Professional Documents
Culture Documents
Carbohydrate
Carbohydrate
Carbohydrate
Metabolism
1
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
5
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.
6
Monosaccharides
White crystalline readily soluble in H2O.
8
D AND L MONOSACCHARIDES
arabinose
The L-isomers of some sugar derivatives that are
9
10
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
Glucose is the most important carbohydrate b/c:
the most abundant monosaccharide in nature
14 01/05/24
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.
15 01/05/24
Examples of Aldoses/ Monosaccharides containing aldehyde functional
group
16
Examples of Ketoses/Monosaccharides containing ketone functional group
17
B. Oligosaccharides
Oligosaccharides contain 2-10 monosaccharide units
disaccharides
Disaccharides
Lactose
18
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.
CH2OH CH2OH
O O
OH H H
H
4 1 O 4 H 1
OH H OH H
H H OH
H OH H OH
-D-Galactose -D-Glucose
20
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
bacteria;
III. it is a mild laxative and helps preventing constipation;
V.the unabsorbed sugar is used as a fuel for large intestinal bacteria that
21
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).
CH2OH CH2OH
O O
H H OH
H
4 1 O 4 H 1
OH H OH H
OH H H
H OH H OH
-D-Glucose -D-Glucose
22
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.
CH2OH
O 1
H H HOH2C O H
H
4 1 2
OH H H OH
OH O CH2OH
H OH OH H
23 -D-Glucose -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
Most of the carbohydrates found in nature occur in the
25
1) Homopolysaccharides
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
26
Homopolysaccharides…
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
27
CH2OH CH2OH
Starch granule O O
H H H H
H H
Amylose 4 1 4 1
OH H OH H
O O O
H OH H OH n
CH2OH CH2OH
O O
Amylopectin H H H H
H H
4 1 4 1
OH H OH H
O O
O
H OH H OH
CH2OH CH2OH CH26 CH2OH
O O O O
H H H H H H H H
H H H H
4 1 4 1 4 1 4 1
OH H OH H OH H OH H
O O O O O
H OH H OH H OH H OH n
28
Homopolysaccharides…
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.
29
CH 2 OH CH 2 OH
H O O
glycogen
H H H
H H
OH H OH H 1
O
OH
O
H OH H OH
CH 2 OH CH 2 OH 6 CH 2 CH 2 OH CH 2 OH
H O H H O H H 5 O H H O H H O H
H H H H H
OH H OH H 4 OH H 1 4 OH H OH H
O O O O OH
OH 2
3
H OH H OH H OH H OH H OH
30
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)
31 that are strong anticancer agents against colorectal cancer.
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
CH 2 OH 6 CH OH CH 2 OH CH 2 OH CH 2 OH
2
O 5 O O H O H O OH
H H H
H H H H H
OH H 1 O 4 OH H 1 O OH H O OH H O OH H
OH H H H
H 2 H
3
H OH H OH H OH H OH H OH
c e llu lo s e
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
van der Waals interactions, that cause cellulose chains
to be straight & rigid, and pack with a crystalline
arrangement in thick bundles - microfibrils.
33
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.
CH2OH CH2OH
O O
H H H H
O 4 1 O 4 1 O
OH H OH H
2 2
H HN C CH3 H HN C CH3
O O n
-D-2-N-Acetyl-glucosamine -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
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
40
41
Structures of the most important GAGs
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
45 extracellular matrix, e.g, collagen.
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
46
blood group cell membrane antigens are important examples.
Carbohydrate Metabolism
47
Carbohydrate metabolism includes:
Digestion of carbohydrates.
Excretion
48
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
49 improve the digestibility of foodstuffs by the enzymes.
ESSENTIAL ORGANS WITH THEIR MAJOR FUNCTIONS
52
Figure 21-14
Digestion of carbohydrates…
following 3 groups:
1) Ready-to-absorb carbohydrates:
The carbohydrates molecule, which do not require digestion &
53
Digestion of carbohydrates…
2) Digestible carbohydrates:
54
Digestion of carbohydrates…
3) Non-digestible carbohydrates:
Dietary fibers
55
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
56 gives maltose, isomaltose and starch dextrins.
Digestion of carbohydrates…
57
Digestion of carbohydrates…
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
58
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
59 border of the intestinal mucosal cells.
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
60 Isomaltose Glucose + Glucose
61
DI
G ES
TI
O N
OF
CA
RB
O HY
DR
AT
ES
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
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:
Function Site
SGLT-1 Absorption of glucose Intestine and renal
by active transport tubules.
(energy is derived from
Na+- K+ pump)
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
2. Storage: in the
detoxication andform of:in the formation of mucopolysaccharide.
enters
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
Fig : The metabolic routes of glucose, the most versatile CHO.
72
Metabolism of Carbohydrate…
73
Glycolysis
74
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).
76
…cont’d 77
…cont’d
78
Energy production of glycolysis:
ATP produced ATP utilized Net energy
79
Differences between aerobic and anaerobic glycolysis:
Aerobic Anaerobic
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
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:
83
Glycolysis From Hydrolysis Products to Common Metabolites
84
2. Oxidative Decarboxylation of Pyruvate
& Krebs' Cycle
After the conversion of glucose into 2 moles of pyruvate
86
Oxidative Decarboxylation of Pyruvate &
Krebs' Cycle…
Krebs' cycle
87
Reactions of the citric acid cycle ( Krebs cycle )
88
Krebs' cycle…
Site: It occurs in the mitochondria where the enzymes
89
Krebs' cycle…
Bioenergetics of Krebs' cycle:
conditions gives:
6/8 ATP at aerobic Glycolysis + 30 ATP at Krebs' cycle
90
Fig: Energy yield for oxidation of a glucose molecule by glycolysis,
pyruvate dehydrogenase and Krebs' cycle.
91
Krebs' cycle…
Biological importance of Krebs' cycle:
◦ Energy production
pyruvate), fat, & ketogenic AAs into CO2 + H2O with generation
of energy
◦ It is a major source of succinyl-CoA which is used for: Synthesis
92
Gluconeogenesis
93
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.
94
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.
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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
96 of citric acid cycle in many tissues.
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.
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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
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Glycolysis and gluconeogenesis
100
Major oxidative pathways of Glucose…
Hexose monophosphate (HMP) shunt
◦ It is an alternative pathway for glucose oxidation that neither
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102
The pentose pathway is a shunt
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.
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Moderate glucose flux Large glucose flux
Pento
Glycolysis Glycolysis Phosp
only Pathw
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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.
intestine
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Metabolism of Carbohydrate…
Glycogen Metabolism
107
Glycogen Metabolism
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Glycogen Metabolism…
Storing carbohydrates is essential for eukaryotes particularly in the
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Glycogen Metabolism…
mobilization as glycogenolysis
Glycogen synthesis & degradation are coordinately
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Glycogenolysis
(Glycogen Breakdown)
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Glycogenolysis
Glycogen phosphorylase is the major enzyme responsible for
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).
Till now, about eleven major types of GSDs have been documented along with
their subtypes.
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Glycogen Storage Diseases (GSD)
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Glycogen Storage Diseases (GSD)
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Control of blood glucose
A very dynamic interplay of different tissues & hormones
118
Control of blood glucose…
Sources & fates of blood glucose
◦ Once in blood, glucose is utilized by all the tissues for their energy as
119
Fig : Sources and fate of blood glucose
120
The role of different tissues in the
regulation of blood glucose
The role of GIT:
injected glucose
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The role of different tissues…
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
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The role of different tissues…
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
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The role of different tissues…
fasting
It lowers blood glucose when its level exceeds the renal
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The role of different hormones in the
regulation of blood glucose
Insulin
Insulin modulates the following MZMs in controlling blood
glucose (hypoglycemic):
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The role of different hormones….
Insulin….
126
The role of different hormones….
Insulin…..
127
The role of different hormones….
Glucagon:
activation of phosphorylase
Stimulation of gluconeogenesis from pyruvate, lactate &
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Variations in Normal Blood Glucose
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
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Diabetes Mellitus
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.
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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
131 by a single gene mutation.
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 Very common association with obesity (67%).
underweight weight).
Severe course and prone to ketoacidosis and Mild course and neither prone to ketoacidosis nor coma.
coma.
Recent weight loss. Weight loss is rare.
Absolute insulin deficiency due to atrophy of Relative insulin deficiency, impaired insulin processing/secretion
β-cells with detectable islet cell antibodies and/or resistance to insulin action. Higher insulin than normal in
and C-peptide is undetectable. early stage or normal level and C-peptide is detectable.
Treated with insulin that is essential for Treated with diet/weight control, exercise, hypoglycemic drugs
survival. and/or insulin, but insulin is not essential for survival at least in
the early stages of the disease.
Prone to develop diabetic complications Yes. Along with several types of cancer.
(retinopathy, nephropathy, neuropathy,
atherosclerotic cardiovascular disease).
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.
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Metabolic changes in diabetes mellitus
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.
Clinical features of 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
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provides amino acids for gluconeogenesis.
Causes of Diabetes Mellitus