that carries the
and simultaneously to the 5 carbon of the net sequence of bases that directs the synthesis of one
deoxyribose. particular protein or RNA molecule.
o Stretches of DNA that spell out (encode) the amino
B. Secondary Structure of DNA acid sequence to be assembled are interrupted by
u The ordered arrangement of nucleic acid strands. long stretches that seemingly do not code for
anything. The coding sequence are called exons,
short for “ expressed sequences”, and the
 BIOCHEMISTRY REVIEWER (MIDTERMS)

noncoding sequences are called introns, short for middle. Special unwinding protein molecules, and
“ intervening sequences.” helicases attach themselves to one DNA strand and
• Exons- nucleotide sequences in DNA or mRNA that cause the separation of the double helix.
code for a protein. u 4. Primers/Premases- Primers are short 4-15
• Introns- nucleotide sequences in DNA or mRNA that do nucleotides long. The enzymes catalyzing this
not code for a protein. synthesis is called primase. Primases form complexes
• In humans, only3% of the DNA codes for proteins, but with DNA polymerase in eukaryotes.
it is estimated that over 70% of the DNA does serve u 5.DNA Polymerase- The key enzymes in replication are
purpose. Introns are not only noncoding DNA the DNA polymerase. Once the two strands are
sequences, however. Satellites are DNA molecules in separated at the replication fork, the DNA nucleotides
which short nucleotides sequences are repeated must be lined up. All four kinds of free DNA nucleotides
hundreds or thousand of times. molecules are present in the vicinity of the replication
• Smaller repetitive sequences, called mini-satellites or fork. These short fragments consist of about 200
microsatellites, are associated with cancer when they nucleotides each, named Okazaki fragments.
mutate. u 6. Ligation- the Okazaki fragments and any nicks
remaining are eventually join together by another
How is DNA Replicated? enzyme, DNA ligase.
u DNA replication occurs in several distinct steps.
u Replication begins at a point in the DNA called an LESSON 7: GENE EXPRESSION AND PROTEIN
original of replication. In human cells, the average SYNTHESIS
chromosome has several hundred origins of replication How Does DNA Lead To RNA And Protein?
where the copying occurs simultaneously. The point on DNA
the DNA where replication proceeds is called the • store house of information.
replication fork. • information stored in DNA must be expressed in the
u Replication is bidirectional and takes place at the same proper combination of amino acids representing a
speed in both directions. One of the synthesis is particular protein.
continuous along the 3’ to 5’ strand, it is called the • the way this expression works is now so well
leading strand. Along the other strand that runs in the 5 established that is called central dogma of molecular
to 3 direction, the synthesis is discontinuous, it is called biology.
the lagging strand.
u The replication process is called semiconservative Central Dogma of Molecular Biology
because each daughter molecule has one parental • States that “the information contained in DNA
strand (conserved) and one newly synthesized one. molecules is transferred to RNA molecules, and then
u One of the more interesting aspects of DNA replication from the RNA molecules the information is expressed
is that the basic reaction of synthesis always requires in the structure of protein”.
an existing chains with a nucleotide that has a free 3’-
hydroxyl to do nucleophilic attack. DNA replication Steps in Transmission of Information
cannot begin without this preexisting chain to latch A. TRANSCRIPTION
onto. We call this chain a primer. In all known forms or • Process in which information encoded in a DNA
replication, the primer is made out of RNA, not DNA. molecule is copied into an mRNA molecule.
• DNA in the nucleus of eukaryotic cell and amino acid
The replication of DNA occurs in the number of distinct are assembles and carried our of the nucleus.
steps: • All the necessary information is copied.
u 1. Opening Up the Superstructure- During replication, • On molecular level: This is accomplished by
the very condense superstructure of chromosomes transcribing the information from the DNA molecule into
must be opened so that it becomes accessible to a molecule of mRNA, it carries the message from the
enzymes and other proteins. nucleus to the site of protein synthesis
u 2. Relaxation of Higher-order Structures of DNA-
Topoisomerases (also called gyases) are enzymes that B. Translation
are facilitated the relaxation of supercoiling in DNA. • Process in which information encoded in mRNA
They so so during the replication by temporary molecule is used to assemble a specific protein.
introducing either single or double-strand breaks of • An exact word-to-word translation occurs.
DNA. • Each word in the protein language has a corresponding
u 3. Unwiding the DNA Double Helix- the replication od
word in the RNA language. this corresponds to the
the DNA molecules starts with the unwinding of the
three bases and one amino acid called genetic code.
double helix, which can occur at either end or in the
 BIOCHEMISTRY REVIEWER (MIDTERMS)

Did you know? What us the Role of RNA in Translation?

- In higher organisms, transcription and translation occur u Translation: is the process by which the genetic
sequentially. Transcription takes place in the nucleus, information preserved in the DNA and transcribed into
mRNA leaves the nucleus and enters cytoplasm, the the mRNA is converted to the language of proteins, the
translation takes place there. amino acid sequence. Three types of RNA participate
- In lower organisms, there is no nucleus, and thus, in this process.
transcription and translation occurs simultaneously in u 3 Types of RNA
the cytoplasm. o mRNA
o rRNA
How is DNA Transcribed into RNA? o tRNA
• Transcription starts when the DNA double helix begins u In larger organisms, including humans, the larger
to unwind at a point near the gene that is to be ribosomal body called the 60S ribosome and the
transcribed. Specific binding proteins binds to the smaller one called the 40S ribosome.
nucleosomes, making the DNA less dense and more u Designation "S" refers to svedberg.
accessible. u Svedberg: a measure of density used in centrifugation.
• HELICASE: a ring- shaped complex six protein u Anticodons: a trinucleotide sequence located at one
subunits which unwinds the double helix. end of a transfer RNA (tRNA) molecule is
• Template & Antisense Strand: The strand of DNA that complementary to a corresponding codon in mRNA.
serves as the template during RNA synthesis. u Codons: the sequence of three nucleotides in mRNA
• Coding and Sense Strand: The DNA strand that is not that code for a specific amino acid.
used as a template for transcription, but which has a
sequence that is same as the RNA produced. Also What is Genetic Code?
called the (+) strand and the sense strand. • By 1961, it was apparent that the order of bases in a
DNA molecule corresponds to the order of amino acids
in a particular protein, but the code was unknown.
Obviously, it could not be a one-to-one
correspondence. There are only four bases, so if A
coded for glycine, G for alanine, C for valine, and I for
serine, there would be 16 amino acids that could not be
coded.
• In 1961, Marshall Nirenberg (1927-2010) and his
• In higher organisms, three kinds of polymerases
coworkers attempted to break the code in a very
catalyze transcription.
ingenious way. They made a synthetic molecule of
o RNA polymerase I (pol-1) - Catalyzes the
mRNA consisting of uracil bases only. They put this
formation of most rRNA
molecule into a cell-free system that synthesized
o RNA polymerase II (pol-2) - Catalyzes that mRNA
proteins and then supplied the system with all 20 amino
formation.
acids. The only polypeptide produced was a chain
o RNA polymerase III (pol-3) - Catalyzes tRNA
consisting solely of the amino acid phenylalanine. This
formation as well as one ribosomal subunit and
experiment showed that the code for phenylalanine
other small regulatory RNA types, like snRNA.
must be UUU or some other multiple of U.
• Promoter
• A series of similar experiments by Nirenberg and other
o control element and it is unique in each gene.
workers followed, and by 1967, the entire genetic code
o they contain consensus sequences such as TATA
had been broken. Each amino acid is coded for by a
box, (TATAAT beginning sequence)
sequence of three bases, called a codon. The first
o All three RNA polymerase interact with their
important aspect of the genetic code is that it is almost
promoter regions via transcription factors that are
universal. The universality of the genetic code implies
binding proteins.
that all living matter on Earth arose from the same
• Enhancer
primordial organisms.
o a DNA sequence that can be far removed from the
• There are 20 amino acids in proteins, but 64 possible
promoter region.
combinations of four bases into triplets. All 64 codons
o they can also bind to transcription.
(triplets) have been deciphered. Three of them—UAA,
o To ensure that mRNA is functional, transcribed
UAG, and UGA—are "stop signs." They terminate
product are capped at both ends. Once the ends
protein synthesis. The remaining 61 codons code for
are capped, the introns are spliced out in a post-
amino acids. Because there are only 20 amino acids,
transcription process.
there must be more than one codon for most amino
 BIOCHEMISTRY REVIEWER (MIDTERMS)

acids. Indeed, some amino acids have as many as six 1. Forming the pre-initiation complex: To initiate
codons. protein synthesis and also this protein are called
• Just as there are three stop signs in the code, there is initiation factors
also an initiation sign. The initiation sign is AUG, which 2. Migration to mRNA: Next, the pre-initiation
is also the codon for the amino acid methionine. complex binds to the mRNA. The ribosomes is
• The genetic code is said to be continuous and aligned on the mRNA by recognizing a special
unpunctuated. If the mRNA is AUGGGCCAA, then the RNA sequence called Shine- Dalgarno sequence.
AUG is one codon and specifies the first amino acid. 3. Forming the full ribosomal complex: The 50S
The GGC is the second codon and specifies the second ribosomal body joins the 30S ribosomal complex .
amino acid. The CAA is the third codon and specifies The complete ribosome carries three sites. The
the third amino acid. There are no overlapping codons one shown in the middle in is called the P site,
and no nucleotides interspersed. because the growing peptide chain will bind
there.The one next to it on the right is called the A
(acceptor) site, because it accepts the incoming
tRNA bringing the next amino acid.

C. Elongation
1. Binding to the A site: At this point, the A site is
vacant and each of the aminoacyl-tRNA molecules
can try to fit itself in. However, only one of the
tRNAs carries the right anticodon that corresponds
to the next codon on the mRNA. This is an alanine
tRNA. The binding of this tRNA to the A site takes
place with the aid of proteins called elongation
factors and GTP.
2. Forming the first peptide bond: At the A site, the
How is Protein Synthesized? new amino acid, alanine (Ala), is bonded to the
There are four major stages in protein synthesis; activation, fMet in a peptide bond by the enzyme peptidyl
initiation, elongation, and termination. At each stage, a transferase. The empty tRNA remains on the P
number of molecular entities participate in the process. site.
3. Translocation: In the next phase of elongation the
A. Activation whole ribosomes moves one codon along the
- Each amino acid is first activated by reacting with mRNA simultaneously with this more the dipeptide
a molecule ATP. is translocated.
- The activated amino acid is then bound to its own 4. Forming the second peptide bond: after
particular tRNA molecule with the aid of an translocation the A site is associated with the next
enzyme that is specific to that particular amino codon on the mRNA.
acid and that particular tRNA molecule:
- The different synthetases recognize their D. Termination
substrates by stretches of nucleotide sequences - After the final translocation, the next codon reads
on the tRNA. The specific recognition by an "stop" (UAA, UGA, or UAG). At this point, no more
enzyme, aminoacyl-tRNA synthetase, of its proper amino acids can be added. Releasing factors then
tRNA and amino acid is often referred to as the cleave the polypeptide chain from the last tRNA
second genetic code. This step is very important via a GTP-requiring mechanism that is not yet fully
because once the amino acid is on the tRNA, there understood. The tRNA itself is released from the P
is no other opportunity to check for the correct site. At the end, the whole mRNA is released from
pairing. In other words, the anticodon of the tRNA the ribosome.
will match up with its matching codon on the
mRNA regardless of whether it is carrying the How are Genes Regulated?
correct amino acid, so the aminoacyl- tRNA • Gene Regulation - The control process by which the
synthetases have to get it right. expression of a gene is turned on or off because RNA
synthesis proceeds on one direction the DNA to be
B. Initiation transcribe runs from 3 to 5 thus control sites are in front
- The initiation stage consists of three steps: off or upstream of the 3 end of the structural genes

A. Control at the transcription level

 BIOCHEMISTRY REVIEWER (MIDTERMS)

o In eukaryotes, transcription is regulated by three different times, controlling what the eventual
entities: promoters, enhancers, and response products of the gene are.
elements.
1. Promoters of a gene are located adjacent to the C. Control on the Translation level
transcription site. They are defined by an initiator 1.The specifying of a tRNA for its unique amino acids
and conserved sequences, such as a TATA box o the attachment of the proper amino acid to the acid
o Protein Synthesis Makes Memories - - Memories to the proper tRna must be achieved. The enzyme
are of two types short term and long term short that catalyzes this reaction, aminoacyl- tRNA
term memories last from seconds to minutes a synthetase (AARS), is specific to each amino acid.
while but long term memories last days, months or For those amino acids that have more than one
even lifetime neuroscientist have long been type of tRNA, the same synthetase catalyzes the
fascinated by what makes one memory stick while reaction for all the tRNA types for that amino acid.
another does not when you meet someone at a o The AARS recognize their tRNAs by specific
party and she tells you her name you might forget nucleotide sequences. the active site of the
it in seconds however your best friend names is enzymes has two Sieving portions, the first
converted to long tern memory and might your sieve excludes any amino acids that are larger
whole life. Both long and short term memories than isoleucine. The second sieving site is thus a
come from connections between neurons called “proofreading” site.
synapses where one neuron emits a signal from 2. Recognition of the stop codon
its axon that is received by the next neurons o Another quality-control measure occur at protein
dendrites. termination. The stop codon must be recognize by
o In figure 11 the event in the initiation of transition release factors, leading to the release of the
are very complicated to DNA and RNA polypeptide chain and allowing the recycling of the
polymerase to initiate transcription they first from ribosomes.Otherwise, a longer polypeptide chain
the pre initiation complex ,another group of could be toxic.
transcription factors speeds up the transcription o The release factor combines with GTP and binds
process by binding to DNA sequences that may be the ribosomal A site when that site is occupied by
located several thousand nucleotides away from the termination codon. Both the GTP and the
the transcription site, these sequences are known peptidyl-tRNA ester bond are hydrolyzed. This
as Enhancers. Hydrolysis release the polypeptide chain and
o The third type of transcription control involves a the deacylated tRNA. Finally, the ribosome
type of enhancer called response Elements these dissociates from the mRNA.
enhancers are activated by their transcription
factors in response to an outside stimulus may be 3. Post-translation Controls
heat, shock, heavy metal toxicity or simply a a) Removal of methionine: a special enzyme,
hormonal signal such as the binding of a steroid methionine aminopeptidase, cleaves the peptide
hormone to it's receptor transcription does not bond.
occur at the same rate throughout the cells entire b) Chaperoning: the tertiary structure of a protein is
life cycle. largely determined by the amino acid sequence
(primary). proteins begin to fold even as they are
B. Control on the Post-Transcriptional level synthesized on ribosomes misfolding may occur
o the dogma stated that “one gene leads to one due to mutation in a gene, lack of fidelity in
mRNA leads to one protein”. The only transcription or translational errors. chaperons
exception to this rule were thought to occur in the help the newly synthesized polypeptide chains to
production of antibodies and other fold properly. they recognize hydrophobic regions
immunoglobulin- based proteins. These proteins exposed on unfolded proteins and bind to them.
were known to undergo a type of post- c) Degradation of misfolded proteins: A third post-
transcriptional modification called alternative transitional control exists in the form of
splicing, whereby the primary mRNA transcript proteasomes. These
can be spliced in different ways to give multiple Cylindrical assemblies include a number of
mRNAs and therefore multiple proteins. subunit with proteolytic activity in the core of the
o alternative splicing provides another powerful cylinder.
technique for controlling gene regulation. Within
the same cell or the same organism, What is Mutation?
different genes can be spliced in different ways at • is an error in the copying of the sequence of bases
 BIOCHEMISTRY REVIEWER (MIDTERMS)

• it can occur during replication. base errors can also

occur during transcription( a non-inheritable error). How and Why Do We Manipulate
• these errors may have widely varying consequences. • How: By the process Genetic engineering (also called
For example, the codon for valine in mRNA can be genetic modification) is a process that uses laboratory-
GUA, GUG,GUC, or GUU . In DNA, these codons based technologies to alter the DNA makeup of an
correspond to GTA, GTG, GTC, and GTT, respectively. organism. This may involve changing a single base pair
If a mistake is made during replication and GTA is (A-T or C-G), deleting a region of DNA or adding a new
spelled as GTG in the copy, there will be no harmful segment of DNA
mutation. Instead, when a protein is synthesized , the • Why: Genome editing is of great interest in the
GTG will appear on the mRNA as GUG. Therefore, prevention and treatment of human diseases.
although a mutation has occurred, the same protein is Currently, genome editing is used in cells and animal
manufactured. models in research labs to understand diseases.

Mutation and Biochemical Evolution Gene Therapy

• we can trace the genetic relationship of different • Viruses can be used to alter somatic cells, where a
species through the variability of their amino acid genetic disease is treated by the introduction of a gene
sequences in different proteins. for example, the blood for a missing protein. This process is called
of all contains hemoglobin, but the amino acid • Gene therapies can work by several mechanisms:
sequences of the hemoglobin are not identical. o Replacing a disease-causing gene with a healthy
• the relationship between different species can also be copy of the gene
established by finding similarities in their mRNA o Inactivating a disease-causing gene that is not
primary structures. because the mutations actually functioning properly
occurred on the original DNA molecule and then were o Introducing a new or modified gene into the body
perpetuated in the progeny by the mutant DNA to help treat a disease
• The most successful form of gene therapy involves the
Silent Mutation gene for adenosine deaminase (ADA), an enzyme
• it is a mutation that changes the DNA but not the amino involved in purine catabolism.
acid incorporated. different codons may require • If this enzyme is missing, dATP builds up in tissues,
alternate versions of the tRNA for a particular amino inhibiting the action of ribonucleotide reductase,
acid. Even though the amino acid incorporated the resulting in a deficiency of the other three
same, the pace with which the ribosome is able to deoxyribonucleoside triphosphates (dNTPs), which are
incorporate the amino acid differs depending on which precursors for DNA synthesis\
codon it is. • Individuals with adenosine deaminase deficiency
• translation kinetics can affect the form of the final develop severe combined immune deficiency (SCID),
protein, if the wild type codon is used, translation the "bubble boy" syndrome, which makes them
proceeds normally and produces the normal susceptible to infection.
conformation of the protein. However, if a silent • The ultimate goal of gene therapy is to take bone
mutation changes the pace of the movement of the marrow cells from affected individuals, introduce the
ribosome, folding difference will result in the creation of gene for ADA into the cells using a virus as a vector,
an abnormal protein conformation and reintroduce the bone marrow cells into the body.
• The first clinical trials for a cure to ADA-SCID were
Central Tumor Suppressor Protein simple enzyme replacement therapies begun in 1982.
• This protein responds to a variety of cellular stresses, The patients in these trials were given injections of
including DNA damage, lack of oxygen (hypoxia), ADA. Later clinical trials sought to correct the gene in
and aberrantly activated oncogenes. The normal mature T cells.
function of p53 protein is to suppress tumor growth. • In 1990, transformed T cells were given to recipients via
When it is mutated or otherwise not present in transfusions. In trials at the National Institutes of Health
sufficient or active form, it is unable to perform this (NIH), two girls, aged 4 and 9 years at the start of
protective function and cancer spreads. The p53 treatment, showed improvement to the extent that they
protein binds to specific sequences of double could attend regular public schools and had no more
stranded DNA. When X-rays or Y-rays damage DNA, than the average number of infections.
an increase in p53 concentration is observed. • Administration of bone marrow stem cells in addition to
• p53 controls the cell cycle by holding it between cell T cells was the next step; clinical trials of this procedure
division and DNA replication and allows the DNA to were undertaken with two infants, aged 4 months and
repair its damages.
 BIOCHEMISTRY REVIEWER (MIDTERMS)

8 months, in 2000. After 10 months, the children were 1. Catabolism (AB = A+B)
healthy and had restored immune systems • The process of breaking down molecules to supply
energy.
Two Types of Delivery Methods in Human Gene Therapy • Those in which molecules are broken down to
1. first, called ex vivo, is the type used to combat SCID. provide the energy needed by cells
Ex vivo means that somatic cells are removed from the 2. Anabolism(A+B = AB)
patient, altered with the gene therapy, and then • Process of synthesizing molecules.
returned to the patient. The most common vectfor this • Building molecules up.
approach is the Maloney murine leukemia virus (MMLV • The same compounds may be synthesized in one
2. Second is in vivo, the virus is used to di- rectly infect part of a cell and broken down in a different part of
the patient's tissues. The most common vector for this the cell.
delivery is the DNA virus adenovirus. A particular vector • These synthesize the compounds needed by cells
can be chosen based on specific receptors on the both simple and complex.
target tissue. Adenovirus has receptors in lung and liver
cells, and it has been used in clinical trials for gene Signaling mechanisms and genetic control play a large part
therapy of cystic fibrosis and ornithine in determining the physiological state of a cell. For example,
transcarbamoylase deficiency. In mice, gene therapy Cancer cell growth, Circadian rhythms and longevity are
has been successful in fighting diabetes. affected by the metabolism of cells.
Epigenetics Circadian Rhythms
• Epigenetic mechanisms involve chromatin remodeling, • Wherein cells are in a more active metabolic state when
where histone proteins can be modified by adding an animal is awake than it is asleep.
methyl, acetyl, or phosphate groups, affecting the
activity of adjacent genes. Cancer Cell Growth
• This can lead to the development of certain disease • When Genes promote which cancer (oncogenes) and
states, such as schizophrenia, immune deficiencies, mutations in genes that suppress cancer (tumor
obesity, diabetes, and heart disease. suppressor genes), can shift metabolic patterns to
• While susceptibility to diseases is often a family trait, those characteristic of tumor cells from those found in
the actual mechanism may require epigenetic changes normal cells.
in a cell's DNA. Epigenetic changes are crucial in • Oncogenes + over Mutation= CANCER
cancer research, but recent studies have focused on • Tumor Suppressor Gene + over Mutation = CANCER
the relationship between epigenetic states and other
• Metabolism = SHIFTED / DISRUPTED
diseases like schizophrenia, immune deficiencies,
obesity, diabetes, and heart disease.
The food we eat consist of many types of compounds
(carbohydrates, lipids, and proteins). All of them can serve
How Cancer and Aging Are Related
as fuels. The body uses a different energy conversion
• Cancer and aging are accompanied by stereotyped pathway for each of these compounds.
changes to the epigenetic landscape, including
progressive loss of DNA methylation over gene-poor Biochemical Pathway
genomic regions. Global hypomethylation arises in • Series of consecutive biochemical reactions.
cells that have undergone many divisions, likely owing • Reactions that enable the chemical energy stored in
to imperfect maintenance. Evidence suggests that our food to be converted to the energy we use every
global hypomethylation represents a “mitotic clock” that minute of our lives.
counts divisions in somatic cells and functions to
• e.g. Glycolysis, Citric Acid Cycle, Electron Transport
restrain aging cells and limit malignant progression. Chain, etc.
Therapies that modulate the pace of methylation loss
or eliminate hypomethylated cells could alleviate aging Catabolic Pathway
associated diseases or cancers. • Where all of the metabolic pathways converged.
• It is a both a phosphoric acid ester and a phosphoric
LESSON 8: BIOENERGETICS: HOW THE BODY acid anhydride.
CONVERTS FOOD TO ENERGY • Function of Catabolic Pathway
Metabolism • Convert the chemical energy in foods to molecules
• The sum total of all the chemical reactions involved in of ATP.
maintaining the dynamic state of the cell. • Allows foods to yield metabolic intermediates
which, body can use for synthesis.
Two Types of Metabolic Reactions
 BIOCHEMISTRY REVIEWER (MIDTERMS)

- Characteristic of the Cristae

Catabolic Pathway (process) o Where enzymes of the oxidative
1. Diverse Catabolic Pathways Funnel Product phosphorylation cycle are localized.
a. The diverse catabolic pathways drop their o The space between the inner and outer
products into the funnel of the common catabolic membranes is the intermembrane space.
pathway, mostly in the form of C2 fragments. They vary during metabolism, possibly
2. Citric Acid Cycle Breaks Molecules Down controlling the rate of reactions.
a. The spinning wheel of the citric acid cycle breaks o Narrow tubular connections to the inner
these molecules down further. membrane. These tubular connections may
3. Carbon Atoms Released as CO2 control the diffusion of metabolites from the
a. The carbon atoms are released in the form of CO2 inside to the intermembrane space.
4. Hydrogen Atoms and Electrons Picked Up. 2. Outer membrane
a. The hydrogen atoms and electrons are picked up - Permeable to small molecules and ions and does
by special compounds such as NAD+ and FAD. not have transporting membrane proteins.
b. NAD+ + Hydrogen &Electron = Reduced NADH 3. Matrix
c. FAD + Hydrogen &Electron = Reduced FADH2 - Inner non-membranous portion of a
5. Electron Transport and Hydrogen Ion Movement mitochondrion.
a. Reduced NADH and FADH2 cascade down into - Where the enzymes of the citric acid cycle are
the stem of the funnel. located.
b. Electrons are transported inside the walls of the
stem
c. H+ ions are expelled to the outside.
6. H+ Ions Drive ATP Production.
a. In their drive to get back, the H+ ions form the
energy carrier ATP.
b. Once back inside, H+ ions combine with the
oxygen that picked up the electrons and produce
water. H+& ATP + Oxygen & Electrons = WATER
(H2O)

The small molecules produced from original large molecules

of food drop into an imaginary collecting funnel that
represents the common catabolic pathway.
At the end of the funnel appears the energy carrier molecule What Are the Principal Compounds of the Common
adenosine triphosphate (ATP). This key molecule plays one Metabolic Pathway?
of the most central roles in body processes. Two Parts of the Catabolic Pathway
1. Citric acid cycle (also called the tricarboxylic acid cycle or
WHAT IS MITOCHONDRIA AND WHAT ROLE DO THEY the Krebs cycle)
PLAY IN METABOLISM? 2. Electron transport chain and phosphorylation
• Mitochondria: Powerhouse of the cell (sing. Which together called the Oxidative phosphorylation
Mitochondrion) pathway.

Parts of the Mitochondria A. Agents for Storage of Energy and Transfer of Phosphate
1. Inner Membrane Groups
- Resistant to the penetration of any ions and of To understand what actually happens in these reactions, we
most uncharged molecules. must first introduce the principal compounds participating in
- Highly corrugated and folded. the common catabolic pathway.
- However, ions and molecules can still get through Three Complex Compounds of Catabolic Pathway:
the membrane they are transported across it by 1. Adenosine monophosphate (AMP)
the numerous protein molecules embedded in it. 2. Adenosine diphosphate (ADP)
a. Cirsta/ Cristae 3. Adenosine triphosphate (ATP)
- Extend into the inner space like the folds of an
accordion. Characteristic of the Three Complex Compound
- Also called the Baffle Model of Mitochondrion. • Heterocyclic amine adenine + sugar D-ribose + B-N-
- Proposed by Romanian-born American cell glycosidic bond = Adenosine
biologist George Palade in 1952.
 BIOCHEMISTRY REVIEWER (MIDTERMS)

o All three of these molecules contain the B. Agents for Transfer of Electrons in Biological Oxidation-
heterocyclic amine adenine and the sugar D- Reduction Reactions
ribose joined together by a B-N-glycosidic bond, • Two other actors in this drama are the coenzymes
forming adenosine. NAD+(nicotinamide adenine dinucleotide) and FAD
• AMP, ADP, and ATP all contain adenosine connected (flavin adenine dinucleotide), both of which contain an
to phosphate groups. ADP core. (The + in NAD+ refers to the positive charge
o ATP contains three phosphates, one phosphoric on the nitrogen.) In NAD+, the operative part of the
ester, and two phosphoric anhydride bonds. coenzyme is the nicotinamide part. In FAD, the
o The only difference between the three molecules operative part is the flavin portion. In both molecules,
is the number of phosphate groups. ADP is the handle by which the apoenzyme binds to the
o In all three molecules of ATP, first phosphate is coenzyme; the other end of the molecule carries out the
bonded to the ribose by a phosphoric ester bond. actual chemical reaction. For example, when NAD+ is
reduced, the nicotin-amide part of the molecule gets
Transfer of Phosphate Groups: ATP AND ADP reduced:
• the transfer of phosphate groups between ATP and • The reduced form of NAD+ is NADH. The same
ADP, and AMP involves adding or removing a reduction happens on the two nitrogens of the flavin
phosphate group, and this transfer represents the portion of FAD:
exchange of energy. • The reduced form of FAD is called FADH2. We view
• ATP and ADP are hydrolyzed to yield phosphate ion NAD+ and FAD cold-zymes as the hydrogen ion and
(inorganic phosphate). electron-transporting molecules.
o Phosphoric Anhydride Bond contains more
chemical energy than ester bond. Thus, they C. Agent for Transfer of Acetyl Groups
release more energy per phosphate group than • The final principal compound in the common catabolic
does AMP. pathway is coenzyme A, which is the acetyl-
o When one phosphate group is hydrolyzed from transporting molecule. Coenzyme A also contains ADP,
each, the following energy yields are obtained: but here the next structural unit is pantothenic acid,
AMP 3.4 kcal/mol; ADP = 7.3 kcal/mol; ATP = 7.3 another B vitamin. Just as ATP can be viewed as an
kcal/mol. ADP molecule to which a -PO3²- group is bonded by a
• ADP and ATP contain high-energy phosphoric high-energy bond, so can acetyl coenzyme A be
anhydride bonds. considered a CoA molecule linked to an acetyl group
o When inorganic phosphate bonds to AMP or ADP, by a high-energy thioester bond, for which the energy
greater amounts of energy are added to the of hydrolysis is 7.51 kcal/mol. The active part of
chemical bond than when it bonds to adenosine. coenzyme A is the mer-captoethylamine. The acetyl
• ATP is a very useful compound for energy storage and group of acetyl coenzyme A is bonded to the SH group:
release.
o ATP releases the most energy and AMP releases What Role Does the Citric Acid Cycle Play in Metabolism?
the least energy when each gives up one • The common catabolism of carbohydrates and lipids
phosphate group. begins when they have been broken down into pieces
o The energy gained in the oxidation of food is of two carbon atoms each. The two-carbon fragments
stored in the form of ATP, although only for a short are the acetyl portions of acetyl coenzyme A. The acetyl
while ATP molecules in the cells normally do not group is now fragmented further in the citric acid cycle.
last longer than about 1 min. • The citric acid cycle serves as the mitochondrial hub for
• ATP are hydrolyzed to ADP and inorganic phosphate to the final steps in carbon skeleton oxidative catabolism
yield energy for carbohydrates, amino acids, and fatty acids. Each
o It drives other processes such as muscle oxidative step, in turn, reduces a coenzyme such as
contraction, nerve signal conduction, and nicotinamide adenine dinucleotide (NADH) or flavin
biosynthesis. As a consequence, ATP is adenine dinucleotide (FADH2).
constantly being formed and decomposed.
• ADP’s turnover rate of ATP is very high. We will now follow the two carbons of the acetyl group
o Estimates suggest that the human body through each step in the citric acid cycle.
manufactures and degrades as much as 40 kg Step 1. Acetyl coenzyme A enters the cycle by combining
(approximately 88 lb) of ATP every day. Even with with a C, compound called oxaloacetate:
these considerations, the body is able to extract • The first thing that happens is the addition of the
only 40 to 60% of the total caloric content of food. CH3 group of the acetyl] CoA to the C = O of the
oxaloacetate, catalyzed by the enzyme citrate
synthase. This event is followed by hydrolysis of the
 BIOCHEMISTRY REVIEWER (MIDTERMS)

thioester to produce the C6 compound citrate ion Step 6. In this step, succinate is oxidized by FAD, which
and CoA. Therefore, Step 1 is a building-up, rather removes two hydrogens to give fumarate (the double bond
than a breaking-down, process. in this molecule is trans):
- This reaction cannot be carried out in the
Step 2. The citrate ion is dehydrated to cis-aconitate, after laboratory, but with the aid of an enzyme catalyst,
which the cis-aconitate is hydrated, but this time to isocitrate the body does it easily. (Recall that FAD and
instead of citrate: FADH, are the oxidized and reduced forms,
respectively, of flavin adenine dinucleotide
THE CITRIC ACID (KREBS)CYCLE
• The citric acid (Krebs) cycle. The numbered steps are Step 7. The fumarate is now hydrated to give the malate ion:
explained in detail in the text. [Hans Krebs (1900-1981),
Nobel laureate in 1953, established the relationships Step 8. In the final step of the cycle, malate is oxidized to
among the different components of the cycle.] give oxaloacetate:
• In citrate, the alcohol is a tertiary alcohol. We learned - Recall that NAD+ and NADH are the oxidized and
that tertiary alcohols cannot be oxidized. The alcohol in reduced forms, respectively, of nicotinamide
isocitrate is a secondary alcohol, which upon oxidation adenine dinucleotide
yields a ketone.
In this process, the two original acetyl carbons of acetyl Co
Step 3. The isocitrate undergoes oxidation and were added to the C4 oxaloacetate to produce a C6 unit,
decarboxylation at the same time: which then lost two carbons in the form of CO2 to produce,
• Decarboxylation The process that leads to the loss at the end of the process, the C4 unit oxalo-acetate. The net
of CO, from a -COOH group effect is that one two-carbon acetyl group enters the cycle
• In oxidizing the secondary alcohol to a ketone, the and two carbon dioxides are given off.
oxidizing agent NAD+ removes two hydrogens. One
of the hydrogens is added to NAD+ to produce How does the citric acid cycle produce energy?
NADH. (Recali that NAD+ and NADH are the We have already learned that one step in the process
oxidized and reduced forms, respectively, of produces a high-energy molecule of GTP. How-ever, most
nicotinamide adenine dinucleotide. of the energy is produced via the other steps that convert
NAD+ to NADH and FAD to FADH2. These reduced
Steps 4 and 5 Next, a complex system removes another coenzymes carry the H+ and electrons that eventually
CO2 once again from the original oxaloacetate portion rather provide the energy for the synthesis of ATP .
than from the acetyl Co portion:
• Recall that NAD+ and NADH are the oxidized and This stepwise degradation and oxidation of acetate in the
reduced forms, respectively, of nicotinamide citric acid cycle results in the most efficient extraction of
adenine dinucleotide energy. Rather than being generated in one burst, the
• We are now down to a C4 compound, succinate. energy is released in small packets that are carried away,
This oxidative decarbox-ylation is more complex step-by-step in the form of NADH and FADH2.
than the first. It occurs in many steps and requires
a number of cofactors. For our purpose, it is The cyclic nature of this acetate degradation has other
sufficient to know that dur ing this second oxidative advantages besides maximizing energy yield:
decarboxylation, a high-energy compound called 1. The citric acid cycle components provide raw materials
guanosine triphosphate (GTP) is also formed. for amino acid synthesis as the need arises. For
• GTP is similar to ATP, except that guanine example, a-ketoglutaric acid is used to synthesize
replaces adenine: Otherwise, the bonds of the glutamic acid.
base to ribose and the phosphates are exactly the 2. The many-component cycle provides an excellent
same as in ATP. The function of TP is also similar method for regulating the speed of catabolic reactions.
to that of ATP- namely, it stores chemical energy
in the form of high-energy phosphoric anhydride The regulation can occur at many different parts of the cycle,
bonds. so that feedback information can be used at many points to
• The energy from the hydrolysis of GTP drives speed up or slow down the process as necessary.
many important biochemical reactions--for
example, the signal transduction in The citric acid cycle is controlled by feedback mechanisms.
neurotransmission When the essential product of this cycle, NADH + H+, and
the end product of the common catabolic pathway, ATP,
accumulate, they inhibit some of the enzymes in the cycle.
Citrate synthase (Step 1), isocitrate dehydrogenase (Step
 BIOCHEMISTRY REVIEWER (MIDTERMS)

2), and a-ketoglutarate dehydrogenase (part of the complex the cells and Na+ does not enter them, special
enzyme system in Step 4 ) are inhibited by ATP and/or by transport proteins in the cell membranes
NADH + H+, This inhibition slows down or shuts off the cycle. constantly pump K+ into and Na+ out of the cells.
Conversely, when the feed material, acetyl CoA, is in C. MECHANICAL ENERGY
abundance, the cycle accelerates. The enzyme isocitrate • The muscle contraction takes place when thick
dehydrogenase (Step 3) is stimulated by ADP and NAD+, and thin filaments slide past each other. The thick
which are the essential reactants from which the end filament is myosin, an ATPase enzyme (that is,
products of the cycle are derived. one that hydrolyzes ATP). The thin filament, actin,
binds strongly to myosin in the contracted state.
What is the Energy Yield Resulting from Electron an H+ However, when ATP binds to myosin, the actin-
Transport ? myosin complex dissociates, and the muscle
• The energy released during electron transport is finally relaxes. When myosin hydrolyzes ATP, it interacts
captured in the chemical energy of ATP molecules. with actin once more, and a new contraction
Therefore, it is instructive to look at the energy yield in occurs.
the universal biochemical currency: the number of ATP D. HEAT ENERGY
molecules. • One molecule of ATP upon hydrolysis to ADP
• Each pair of protons entering a mitochondrion results in yields 7.3 kcal/mol. Some of this energy is
the production of one ATP molecule. released as heat and used to maintain body
• For each NADH molecule, three pairs of protons are temperature. If we estimate that the specific heat
pumped into the intermembrane space in the electron of the body is about the same as that of water, a
transport process. Therefore, for each NADH molecule, person weighing 60 kg would need to hydrolyze
we get three ATP molecules. approximately 99 moles (approximately 50 kg) of
• For each FADH2 molecule, only four protons are ATP to raise the temperature of the body from
pumped out of the mitochondrion. Therefore, only two room temperature, 25°C, to 37°C.
ATP molecules are produced for each.
• For each C2 fragment entering the citric acid cycle, we
obtain three NADH and one FADH2 plus one GTP,
which is equivalent in energy to one ATP. Thus, the
total number of ATP molecules produced per C2
fragment is:
• Each C2 fragment that enters the cycle produces 12
ATP molecules and uses up two O2 molecules. The
total effect of the energy-production chain of reactions
discussed in this chapter (the common catabolic
pathway) is to oxidize one C2 fragment with two
molecules of O2 to produce two molecules of CO2 and
12 molecules of ATP:
• C2 + 2O2 + 12ADP + 12Pi → 12ATP + 2CO2

HOW IS CHEMICAL ENERGY CONVERTED TO OTHER

FORMS OF ENERGY?
A. CONVERSION TO OTHER FORMS OF CHEMICAL
ENERGY
• The activity of many enzymes is controlled and
regulated by phosphorylation. For example, the
enzyme phosphofructokinase-2 (PFK-2), which
catalyzes the formation of fructose-2,6-
bisphosphate, (Chemical Connections 4E). A key
allosteric effector in the glycolytic pathway that
catabolizes glucose (Section 9-2), is activated by
phosphorylation.
B. ELECTRICAL ENERGY
• The body maintains a high concentration of K+
ions inside its cells even though the K+
concentration is low outside the cells. The reverse
is true for Na+. So that K+ does not diffuse out of