Biochem4.pptx

1
Carbohydrates: Chemistry &
Metabolism

 Carbohydrates (sugars) are organic compounds
containing carbon, hydrogen and oxygen with the
general formula CnH2nOn, where, hydrogen and
oxygen are present in 1:2 ratio like that in water, i.e.,
they may be regarded as hydrates of carbons with one
molecule of water for each carbon atom, i.e.,
Cn(H2O)n.
 Carbohydrates are defined as polyhydroxy
aldehydes or ketones and their derivatives or as
substances that yield one of these compounds on
hydrolysis.
Example: Glucose, Lactose, Starch and Glycogen
2

Functions of Carbohydrates
Source of energy; The relative ease with which they can be stored, when
in excess, and mobilized, when needed, makes them excellent energy
storage molecules.
Structural & protective element
Connective tissues of animals
 Cell walls of bacteria (peptidoglycan) & plants (cellulose)
Bacterial and plant cell walls consist of cross- linked carbohydrates that form a
strong structural barrier preventing cell lysis due to osmotic stress.
Other carbohydrate polymers
 Lubricate skeletal joints/synovial fluid & the constituents of vitreous fluids.
 Recognition & adhesion b/n cells: modified carbohydrate residues serve as
intercellular signaling moieties when covalently-linked to cell surface
glycoproteins.
Structural components of nucleic acids (RNA ,DNA & other nucleotides)
Metabolic precursors of all other biomolecules: proteins , nucleotides ,
coenzymes, fatty acids..
3

4
All of these functions are made possible by the characteristic
chemical features of carbohydrates, such as the:
Existence of at least one & often two or more asymmetric
centers,
Ability to exist either in linear or ring structures,
Capacity to form polymeric structures via glycosidic
bonds,
Potential to form multiple hydrogen bonds with water or other
molecules in their environment

5
Diseases associated with abnormal carbohydrate metabolism
Includes:
 Diabetes mellitus
 Galactosemia
 Lactose intolerance
 Glycogen storage diseases, etc.

6
Classification of Carbohydrates
They could be grouped into three types:
 Monosaccharides (simple sugars):
 They are simplest form of sugars, which cannot be further
hydrolyzed.
 They represent the building units and hydrolytic end products
of the more complex carbohydrates.
 Oligosaccharides:These are the conjugates of carbohydrates
where 2-10 monosaccharide units are linked to each other.
 Polysaccharides:These are higher polymers of
carbohydrates and contain more than 10 monosaccharide
units per molecule.

Monosaccharides
White crystalline readily soluble in H2O.
They vary from trioses to heptoses (based on number of
carbon).
Can be aldose or ketose type
All except dihydroxyacetone contain at least one asymmetrical
(chiral) carbon (a carbon atom attached to four chemically
different groups) and are, therefore, optically active.
They exist in either of the two conformations, D or L, based on
the position of the OH group on asymmetric carbon furthest from
the carbonyl carbon.
7

 D AND L NOTATIONS
By convention, the letter L is assigned to the structure with
the —OH on the left
The letter D is assigned to the structure with —OH on the
right
8

D AND L MONOSACCHARIDES
 Stereochemistry determined by the asymmetric
center farthest from the carbonyl group
 Most monosaccharides found in living organisms are D
 Some sugars occur naturally in their L-Isomer , e.g., L-
arabinose
 The L-isomers of some sugar derivatives that are
common components of glycoconjugates
9

Important Monosaccharides
D-glyceraldehyde and dihydroxyacetone are aldo- and keto-trioses,
respectively, that are intermediary compounds in carbohydrate and
lipid metabolism.
D-Ribose is the most important pentose obtained from Nucleic acids
hydrolysis, component of RNA, DNA, ATP, GTP etc. and a number
of coenzymes. It is a reducing aldo-sugar synthesized in the body
from glucose.
Glucose (or dextrose) is the blood sugar. Glucose is the building
unit and end product of hydrolysis of starch, dextrin, glycogen,
sucrose, maltose and lactose. All monosaccharides ingested may be
converted into glucose in the body and all can be synthesized
from it.
11

12
Glucose is the most important carbohydrate b/c:
the most abundant monosaccharide in nature
as glucose that the dietary carbohydrate is mainly absorbed;
into the blood stream or into w/c it is converted in the
liver
it is a major fuel of mammalian tissues
it is converted to other carbohydrates having specific
functions such as;
Glycogen  storage
Ribose  nucleic acids
Galactose  lactose of milk & complexes with lipids &
proteins

Cont’d…
Mannose is a subunit in glycoproteins and neuraminic acid.
It is obtained by hydrolysis of the plant mannosans and
gums.
Galactose is a subunit of the milk sugar, lactose. It is also a
constituent of the structure of glycoproteins, glycolipids and
mucopolysaccharides.
Fructose is the sweetest sugar. It is the main sugar in bee's
honey and fruits. It is obtained from inulin and sucrose
hydrolysis. Fructose is called the semen sugar, since it is
present in seminal fluid and is the source of energy for the
spermatozoa.
13

Naming of monosaccharides
1. According to the presence of aldehyde or ketone group:
Aldose Vs ketose
2. According to the number of carbon atoms:
Trioses, tetroses, pentoses, Hexoses, heptoses
3. According to both the presence of aldehyde or ketone groups
and number of carbon atoms:
Aldotrioses Vs ketotrioses, aldohexoses Vs ketohexoses etc.
4. According to positions of hydroxyl groups on asymmetrical
carbon atoms (stereoisomers like D or L configuration,
epimers, anomers..)
2/3/2023
14

Classification of monosaccharides
1. Trioses: monosaccharides containing 3 carbons
a) aldotriose: Glyceraldehyde
b) ketotriose: Dihydroxyacetone
2. Tetroses: monosaccharides containing 4 carbons.
a) aldotetrose: Erythrose
b) ketotetrose: Erythulose: the suffix –ulose is for ketone group
3. Pentoses: monosaccharides containing 5 carbons.
a) aldopentoses: Ribose, arabinose, xylose and lyxose
b) ketopentoses: Ribulose and xylulose
4. Hexoses: monosaccharides containing 6 carbons.
a) aldohexoses: Glucose, mannose and galactose
b) ketohexoses: fructose
5. Heptoses: As sedoheptulose which is formed in the course of glucose
oxidation by pentose phosphate pathway.
2/3/2023
15

Examples of Aldoses/ Monosaccharides containing aldehyde functional
group
16

Examples of Ketoses/Monosaccharides containing ketone functional
group
17

B. Oligosaccharides
18
 Oligosaccharides contain 2-10 monosaccharide units
 The most abundant oligosaccharides found in nature are the
disaccharides
 Disaccharides
 When 2 monosaccharide's are covalently bonded together by
glycosidic linkages a disaccharide is formed
 Glycosidic bond is formed when the -OH group on 1 of the sugars
reacts with the anomeric C on the 2nd sugar
 Biologically important disaccharides: sucrose, maltose, &
Lactose

Reducing disaccharides: contain a free anomeric carbon.
Maltose (malt sugar)
Contains two D-glucose residues (-1→4-glucosidic linkage)
is a reducing & fermentable sugar.
Produced by partial acid or enzymatic (amylase) hydrolysis of dietary
starch and glycogen.
It is hydrolyzed into two glucose molecules by HCl or by the intestine
maltase enzyme.
Isomaltose: it is similar to maltose except that it has an α-1→6-
glucoside linkage
19
-D-Glucose
O
H
OH
H
H
OH
H
OH
CH2OH
H
O
H H
OH
H
OH
H
OH
CH2OH
H
O
1
1 4

4

O
H
OH
H
H
OH
H
OH
CH2OH
H
O
H H
OH
H
OH
H
OH
CH2OH
H
O
1
1 4

4

-D-Glucose
Maltose

20
Lactose (milk sugar): It is formed of -galactose and glucose
molecule linked by -1,4-glycosidic linkage. It has a free
anomeric carbon.
• it is non-fermentable because of the -nature of its glucosidic
linkage. It is hydrolyzed by HCl or by intestine enzyme,
lactase, into galactose and glucose.
-D-Glucose
-D-Galactose
O
OH
H H
H
OH
H
OH
CH2OH
H
O
H H
OH
H
OH
H
OH
CH2OH
H
1
1 4

4

O

Milk Lactose and Baby Food
Lactose is the most suitable sugar as a milk sweetener for baby
feeding because:
I.it has the lowest degree of sweetness that delays loss of the baby
appetite
II.it is non-fermentable and so no gases are produced by the large
intestine bacteria;
III. it is a mild laxative and helps preventing constipation;
IV.it is not an irritant to the stomach and helps preventing vomiting;
V.the unabsorbed sugar is used as a fuel for large intestinal bacteria
that produces some vitamins and,it facilitates absorption of milk
minerals.

Cellobiose: It is composed of a -glucose unit linked to a
glucose molecule by -1,4-glucosidic linkage. It is
produced by partial acid hydrolysis of cellulose. It is non-
fermentable, non-digestible (because humans lack an
enzyme that can hydrolyze the -glycosidic linkage of
cellobiose or cellulose fibers).
22
-D-Glucose
O
H
OH H
H
OH
H
OH
CH2OH
H
O
H OH
H
H
OH
H
OH
CH2OH
H
1
1 4
4

O

-D-Glucose

23
Non-reducing disaccharides
Sucrose: It is the major cane and beet sugar, commonly
named as table sugar. It is formed of -glucose linked to -
fructose by --1,2-glycosidic linkage.
• It is a fermentable but non-reducing sugar.
• when hydrolyzed by the intestinal sucrase enzyme or by
HCl, the produced fructose and glucose mixture.
-D-Glucose
O
H
OH
H
H
OH
H
OH
CH2OH
H
O
HOH2C H
CH2OH
OH
H
OH
H
1 2
4 
1

O
-D-Fructose

Sucrose is not the sweetest sugar
Although used as sweetener in most of the food preparations,
sucrose is not the sweetest of them all. Fructose is almost twice as
sweet as sucrose. With sucrose as a reference (with 100 degree
sweetness), the degree of sweetness of some sugars is as follows:
173 for fructose; 74 for glucose; 32 for maltose and galactose and
16 for lactose.
Diabetes mellitus patients and people on weight reduction protocols
avoid sucrose as sweetener. Most of the artificial sweeteners
commonly known as ‘Sugar Free’ contain aspartame, which is a
dipeptide L-aspartyl-L-phenylalanine methyl ester. Aspartame is also
added to the beverages marketed as ‘low caloric’ or ‘Diet drinks’.
Sucralose is currently the sweetest compound available
commercially and is an amazing nearly 600 times sweeter than
sucrose because of its differential binding properties to taste receptor
proteins on the tongue.
24

C. Polysaccharides
25
 Most of the carbohydrates found in nature occur in the
form of high molecular polymers → polysaccharides
 There are 2 types of polysaccharides
A. Homopolysaccharides: contain only one type of
monosaccharide building blocks
B. Heteropolysaccharides: contain 2 or more different
kinds monosaccharide building blocks

1) Homopolysaccharides
26
 Example of homopolysaccharides: Starch, glycogen, Cellulose
& dextrins
a) Starch
 One of the most important storage polysaccharide in plant
cells
 Abundant in tubers, such as potatoes & in seeds such as
cereals
 Consists of 2 polymeric units made of glucose:
 Amylose & Amylopectin

Homopolysaccharides…
27
 Amylose
 Unbranched form of starch, consists of glucose residues in α -1,4
linkage
 Amylopectin
 Branched form, has about 1 α -1,6 linkage per 30 α -1,4 linkages,
in similar fashion to glycogen except for its lower degree of
branching
 More than half the carbohydrate ingested by human beings
is starch
 Both amylopectin & amylose are rapidly hydrolyzed by α-amylase,
an enzyme secreted by the salivary glands & the pancreas

28
6
O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2
H
O
1
4

4
Amylose
O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2OH
H
O
1
1 4

4
 O
O
O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2OH
H
O
1
1 4

4
 O
O
O
H H
H
OH
H
OH
CH2OH
H
O
1
4
 O
O
H H
H
OH
H
OH
CH2OH
H
O
1
4
 O
1

6
O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2
H
O
1
4

4
Amylopectin
Starch granule O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2OH
H
O
1
1 4

4
 O
O
O
H H
H
OH
H
OH
CH2OH
H
O
H H
H
OH
H
OH
CH2OH
H
O
1
1 4

4
 O
O
O
H H
H
OH
H
OH
CH2OH
H
O
1
4
 O
O
H H
H
OH
H
OH
CH2OH
H
O
1
4
 O
1

n
n
Fig. The structure of Starch.
It is stored in plants as granules (to the right) that are formed of:
the -helical unbranched amylose core (upper panel) &
the highly branched-chain amylopectin shell (the lower panel)

Homopolysaccharides…
29
b) Glycogen
 Main storage polysaccharide of animal cells
 Present in liver & in skeletal muscle
 Like amylopectin glycogen is a branched polysaccharide of D-glucose
units in α - (1,4) linkages, but it is highly branched
 The branches are formed by α-(1,6)-glycosidic bonds, present about
once in 10 units
 This makes glycogen molecule more compact and highly branched than
amylopectin with higher molecular weight.
 Therefore liver cell can store glycogen within a small
space
The branching structure of glycogen helps degrading and
synthesizing it very rapidly, where, several enzymes work
simultaneously.

30
H O
OH
H
OH
H
OH
CH2OH
H
O H
H
OH
H
OH
CH2OH
H
O
H
H H O
O
H
OH
H
OH
CH2
H
H H O
H
OH
H
OH
CH2OH
H
OH
H
H O
O
H
OH
H
OH
CH2OH
H
O
H
O
1 4
6
H O
H
OH
H
OH
CH2OH
H
H H O
H
OH
H
OH
CH2OH
H
H
O
1
OH
3
4
5
2
glycogen

C. Cellulose: It is the major structural plant polysaccharide
occurring in nature.
It forms the skeleton of plant cells and vessels, and, is the
major component of plant fibers.
It is water-insoluble straight chain polymer composed of -
glucose units linked by -1,4-glucosidic linkage.
Although it is indigestible in human, it gives very
important benefits as dietary fibers.
Dietary fibers prevent constipation by increasing peristalsis;
adsorbs endogenous and exogenous toxins, bile acids and
cholesterol and prevents their absorption into the body. This
help lowering blood cholesterol.
Its fermentation by large intestinal bacteria gives some
vitamins and volatile fatty acids (particularly butyric acid)
that are strong anticancer agents against colorectal cancer.
31

Cellulose is the major food for herbivorous animals which
have the cellulose digesting enzyme cellulase. The acid
(HCl) hydrolysis of cellulose results in cellobiose.
Cellulose derivatives, such as cellulose acetate and
nitrocellulose, are used as the stationary phase in
electrophoresis and chromatography.
D. Inulin: It is a fructose polymer present in onions. It is not
metabolizable in human body but has a small molecular
weight and is water soluble. Therefore, its intravenous
injection is used to determine the glomerular filtration
rate of the kidney by the test known as ’Inulin clearance
test’.
32

33
Cellulose, a major constituent of plant cell walls, consists of
long linear chains of glucose with β(1  4) linkages.
Every other glucose is flipped over, due to b linkages.
This promotes intra-chain and inter-chain H-bonds and
cellulose
H O
OH
H
OH
H
OH
CH2OH
H
O
H
OH
H
OH
CH2OH
H
O
H H O
O H
OH
H
OH
CH2OH
H
H O
H
OH
H
OH
CH2OH
H
H
OH
H O
O H
OH
H
OH
CH2OH
H
O
H H H H
1
6
5
4
3
1
2
van der Waals interactions, that cause cellulose chains
to be straight & rigid, and pack with a crystalline
arrangement in thick bundles - microfibrils.

E. Chitin: It is a linear homopolysaccharide that forms the
exoskeleton of insects and is composed of -N-acetyl-
glucosamine units joined by -1,4-glucosidic linkage. The
only chemical difference from cellulose is the replacement
of the OH at C-2 with an acetylated amino group. Similar
to cellulose, chitin cannot be digested by vertebrates and is
probably the second most abundant polysaccharide,
next to cellulose, in nature.
O
H
H
HN
OH
CH2OH
H
1
2
4
O
H
H
HN
H
OH
CH2OH
H
1 O
-D-2-N-Acetyl-glucosamine
n
C CH3
O
4
C CH3
O
2
H
O O
-D-2-N-Acetyl-glucosamine
34 Fig. A short segment of chitin

F. Dextran: is a highly branched bacterial and yeast
polysaccharide made up of - 1,6 linked poly-D-glucose
with -1,3; -1,4; and -1,2 branches. Dental caries/tooth
decay, caused by Streptococcus bacterium growing on the
surface of teeth synthesizes and secretes dextran. The
bacterium contains the dextran-sucrase, a
glucosyltransferase that transfers glucose units from dietary
sucrose to form the complex dextran molecule. The dextran-
sucrase enzyme is specific for sucrose and does not catalyze
the polymerization of free glucose, or glucose from other
disaccharides or polysaccharides. Dextran is used for the
treatment of hypovolumic shock as in cases of hemorrhagic
shock.
35

Therapeutic Applications of Dextran
Dextran forms a colloidal solution in water and is used as a
plasma substitute to restore blood pressure in cases of
hemorrhagic shock. It stays in plasma for a longer time and
retains intravascular water to maintain plasma volume.
Dextran ferrous sulfate is a suitable form for intramuscular
injection of iron for treatment of iron deficiency anemia.
Sodium dextran sulfate is an anticoagulant.
36

Hetero  Different
Polysachharides composed of different type of monosaccaharide
units are known as ‘Hetero-polysaccaharides’.
They have repeating units of two or three monosaccaharide and
generally contain an amino-sugar and a uronic acid.
They are also known as ‘Muco-Polysachharides’.
Functions
 Provide shape & extracellular support for cells & tissues,
 Act as lubricants
 Mediate in the cell-cell interactions.
 Act as biological anti-coagulants and anti-freeze agents
 Immunogenic and serve as targets for detection and development
of vaccines against the bacteria and viruses
 Serve as the receptors for hormones
37

Heteropolysaccharides
They provide protection, shape, extracellular support, or site of
recognition for the cells.
They are of two types:
A. Non-nitrogenous heteropolysaccharides: They do not contain
sugaramines.
Plant gums, mucilages, and Pectins
 Composed of pentoses, hexoses and uronic acids
 Used as emulsifying agents and for the treatment of diarrhea.
Agar
 Composed of the unbranched polymer agarose and the branched
agaropectin.
 Used for supporting material in gel electrophoresis, bacterial
growing culture, for vitamins and drugs packaging capsules.
38

B. Nitrogenous heteropolysaccharides: contain sugar amines.
Proteoglycans, glycoproteins, and glycolipids
Glycosaminoglycans are the structural and functional units of
proteoglycans.
The extracellular matrix in the tissues of multicellular animals
is composed of an interlocking meshwork of
heteropolysaccharides and fibrous proteins such as collagen,
elastin, fibronectin, and laminin.
The heteropolysaccharides, called glycosaminoglycans
(GAGs; also named, mucopolysaccharides), are a family of
linear unbranched polymers composed of repeating
disaccharide units.
The two repeating units are amino sugar (mainly, N-
Acetylglucosamine or N-acetylgalactosamine) and Uronic
acid (mainly, D-glucuronic acid or L-iduronic acid).
39

Due to their ionizable -OH and sulfate groups, GAGs have
more negative charges causing to retain much water and
making them highely an incompressible substance
The major GAGs are:
 Hyaluronic acid
Peptidoglycan
 Chondroitin sulfate
 Dermatan sulfate
 Keratan sulfate
 Heparin
 Heparan sulfate
40

Structures of the most important GAGs
41

Hyaluronic acid: forms clear, highly viscous solutions that
serve as lubricants in the synovial fluid of joints and vitreous
humor of the eye. It is also an essential component of the
extracellular matrix of cartilage and tendons, to which it
contributes tensile strength and elasticity as a result of its
strong interactions with other components of the matrix.
Hyaluronidase, an enzyme secreted by some pathogenic
bacteria, can hydrolyze the glycosidic linkages of hyaluronic
acid, causing tissues more susceptible to bacterial invasion.
Similar enzyme in sperm also hydrolyzes an outer
glycosaminoglycan coat around the ovum, allowing sperm
penetration during fertilization. This enzyme is called
“spreading factor”.
42

 Chondroitin sulfates: are present in cornea of the eye, tendons,
ligaments, bones, cartilage, heart valves and connective tissue
matrix. They form incompressible substances by means of their
ionizable -OH and sulfate groups, creating negative charges
leading to inter- and intra-molecular repulsion.
 Dermatan sulfate: is located in skin, wall of blood vessels and
heart valves.
 Keratan sulfate: is located in cornea, bone, cartilage and a
variety of horny structures formed of dead cells: horn, hair,
hoofs, nails, and claws.
 Heparin: is a water soluble natural anticoagulant made in mast
cells and basophils and released into the blood, where it inhibits
blood clotting.
 Heparan sulfate: is similar to heparin in structure but has less
sulfates and more N-acetylation of the glucosamine. It is
basement membrane and cell surface GAG component.
43

Peptidoglycan
They are linear heteropolymer of alternating β-N-
acetylglucosamine and β-N-acetylmuramic acid residues
linked by β1-4 bonds. Within the bacterial cell wall, they
are cross-linked by short peptides (containing D-amino
acids).
However, the mammalian lysosomal enzyme lysozyme
kills bacteria by hydrolyzing the β1-4 glycosidic bond.
Penicillin and related antibiotics kill bacteria by
preventing synthesis of the cross-links, leaving the cell
wall too weak to resist osmotic lysis.
44

Glycoproteins
Glycoproteins contain covalently linked oligosaccharides that are
smaller but more structurally complex, and therefore more
information-rich, than GAGs.
Can be attached to proteins with one of two configurations:
i) O-linked - carbohydrate bonded to -OH of Ser or Thr
ii) N-linked - carbohydrate linked to –NH2 of Lys or Asn
They are found on the outer face of the plasma membrane, in the
extracellular matrix, and in the blood.
Inside cells they are found in specific organelles such as Golgi
complexes, secretory granules, and lysosomes.
Examples: antibodies, the intrinsic factor important for
absorption of vitamin B12, plasma transport proteins, enzymes
(e.g., the blood clotting cascade), and as structural components
of the extracellular matrix, e.g, collagen.
45

46
Glycolipids/ Lipopolysaccharides
Are carbohydrate-lipid conjugates in which the hydrophilic
head groups are oligosaccharides, which, as in glycoproteins,
act as specific sites for recognition by carbohydrate-binding
proteins.
Bacterial cell wall lipopolysaccharides and the human ABO
blood group cell membrane antigens are important examples.

48
Carbohydrate metabolism includes:
 Digestion of carbohydrates.
 Absorption of digested carbohydrates.
 Utilization of carbohydrates which includes:
 Anabolic pathways: Transforming small molecules into big
molecules, constituting the body structures and machinery. It is energy
requiring, e.g., glycogenesis and gluconeogenesis.
 Catabolic pathways: Breakdown of large molecules into smaller
molecules to produce energy or smaller molecules or reducing
equivalents, e.g., glycolysis, HMPshunt, and Kreb’s cycle.
 Excretion

49
 Food is the basic and essential requirement for man for his
very existence.
 The food we eat consists of carbohydrates, proteins, lipids,
vitamins and minerals.
 The bulk of the food ingested is mostly in a complex
macromolecular form which cannot, as such, be absorbed by
the body.
 Digestion is a process involving the hydrolysis of large and
complex organic molecules of foodstuffs into smaller and
preferably water-soluble molecules which can be easily
absorbed by the gastrointestinal tract for utilization by the
organism.
 Digestion of macromolecules also promotes the absorption of fat
soluble vitamins and certain minerals.
 Cooking of the food, and mastication (in the mouth) significantly
improve the digestibility of foodstuffs by the enzymes.

ESSENTIAL ORGANS WITH THEIR MAJOR FUNCTIONS
50
Organ Major function(s)
Mouth Production of saliva containing α -amylase;
partial digestion of polysaccharides.
Stomach Elaboration of gastric juice with HCI and
Proteases partial digestion of proteins.
Pancreas Release of NaHCO3 and many enzymes required for
intestinal digestion.
Liver Synthesis of bile acids.
Gall bladder Storage of bile
Small intestine Final digestion of foodstuffs, absorption of digested
products
Large intestine Mostly absorption of electrolytes, bacterial utilization of
certain Un absorbed foods.

Introduction to CHO digestion
51
 Carbohydrates are the largest source of dietary calories
for most of the world’s population.
 The major carbohydrates in the diet are polysaccharides:
Starch and glycogen.
 It also contains disaccharides: Sucrose (cane sugar), lactose
(milk sugar) and maltose and in small amounts
monosaccharides like fructose and pentoses.
 The hydrolysis of glycosidic bonds is carried out by a group
of enzymes called glycosidases.
 These enzymes are specific to the bond, structure and
configuration of monosaccharide units.

Figure 21-14
Carbohydrate Digestion:
Breakdown to monosaccharide, which can
be absorbed
52

Digestion of carbohydrates…
53
 The dietary carbohydrates can be divided into the
following 3 groups:
1) Ready-to-absorb carbohydrates:
 The carbohydrates molecule, which do not require digestion &
are absorbed as such
◦ E.g. Monosaccharides glucose, mannose,
galactose, fructose & pentoses

54
2) Digestible carbohydrates:
◦ The carbohydrates that are completely digested into
their respective monosaccharides
◦ These include starch, glycogen, maltose, sucrose, &
lactose (oligosaccharides & polysaccharides)
 Lactose & glycogen are major carbohydrates from animal sources

55
3) Non-digestible carbohydrates:
 There are carbohydrate molecules - dietary fibers - that
cannot be digested in human GIT
 Primarily due to the absence of specific digestive enzymes
Dietary fibers
 Dietary fibers are the indigestible portion of dietary
cereal, seeds, & vegetable carbohydrates that are
plant polysaccharides like:
 Insoluble fibers: Cellulose, hemicellulose, lignin
 Soluble fibers: Gums, mucilages, pectins &
raffinose
 They are required at 19-38 gm/day that increases
with age
1

56
I. Digestion of carbohydrate by salivary α -amylase (ptylin) in
the mouth:
A. This enzyme is produced by salivary glands. Its optimum pH is
6.7
B. It is activated by chloride ions (cl-).
C. It acts on cooked starch and glycogen breaking α 1-4 bonds,
converting them into maltose .
Because both starch and glycogen also contain α-1-6 bonds, the
resulting digest contains isomaltose [a disaccharide in which two
glucose molecules are attached by α -1-6 linkage].
E. Because food remains for a short time in the mouth, digestion of
starch and glycogen may be incomplete and gives a partial
digestion products called: starch dextrins (amylodextrin,
erythrodextrin and achrodextrin).
F. Therefore, digestion of starch and glycogen in the mouth
gives maltose, isomaltose and starch dextrins.

57
 Mastication & digestion
 Mastication of food in the mouth gives time for ptyalin in the
buccal cavity to act on the polysaccharides
 But the carbohydrates in liquids like milk, soup, fruits
& cold drinks escape salivary digestion

58
II . Carbohydrate digestion in the stomach:
◦ Salivary amylase continues to act on starch, glycogen
or dextrins for 2 - 3 min only & becomes ineffective
b/c of the extreme acidic pH of 1 – 2
◦ There is no carbohydrate-splitting enzyme in the
stomach
 However, HCl hydrolyzes polysaccharides &
disaccharides, particularly sucrose into glucose &
fructose

II. ln the stomach: carbohydrate digestion stops temporarily due to
the high acidity which inactivates the salivary - amylase.
III. Digestion of carbohydrate by the pancreatic - amylase in
the small intestine.
A. α-amylase enzyme is produced by pancreas and acts in small
intestine. Its optimum pH is 7.1.
B. It is also activated by chloride ions.
C. It acts on cooked and uncooked starch, hydrolysing them
into maltose and isomaltose.
Final carbohydrate digestion by intestinal enzymes:
 The final digestive processes occur at the small intestine and
include the action of several disaccharidases. These enzymes are
secreted through and remain associated with the brush border of
the intestinal mucosal cells.
59

The disaccharidases include:
1. Lactase (β-galactosidase) which hydrolyses lactose into two molecules of
glucose and galactose:
Lactase
Lactose Glucose + Galactose
2. Maltase ( α-glucosidase), which hydrolyses maltose into two molecules of
glucose:
Maltase
Maltose Glucose + Glucose
3. Sucrose (α-fructofuranosidase), which hydrolyses sucrose into two molecules
of glucose and fructose:
Sucrase
Sucrose Glucose + Fructose
4. α - dextrinase (oligo-1,6 glucosidase) which hydrolyze (1 ,6) linkage of
isomaltose.
Dextrinase
Isomaltose Glucose + Glucose
60

 Digestion of cellulose:
A. Cellulose contains β(1-4) bonds between glucose molecules.
B. In humans, there is no β (1-4) glucosidase that can digest
such bonds. So cellulose passes as such in stool.
C. Cellulose helps water retention during the passage of food
along the intestine  producing larger and softer feces 
preventing constipation.
62

Absorptions
A.The end products of carbohydrate digestion are
monosaccharides: glucose, galactose and fructose.
 They are absorbed from the jejunum to portal veins to
the liver, where fructose and galactose are
transformed into glucose.
B. Two mechanisms are responsible for absorption of
monosaccharides: active transport (against concentration
gradient i.e. from low to high concentration) and passive
transport (by facilitated diffusion).
63

Mechanisms of absorption:
A. Active transport:
1. Mechanism of active transport:
a) In the cell membrane of the intestinal cells, there is a mobile carrier
protein called sodium dependant glucose transporter (SGLT-1) It
transports glucose to inside the cell using energy.
 The energy is derived from sodium-potassium pump. The transporter has 2
separate sites, one for sodium and the other for glucose.
 It transports them from the intestinal lumen across cell membrane to the
cytoplasm.
 Then both glucose and sodium are released into the cytoplasm allowing the
carrier to return for more transport of glucose and sodium.
64

b) The sodium is transported from high to low concentration (with
concentration gradient) and at the same time causes the carrier to transport
glucose against its concentration gradient.
 The Na+ is expelled outside the cell by sodium pump. Which needs ATP as a
source of energy.
 The reaction is catalyzed by an enzyme called "Adenosine triphosphatase
(ATPase)".
 Active transport is much more faster than passive transport.
c) Insulin increases the number of glucose transporters in tissues containing
insulin receptors e.g. muscles and adipose tissue.
65

B. Passive transport (facilitated diffusion):
 Sugars pass with concentration gradient i.e. from high to
low concentration. It needs no energy. It occurs by means of a
sodium independent facilitative transporter (GLUT -5).
 Fructose and pentoses are absorbed by this mechanism. Glucose
and galactose can also use the same transporter if the
concentration gradient is favorable.
C. There is also sodium – independent transporter (GLUT-2),
that is facilitates transport of sugars out of the cell i.e. to
circulation.
66

Summary of types of functions of most important
glucose transporters:
Site
Function
Intestine and renal
tubules.
Absorption of glucose
by active transport
(energy is derived from
Na+- K+ pump)
SGLT-1
Intestine and sperm
Fructose transport and
to a lesser extent
glucose and galactose.
GLUT - 5
-Intestine and renal
tubule
-β cells of islets-liver
Transport glucose out
of intestinal and renal
cells  circulation
GLUT - 2
67

Defects of carbohydrate digestion and absorption:
A. Lactase deficiency = lactose intolerance:
1. Definition:
a) This is a deficiency of lactase enzyme which digest lactose into
glucose and galactose
b) It may be:
(i) Congenital: which occurs very soon after birth (rare).
(ii) Acquired: which occurs later on in life (common).
2. Effect: The presence of lactose in intestine causes:
a) Increased osmotic pressure: So water will be drawn from the tissue
(causing dehydration) into the large intestine (causing diarrhea).
b) Increased fermentation of lactose by bacteria: Intestinal bacteria
ferment lactose with subsequent production of CO2 gas. This causes
distention(to extend or expand as from internal pressure;to swell) and
abdominal cramps.
c) Treatment: Treatment of this disorder is simply by removing lactose
(milk) from diet.
68

B. Sucrase deficiency:
A rare condition, showing the signs and symptoms of
lactase deficiency. It occurs early in childhood.
C. Monosaccharide malabsorption:
This is a congenital condition in which glucose and
galactose are absorbed only slowly due to defect in the
carrier mechanism. Because fructose is not absorbed
by the carrier system, its absorption is normal.
69

IV. Fate of absorbed sugars:
Monosaccharides (glucose, galactose and fructose)
resulting from carbohydrate digestion are absorbed
and undergo the following:
A. Uptake by tissues (liver):
After absorption the liver takes up sugars, where
galactose and fructose are converted into glucose.
B. Glucose utilization by tissues:
Glucose may undergo one of the following fate:
70

1. Oxidation: through
a) Major pathways (glycolysis and Krebs' cycle) for production of energy.
b) Hexose monophosphate pathway: for production of ribose, deoxyribose
and NADPH + H+
c) Uronic acid pathway, for production of glucuronic acid, which is used in
detoxication and enters in the formation of mucopolysaccharide.
2. Storage: in the form of:
a) Glycogen: glycogenesis.
b) Fat: lipogenesis.
3. Conversion: to substances of biological importance:
a) Ribose, deoxyribose  RNA and DNA.
b) Lactose  milk.
c) Glucosamine, galactosamine  mucopolysaccharides.
d) Glucoronic acid  mucopolysaccharides.
e) Fructose  in semen.
71

72
Fig : The metabolic routes of glucose, the most versatile CHO.
The 3 fates of glucose are; a) storage as glycogen, b) catabolism to
yield energy, &, c) conversion to other sugars & generation of reducing
power.

Metabolism of Carbohydrate…
The catabolic pathways of
glucose
73

I. Glycolysis (Embden Meyerhof Pathway):
Definition:
 glycolysis (from the Greek glykys, meaning “sweet,” and lysis, meaning
“splitting”), a molecule of glucose is degraded in a series of enzyme-
catalyzed reactions to yield two molecules of pyruvate (in the presence
of oxygen) or lactate (in the absence of oxygen).
Site:
cytoplasm of all tissue cells, but it is of physiological importance in:
1. Tissues with no mitochondria: mature RBCs, cornea and lens.
2. Tissues with few mitochondria: Testis, leucocytes, medulla of the
kidney, retina, skin and gastrointestinal tract.
3. Tissues undergo frequent oxygen lack: skeletal muscles especially
during exercise.
75

Steps:
Stages of glycolysis
1. Stage one (the energy requiring stage):
a) One molecule of glucose is converted into two molecules of
glycerosldhyde-3-phosphate.
b) These steps requires 2 molecules of ATP (energy loss)
2. Stage two (the energy producing stage):
a) The 2 molecules of glyceroaldehyde-3-phosphate are converted into
pyruvate (aerobic glycolysis) or lactate (anaerobic glycolysis(.
b) These steps produce ATP molecules (energy production).
Energy (ATP) production of glycolysis:
ATP production = ATP produced - ATP utilized
76

Energy production of glycolysis:
Net energy
ATP utilized
ATP produced
2 ATP
2ATP
From glucose to
glucose -6-p.
From fructose -6-p to
fructose 1,6 p.
4 ATP
(Substrate level
phosphorylation)
2ATP from 1,3 DPG.
2ATP from
phosphoenol
pyruvate
In absence of oxygen
(anaerobic
glycolysis)
6 ATP
Or
8 ATP
2ATP
-From glucose to
glucose -6-p.
From fructose -6-p to
fructose 1,6 p.
4 ATP
(substrate level
phosphorylation)
2ATP from 1,3 BPG.
2ATP from
phosphoenol
pyruvate.
In presence of
oxygen (aerobic
glycolysis)
+ 4ATP or 6ATP
(from oxidation of 2
NADH + H in
mitochondria).
79

Differences between aerobic and anaerobic glycolysis:
Anaerobic
Aerobic
Lactate
Pyruvate
1. End product
2 ATP
6 or 8 ATP
2 .energy
Through Lactate
formation
Through respiration
chain in mitochondria
3. Regeneration of
NAD+
Not available as lactate
is cytoplasmic substrate
Available and 2 Pyruvate
can oxidize to give 30
ATP
4. Availability to
(tricarboxylic acid
cycle) TCA in
mitochondria
80

Substrate level phosphorylation:
This means phosphorylation of ADP to ATP at the reaction itself .in
glycolysis there are 2 examples:
- 1.3 Bisphosphoglycerate + ADP → 3 Phosphoglycerate + ATP
- Phospho-enol pyruvate + ADP → Enolpyruvate + ATP
I. Special features of glycolysis in RBCs:
1. Mature RBCs contain no mitochondria, thus:
a) They depend only upon glycolysis for energy production (=2 ATP).
b) Lactate is always the end product.
2. Glucose uptake by RBCs is independent on insulin hormone.
3. Reduction of met-hemoglobin: Glycolysis produces NADH+H+, which
used for reduction of met-hemoglobin in red cells.
81

Biological importance (functions) of glycolysis:
1. Energy production:
a) anaerobic glycolysis gives 2 ATP.
b) aerobic glycolysis gives 8 ATP.
2. Oxygenation of tissues:
Through formation of 2,3 bisphosphoglycerate, which decreases the affinity of
Hemoglobin to O2.
3. Provides important intermediates:
a) Dihydroxyacetone phosphate: can give glycerol-3-phosphate, which is
used for synthesis of triacylglycerols and phospholipids (lipogenesis).
b) 3- Phosphoglycerate: which can be used for synthesis of amino acid
serine.
c) Pyruvate: which can be used in synthesis of amino acid alanine.
4. Aerobic glycolysis provides the mitochondria with pyruvate, which gives
acetyl CoA Krebs' cycle.
82

Importance of lactate production in anerobic glycolysis:
1. In absence of oxygen, lactate is the end product of glycolysis:
2. In absence of oxygen, NADH + H+ is not oxidized by the
respiratory chain.
3. The conversion of pyruvate to lactate is the mechanism for
regeneration of NAD+.
4. This helps continuity of glycolysis, as the generated NAD+ will be
used once more for oxidation of another glucose molecule.
Glucose  Pyruvate  Lactate
83

Glycolysis From Hydrolysis Products to Common Metabolites
84

2. Oxidative Decarboxylation of
Pyruvate & Krebs' Cycle
85
 After the conversion of glucose into 2 moles of pyruvate
through the cytoplasmic aerobic steps of glycolysis,
pyruvate is transported to mitochondria to be
oxidatively decarboxylated into acetyl-CoA
 The reaction is catalyzed by the pyruvate
dehydrogenase enzyme complex in the state of
energy demand
 In tissues with high-energy content, pyruvate is
directed into the synthesis of glucose

Oxidative Decarboxylation of Pyruvate
& Krebs' Cycle…
87
 Krebs' cycle
 It is the terminal oxidative pathway for most of the biomolecules
 Carbohydrates, lipids as well as proteins pour their partially
oxidized catabolites into the Krebs’ cycle to complete the
catabolism
 It is the cyclic pathway by which active acetyl-CoA produced
from pyruvate, ketogenic AAs or oxidation of FAs & ethanol is
completely oxidized into CO2, with electron-containing H
transfer to FADH2 & NADH.H+

Reactions of the citric acid cycle ( Krebs cycle )
88

Krebs' cycle…
89
 Site: It occurs in the mitochondria where the enzymes
required are located free in the matrix or attached to the
inner mitochondrial membrane
◦ This allows enzymes of the Krebs' cycle to be in
close proximity with the enzymes of the respiratory
chain to facilitate the transfer of reducing equivalents.
 Dysfunctional mitochondria as in cancer cells lead to
accumulation of pyruvate that is converted into lactate

Krebs' cycle…
90
 Bioenergetics of Krebs' cycle:
 For each mole of glucose 2 moles of pyruvate are
produced, which are oxidized by oxidative
decarboxylation followed by TCA cycle
 30 ATP are produced from oxidation of 2 pyruvates to
CO2 & H2O
 Therefore, complete oxidation of one glucose molecule in
aerobic conditions gives:
 6/8 ATP at aerobic Glycolysis + 30 ATP at Krebs'
cycle

91
Fig: Energy yield for oxidation of a glucose molecule by glycolysis,
pyruvate dehydrogenase and Krebs' cycle.

Krebs' cycle…
92
 Biological importance of Krebs' cycle:
◦ Energy production
 Oxidation of acetyl-CoA formed from carbohydrates
(as pyruvate), fat, & ketogenic AAs into CO2 + H2O
with generation of energy
◦ It is a major source of succinyl-CoA which is used
for: Synthesis of Hb & other porphyrins; Ketolysis;
Detoxication by conjugation
◦ It provides intermediates for synthesis of non-
essential AAs, e.g.,: -Ketoglutarate, Oxaloacetate
Fig. A summary of catabolism, showing the central role of the citric acid
cycle. Note that the end products of the catabolism of carbohydrates, lipids, and amino
acids all appear. (PEP is phosphoenolpyruvate; a-KG is a-ketoglutarate; TA is transamination;
→→→ is a multistep pathway.)

94
 It is the formation of glucose from non-carbohydrate
precursors.
 It is particularly important for tissues dependent on blood
glucose such as RBCs and brain.
 The daily glucose requirements of the adult brain is 120 grams,
whereas, the whole body requires 160 grams.
 The body stores are 210 grams (190 grams from liver glycogen and
20 grams in body fluids) enough for a day.
 In a longer period of starvation or during intense exercise, glucose
must be formed from non-carbohydrate sources for survival.
 These non-carbohydrate precursors include lactate, pyruvate,
propionate, glycerol (from diet and lipolysis), and glucogenic
amino acids.

95
 Site:
 Mitochondria and cytosol of Liver and kidney are almost the only
organs able to synthesize glucose from non-carbohydrate sources.
 The liver being the largest organ in the body, exceeding the
combined weights of the kidneys and thus contributes more in
maintaining blood glucose levels by gluconeogenesis.
 Gluconeogenesis is very limited in:
 Skeletal muscle due to deficiency of G-6-Pase
Heart and smooth muscles and adipocytes due to deficiency of
F-1,6-BPase.
 Steps:
 It is essentially the reverse of glycolysis, except at the three
irreversible reactions that different enzyme(s) to be used.

There is always a basal requirement of glucose even if fatty acid oxidation is
supplying enough energy in the tissues.
Gluconeogenesis supplies body cells with glucose after 4-6 hours of last
meal and becomes fully active as stores of glycogen are depleted.
Besides its role in glucose production, gluconeogenesis is the way by which
lactate produced during muscular contraction and in RBCs is detoxicated into
glucose and cycled back to these tissues (Cori's cycle).
Many Tissues Require Glucose
A number of tissues are dependent upon blood glucose as the only source of
energy. These tissues include brain and nervous system, RBCs, kidney
medulla, Lens, cornea and some regions of the retina, white and red
skeletal muscles (under anaerobic conditions), testes and leukocytes. For
all tissues, glucose is required for pentose pathway and glycolipids and
glycoprotein synthesis.
Glucose is especially needed for adipose tissue as a precursor of glycerol
(glycerokinase is absent in adipose) and mammary glands as a precursor of
lactose. Glucose renews oxaloacetate (from pyruvate) and other intermediates of
citric acid cycle in many tissues.
96

Most of the step of glycolysis are reversible and hence can be
reversed for the synthesis of glucose.
The Three irreversible steps of glycolysis that are Irreversible and
hence need to be bye-passed are the reactions catalyzed by:
a) Pyruvate kinase,
b) Phosphofructokinase-1 and
c) Hexokinase.
97

Gluconeogenesis from Lactate and Pyruvate (Cori's Cycle)
 The cycle of reactions that includes glucose conversion to lactate in
muscle and lactate conversion to glucose in liver is called the Cori's cycle
• Cori's Cycle is not limited to the anaerobic oxidation of glucose in active muscles,
but also encompasses the tissues like RBCs and adipocytes.
Prevents lactic acidosis in muscles
Also important in producing ATP
99

Glycolysis and gluconeogenesis
100

Major oxidative pathways of Glucose…
101
 Hexose monophosphate (HMP) shunt
◦ It is an alternative pathway for glucose oxidation that
neither produces ATP nor utilizes it
◦ It produces NADPH.H+ (reducing equivalents), ribose-5-
phosphate, & is the pathway for metabolism of dietary
pentoses.
◦ Intracellular site 7 tissue distribution
 It operates in the cytosol of tissues characterized by
high rate of proliferation & active fatty acid &
steroid synthesis → liver, adipose tissues, lactating

The pentose pathway is a shunt
103
 The pathway begins with the glycolytic intermediate
glucose 6-P.
 It reconnects with glycolysis because two of the end
products of the pentose pathway are glyceraldehyde 3-P
and fructose 6-P; two intermediates further down in the
glycolytic pathway.
 It is for this reason that the pentose pathway is often
referred to as a shunt.

Moderate glucose flux
Glycolysis
only
Large glucose flux
Glycolysis
Pentose
Phosphate
Pathway
104

Metabolic Importance of NADPH
The produced NADPH is utilized for the following metabolic and synthetic
pathways:
•Synthesis, elongation, and desaturation of fatty acids.
•Synthesis of cholesterol and other steroids.
•Synthesis of sphingosine and cerebrosides.
•Synthesis of non-essential amino acids, e.g., glutamate and tyrosine from
phenylalanine.
•Regeneration of reduced glutathione.
•Metabolic hydroxylation of endogenous metabolites and xenobiotics with Cyt-
P450.
•In the reversible UDP-glucose dehydrogenase reaction.
•Coenzyme for methemoglobin reductase.
•NADPH oxidase to produce O2- in phagocytic cells.
•Reversible production of NADH.H+ by NADPH.H+/NAD transhydrogenase that
could be used for energy production.
•Synthesis of fructose from glucose.
•Conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide
reductase.
•Synthesis of neurotransmitters.
105

Major oxidative pathways of Glucose…
106
 Uronic acid pathway
 It is another minor alternative pathway for glucose
oxidation by which glucuronic acid, ascorbic acid
& pentoses are synthesized.
 It is a major fate for UDP-glucose(uridine diphosphate
glucose) that neither requires nor generates ATP
 Glucuronic acid could also be acquired from the
digestive product of dietary mucopolysaccharides
 It occurs in cytosol of many tissues, esp. liver, kidney
and intestine

Glycogen Metabolism
107

Glycogen Metabolism
108
 It is the storage form of carbohydrate in animals,
present mainly in liver & muscles.
 Although almost 10% of the liver by wt is composed of
glycogen, its contribution in muscle by wt never exceeds
1%
 Still, owing to the huge total muscle mass, the total
amount of glycogen stored in muscles is much
higher than that in liver

Glycogen Metabolism…
109
 Storing carbohydrates is essential for eukaryotes particularly
in the form of glycogen due to the following advantages:
 Dietary intake of glucose & glucose precursors is
sporadic
 Storage of glucose in the form of fat is not suitable
 Glucose cannot be stored as such within the cells

Glycogen Metabolism…
110
 Synthesis of glycogen is known as
glycogenesis & its mobilization as
glycogenolysis
 Glycogen synthesis & degradation are coordinately
regulated, so that at a time only one of them is
operating, to prevent futile energy wasting cycles

Glycogenolysis
(Glycogen Breakdown)
 The mobilization of glucose from the glycogen stores is
known as glycogenolysis.
 It is the process of glycogen catabolism (or hydrolysis or
breakdown) into glucose that diffuses into blood from the
liver; or into glucose-6-phosphate that is retained for
utilization through glycolysis in the muscles.
111

Glycogen phosphorylase is the major enzyme responsible for
glycogenolysis.
Glycogenolysis
It hydrolyzes the terminal -1,4-glucosidic bond of a linear branch of glycogen
molecule by addition of inorganic phosphate (Pi, i.e., phosphorolysis).
Phosphorylase continues acting on the -1,4-glucosidic linkage of linear
branch and stops working when there are only four glucosyl units remaining
from the branch point (-1,6) due to steric hindrance.
112

Glycogen Storage Diseases (GSD)
Glycogen storage diseases (or glycogenosis) are a group of inherited disorders
characterized by deposition (over-storage) of an abnormal type or quantity of
glycogen, or, failure of storage or mobilization of glycogen into/from the
tissues. They are mainly due to deficiency of one of the enzymes of
glycogenesis or glycogenolysis, phosphofructokinase or lysosomal
glycosidases.
The first clinical description of a patient with glycogen storage disease was
reported by Van Creveld (1928), that of a 7-year old boy who presented with a
markedly enlarged liver, obesity and small genitalia. This was the first
reported patient with GSD III, as proved later enzymatically.
The description of GSD I by von Gierke (1929) came next. Pompe (1932)
described a case of 'idiopathic hypertrophy of the heart, now known to be
GSD II.
Till now, about eleven major types of GSDs have been documented along with
their subtypes.
113

114

Type I (von Gierke’s disease)
The von Gierke’s disease is characterized by the deficiency of glucose-6-phosphatase in the liver cells and in
the intestinal mucosa. The liver and kidney are involved, and hypoglycemia is a major problem. Lipidemia
also occurs and may lead to xanthoma formation. Survival to adulthood, previously rare, is now the usual
situation. Von Gierke's disease occurs at a rate of about 1 in 200,000 people.
Type II (Pompe’s disease)
Glycogen storage disease II, an autosomal recessive disorder, is the prototypic lysosomal storage disease. It
is a fatal disorder characterized by deficiency of lysosomal -1,4- and -1,6-glycosidase (acid maltase),
which act on glycogen to hydrolyze it. Glycogen accumulates in lysosomes of all tissues, mainly skeletal and
cardiac muscle that disrupts the function of the muscle cells causing cardiomegaly, heart failure and death
before age of two in the infantile form.The expected number of individuals born with GSD II has been
estimated to be 1 in 40,000 births.
Type III (Limit Dextrinosis, Cori’s or Forbes' disease)
The deficiency in this disorder concerns glycogen debranching enzyme. Since the branches are not removed
from glycogen, the structure of stored glycogen is abnormal “Limit Dextrin Type” with short and missing
outer chains. The overall incidence of type III GSD in the United States is about 1 in 100,000 live births, it is
unusually frequent among North African Jews in Israel (prevalence 1 in 5,400; carrier prevalence 1 in
35).
Patients have liver involvement manifested by Hepatomegaly and hypoglycemia.
115

Type IV (Andersen’s disease; Amylopectinosis)
The first case of GSD IV was reported by Anderson (1956) as 'familial cirrhosis of the liver with storage of
abnormal glycogen.' Ten years later, the biochemical defect was identified to be the deficiency of the
Glycogen branching enzyme (GBE1). The enzyme deficiency results in tissue accumulation of abnormal
glycogen with fewer branching points and longer outer branches, resembling an amylopectin-like structure,
also known as polyglucosan.
Type V (McArdle’s disease)
McArdle's disease is a relatively benign disorder, except that the patients are at risk of renal failure as a
complication of myoglobinuria. McArdle disease is caused by mutation in the gene encoding muscle
glycogen phosphorylase. The inheritance appears to be autosomal recessive, although some reports of
dominant characteristics have been published. The range of the onset of clinical features is as wide as 4
weeks to 60 years. Mostly the patients with GSD V are advised to avoid heavy exercise. Ingesting sucrose
before exercise would increase the availability of glucose and would, therefore, improve exercise tolerance
in patients with McArdle disease.
Type VI (Hers' disease)
Glycogen Storage Disease VI (Hers’ disease) is also a relatively benign disorder caused by the partial or total
lack of liver glycogen phosphorylase. The disease appears to be inherited through autosomal recessive traits
Liver glycogen phosphorylase enzyme brings about glycogenolysis in liver to contribute to the blood glucose.
The inability of the patients to utilize liver glycogen for maintenance of blood glucose results in moderate
hypoglycemia, which may then trigger oxidation of fatty acids causing ketosis. The clinical picture is one of
mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent Hepatomegaly. Heart and
skeletal muscle are not affected. The prognosis seems to be excellent.
Glycogen Storage Diseases (Cont…)
116

F. Control of blood glucose &
DM
117

Control of blood glucose
118
 A very dynamic interplay of different tissues & hormones
integrates all the glucose consuming & regenerating
MZMs to control blood glucose level & responding
rapidly & efficiently to minute variations in it
 This is due to the devastating consequences of shifts
in blood glucose levels towards hypo- or
hyperglycemia

Control of blood glucose…
119
 Sources & fates of blood glucose
◦ Blood sugar (glucose) is contributed mainly by:
 Dietary CHOs, liver glycogen & gluconeogenesis
◦ Once in blood, glucose is utilized by all the tissues for their
energy as well as for the synthesis of a number of biomolecules
◦ NB: about 40% of the absorbed glucose is used for lipogenesis
◦ Liver glycogen is enough to cover about 8 hrs of fasting,
whereas lactate from muscle glycogen can cover 25 hrs

120
Fig : Sources and fate of blood glucose

The role of different tissues in the
regulation of blood glucose
121
 The role of GIT:
◦ It prevents hyperglycemia (an excess of glucose in
the bloodstream, often associated with diabetes
mellitus.)
after carbohydrate meal by slowing the evacuation of the
stomach
◦ Upon contact with glucose, the intestinal mucosa secretes
certain factors into the blood, which stimulate insulin
secretion

The role of different tissues…
122
 The role of the liver:
◦ Liver cells are freely permeable to glucose, whereas, the
extra-hepatic cells particularly muscles & fat cells are
relatively impermeable & require insulin stimulation
◦ After meal (during hyperglycemia), liver acts to ↓ blood
glucose level by; oxidation of glucose, glycogenesis,
synthesis of non-essential AAs, cholesterol synthesis &
lipogenesis & TAG synthesis into VLDL
◦ During fasting (hypoglycemia), deficiency of glucose in the
bloodstream.
 liver increases blood glucose by glycogenolysis&
gluconeogenesis
◦ The main control is the insulin/glucagon ratio

123
 The role of muscles & adipose tissue:
 After meal, muscles prevent hyperglycemia by
utilizing glucose in glycogenesis, while adipose
tissue utilizes blood glucose in lipogenesis
 Hypoglycemia triggers glycogenolysis in muscles &
lipolysis in adipose
 Muscle glycogenolysis & glycolysis result in the
supply of lactate & AAs for the synthesis of
glucose by liver in response to epinephrine &
glucocorticoids
 Lipolysis in adipose tissue supplies glycerol as a
gluconeogenic substrate in response to glucagon &
epinephrine

124
 The role of kidneys:
 Kidney is a major controlling system of blood glucose
level by reabsorbing glucose secreted into urine
 It adds little glucose into the blood by gluconeogenesis
during fasting
 It lowers blood glucose when its level exceeds the renal
threshold (160-180 mg/dl)

The role of different hormones in the
regulation of blood glucose
125
 Insulin
 Insulin modulates the following MZMs in controlling
blood glucose (hypoglycemic):
Insulin increases glucose uptake by extrahepatic
tissues decrease blood glucose level
 NB: Most tissues (liver, brain, intestine, heart,
RBCs & kidneys) are insulin-independent for this
process

The role of different hormones….
126
 Insulin….
 In liver insulin stimulates glucose oxidation
 It inhibits gluconeogenesis by inhibiting synthesis
 It stimulates glycogenesis by stimulating glycogen
synthase
 It inhibits glycogenolysis by inhibiting glycogen
phosphorylase through lowering of cAMP

127
 Insulin…..
◦ Therefore, the net effect of insulin on carbohydrate
metabolism:
To lower blood glucose by:
◦ Increasing its oxidation in extrahepatic tissues
◦ Promoting its storage in liver as glycogen &
◦ Halting the release of glucose from liver by
inhibiting gluconeogenesis & mobilization of
glucose from glycogen

128
 Glucagon:
 Glucagon is the primary hormone that increases
blood glucose
 It is a hyperglycemic hormone through:
 Stimulation of glycogenolysis by cAMP-
dependent activation of phosphorylase
 Stimulation of gluconeogenesis from pyruvate,
lactate & AAs by stimulating phosphoenol pyruvate
carboxykinase

Variations in Normal Blood Glucose
129
 Normoglycemia:
◦ Normal fasting plasma glucose level (2 or more
hrs after the last meal & up to 14 hrs b/n meals,
post-prandial) is 60-126 mg/dL (ideally less than
100 mg/dL or 5.6 mM/L)
 Hyperglycemia:
◦ It is the rise of blood glucose level above 126
mg/dL
 Hypoglycemia: It is the decrease in blood sugar
level below 40 mg/dL

Diabetes Mellitus
130
 Diabetes Mellitus is a chronic polygenic syndrome with impaired
carbohydrate metabolism.
 Diabetes mellitus and its complications (diabetic ketoacidosis and
nonketotic hyperosmolar syndrome) are the most common disorders of
carbohydrate metabolism.
 The carbohydrate metabolism is impaired due to deficiency or
ineffectiveness of insulin (peripheral insulin resistance) or decreased
insulin/anti-insulin hormone ratio leading to chronic hyperglycemia
and glycosuria (a condition characterized by an excess of sugar in the urine)
along with secondary changes in metabolism of protein, lipids, water and
electrolytes with grave consequences, if not treated.
 Typically, its symptoms include polydypsia (excessive thirst), polyuria
(increased frequency of urination), polyphagia (hunger), glucosuria,
lipemia(the presence in the blood of an abnormally high concentration of
emulsified fat) and risk of developing vascular disease, peripheral
neuropathy, impaired immunity, ketoacidosis and weight loss particularly
in type 1 diabetes mellitus.

Types of Diabetes Mellitus
Primary diabetes is mainly of type I or II
Type 1 diabetes requires insulin for treatment and hence the other name; Insulin
Dependent Diabetes Mellitus (IDDM). It represents <10% of all diabetic
individuals. It is an autoimmune disease in which the body's own immune
system destroys β-cells of the pancreas, rendering it unable to produce insulin.
The disorder is detected at an early age (<15 years) that acquires it the third
name; Early or Juvenile-Onset diabetes. It follows an acute disease which may
present as diabetic ketoacidosis.
Type 2 diabetes represents ~90% of all diabetes cases and presents with
peripheral resistance to the effects of insulin or a defect in insulin
processing/secretion. The disorder, also known as non-insulin dependent
diabetes mellitus (NIDDM) because it does not requires insulin as a treatment
in most of cases. It manifests at a later age (>40 years) that acquires it the third
name; Late or Adult-Onset Adult diabetes and has a slow and silent onset.
Gestational diabetes; and “other types” are very rare and a number of them are
caused by a single gene mutation.
131

Type 1, IDDM, Juvenile Onset Type 2, NIDDM, Maturity Onset
Phenotype Less frequent (~10% of all cases). More frequent (~90%).
Before age 15 and males are more affected Middle age (most commonly >30 years) and females are more
affected.
Abrupt onset. Gradual onset.
Positive autoimmune markers. No autosomal predisposition, but there is a strong genetic
predisposition affecting expression of a number of proteins, e.g.,
pancreatic glucokinase (MODY 2), GLUT-2, glucagon receptor,
glucagon-like protein-1, glucokinase regulatory protein,
hexokinase-1 and peroxisome proliferator-activated receptor γ
(PPARγ).
No association with obesity (normal or
underweight weight).
Very common association with obesity (67%).
Severe course and prone to ketoacidosis and
coma.
Mild course and neither prone to ketoacidosis nor coma.
Recent weight loss. Weight loss is rare.
Absolute insulin deficiency due to atrophy of
β-cells with detectable islet cell antibodies and
C-peptide is undetectable.
Relative insulin deficiency, impaired insulin processing/secretion
and/or resistance to insulin action. Higher insulin than normal in
early stage or normal level and C-peptide is detectable.
Treated with insulin that is essential for
survival.
Treated with diet/weight control, exercise, hypoglycemic drugs
and/or insulin, but insulin is not essential for survival at least in
the early stages of the disease.
Prone to develop diabetic complications
(retinopathy, nephropathy, neuropathy,
atherosclerotic cardiovascular disease).
Yes. Along with several types of cancer.
No response to hypoglycemic drugs. There is an initial response in most patients.
Genotype Increased prevalence in relatives. Increased prevalence in relatives.
Identical twin studies: ≤50% concordance. Identical twin studies: usually above 90% concordance.
132

The major metabolic effects of diabetes (particularly in type 1 diabetes) are:
• Decreased glucose uptake and utilization (low pace of glycolysis).
• Decreased uptake of amino acids.
• Increased gluconeogenesis from amino acids and glycerol.
• Enhanced glycogenolysis.
• Increased lipolysis.
• Ketogenesis.
• Cholesterol synthesis.
• Increased concentration of blood free fatty acids.
Metabolic changes in diabetes mellitus
Glucose accumulates in blood (hyperglycemia) that exceeds the renal
reabsorption limit (renal threshold) and hence is excreted in urine in large
amounts (glucosuria). Glucose is osmotically active and, hence, draws large
amount of water into the plasma (hyperosmosis) causing polyuria that leads to
thirst (polydypsia) and intracellular glucose starvation causes hunger
(polyphagia). Weakness, tiredness, muscle wasting and weight loss occur due to
inability of muscles to take up glucose and tissue protein catabolism that
provides amino acids for gluconeogenesis.
Clinical features of diabetes mellitus
133

Causes of Diabetes Mellitus
•Absolute or relative insufficiency of insulin
• Insufficient secretion,
• Accelerated inactivation of insulin (as in thyrotoxicosis).
• Defective processing of proinsulin into insulin
• Peripheral resistance to insulin due to defects in its receptor and sub-
receptor mediators.
• Increased production of the anti-insulin hormones, as in Cushing's syndrome,
acromegaly, increased glucagon (glucagonoma) and pheochromocytoma, and
stresses such as pregnancy and obesity.
• Genetic autosomal recessive predisposition.
• Autoimmune destruction of pancreatic β-cells, pancreatitis and pancreatic
cancer.
• Viral infection, e.g., mumps and influenza.
• Over-eating, particularly of carbohydrates with under activity (excessive
carbohydrate diet as a cause of diabetes mellitus is debatable, but recent
findings suggest a correlation).
134

Biochem4.pptx

More Related Content

Similar to Biochem4.pptx (20)

More from agent4731 (12)

Recently uploaded (20)

Biochem4.pptx