CHEMISTRY AND METABOLISM

OF CARBOHYDRATES

By: Oman Ph. (MSc)

Department of Medical Biochemistry

School of Medicine, WSU
7/22/2021 By Oman Ph. 1
 Learning Objectives
❖After this lectures, you should be able to:
▪ Define CHOs in chemical terms

▪ Identify structural & functional roles of CHOs

▪ Know the different metabolic path ways of CHOs

▪ Recognize mechanism of diseases associated with impaired

metabolism of CHOs
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 Topics to be discussed (Chemistry, Metabolism)
▪ Review of Chemistry of CHOs
▪ Classification of CHOs
• Digestion and absorption
• Metabolism of Glucose
– Glycolysis
– TCA cycle
– HMP/PPP
– Gluconeogenesis
– Glycogen metabolism
7/22/2021 By Oman Ph. 3
 Introduction
Carbohydrates
• Are polyhydroxy aldehydes or ketones, CHO

H C OH
or substances that yield such compounds
HO C H
on hydrolysis H C OH

H C OH

• Some also contain P, or S CH2OH

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 Some Biological Importance of CHOs
• Energy/storage
• Structural components of free nucleotides; eg: ATP, CTP…
- DNA, RNA and coenzymes
• Metabolic precursors of all other biomolecules
• Structural and protective elements
– Connective tissues of animals
– Cell walls of bacteria & plants
• Other CHO polymers
– Lubricate skeletal joints
• Participate in the cell-cell interaction and recognition
– Glycoconjugates (glycoproteins and glycolipids)
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 Classification of Carbohydrates
▪ Monosaccharides
• Simplest form of CHO, which cannot be further hydrolyzed.
• The building units and hydrolytic end products of the more
complex CHOs
▪ Oligosaccharides
• 2-10 monosaccharide
▪ Polysaccharides
• >10 monosaccharide

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 1. Monosaccharides
• Vary from trioses to Nanose

• Either aldose (-CHO) or a ketose (-C=O) CH2OH

C O
• General formula is Cn(H2O)n , where , n≥ 3
CH2OH
• Contain at least one asymmetrical (chiral) carbon, (except DHA)

• Exist in either of the two conformations (D or L)

• Shows reducing property

• Most have a sweet taste D-Glyceraldehyde

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 Important monosaccharides
I) D-glyceraldehyde and DHA: are aldo and keto-trioses, respectively
– intermediary compounds in carbohydrate and lipid
metabolism.

CH2OH

C O

CH2OH

D-Glyceraldehyde Dihydroxyacetone

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 II) Ribose(D) : is the most
important pentose

– it is a component of
• ATP, RNA (ribose)
• DNA (D-ribose)

– It is a reducing aldo-sugar
synthesized from glucose (HMS)

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III) Glucose (dextrose ): is the grape and blood sugar
– It is fermentable and is a reducing aldo-hexose.

– It is the building unit and end product of hydrolysis of starch,

glycogen, dextrin, sucrose, maltose and lactose.
CHO

– It is the major body sugar; H C OH

HO C H
all monosaccharides ingested
H C OH
may be converted into glucose H C OH
D-Glucose
in the body. CH2OH

– Inborn and acquired impairment of glucose metabolism DM.

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 IV) Galactose:

– It is non-fermentable reducing aldo-sugar

CHO
– a subunit of the milk sugar, lactose H C OH

HO C H
– Inborn errors of its metabolism HO C H
are connected with the disease H C OH
known as galactosemia CH2OH

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V) Mannose: is reducing aldo-sugar VI) Fructose : is reducing keto-hexose
that is a subunit in in glycoproteins – is the sweetest sugar known
and neuraminic acid – It is the main sugar in bee's
honey and fruits
CHO
– It is obtained from inulin and
HO C H sucrose
HO C H
CH2OH
H C OH C O
H C OH HO C H

CH2OH H C OH

H C OH

D-Mannose CH2OH

D-Fructose
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 Chemical Properties of Monosaccharides
A) Susceptibility to oxidation (sugar acids):
➢ Oxidation of the aldehyde and/or the terminal alcoholic
▪ aldehyde (aldonic acid)
▪ terminal alcoholic (uronic acid)
CH2OH COOH
O O
H H H H
H H
OH H OH H
OH OH
OH OH
H OH H OH
-D-Glucose -D-Glucuronic acid
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 Clinical Applications of Sugar Acids
❖ Gluconic Acid and Calcium administration:
▪ Calcium gluconate injection, is used to treat conditions arising from
calcium deficiencies;
➢ hypocalcemic tetany related to;

– hypoparathyroidism (common)
– luck of Vit-D
– rapid growth or pregnancy

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• UDP-glucose, UDP-glucuronic acid in the liver, used for;
a) conjugate with endogenous metabolites such as bilirubin and
steroids to facilitate their excretion

b) conjugate with exogenous toxins to facilitate their

detoxication and excretion

c) participate in the structure of mucopolysaccharides

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• L-Ascorbic acid (vitamin C) in plants and in animals
other than primates and guinea pigs is a biosynthetic
derivative of D-glucuronic acid.

CH2OH COOH
O O
H H H H
H H
OH H OH H
OH OH
OH OH
H OH H OH
-D-Glucose -D-Glucuronic acid
Ascorbic acid (vitamin C)

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 Reducing properties of monosaccharides
▪ All monosacharides and other sugars capable of reducing
cupric ion are called reducing sugars.

▪ The reduction of Cu+2 to Cu+1 state in alkaline medium forms

the basis of Fehling’s and Benedict’s tests for reducing sugar

➢ the routine diagnostic detection of glucose in urine of diabetes

mellitus patients by Benedict’s test
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 B) Susceptibility to reduction (sugar alcohols)
▪ Reduction of the aldehyde or the ketone
– sugar alcohols
Eg; Glyceraldehyde, Glycerol
Glucose , Sorbitol

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 Some important sugar alcohols
➢ Sorbitol
▪ an intermediate in conversion of glucose into fructose in the
seminal vesicles for sperm nutrition
▪ a base in several pharmaceutical preparations
▪ is an abnormal product from the hyperglycemia associated with
DM and its intracellular accumulation cellular damage (cataract).

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▪ Mannitol that is injected IV to
CHO
reduce intracranial HTN; HO C H

HO C H

H C OH

– Meningitis H C OH

CH2OH
– Cerebral edema Mannose
– Thrombosis

▪ has been used for the

assessment of kidney function

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 C) Effects of acids on sugars
• Reaction of monosaccharides with H3PO4 adds a phosphate at C1, C3
or C6 to form sugar phosphates.
• In the living systems
– kinases

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 Sugar Derivatives
I) Deoxy sugars: are monosaccharides with a hydrogen atom replacing
one of its -OH groups.

➢ This replacement may occur at C2, C3 or C6.

❑ 2-deoxyribose (DNA)

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II) Glycosides: are products of reaction between the -OH group of
a monosaccharide with an -OH or -NH2 group from another
compound.

➢ The sugar part , glycan moiety and the non-sugar part, aglycan moiety

➢ Eg: glucose => glucosides

galactose => galactosides

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 Glycosides and Medicine
A) Cardiac glycosides (Digitalis,
Degoxin):
• are compounds containing a
glycoside (sugar and steroids as the
aglycone), used to treat heart failure) .

• All contain steroids as the aglycone,

these include derivatives of digitalis
& strophanthus such as ouabain.

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 Digoxin Mechanism of Action
• Digoxin is a selective inhibitor of the
plasma membrane Na+-K+ pump.

• Ca++ efflux is decreased because the

gradient for Na+ entry is decreased, while
Ca++ influx is increased because the
gradient for Na+ efflux is increased.

• The net result is a rise in the intracellular

Ca++ concentration.

• In response to this rise, the SR of the

digoxin-treated cell sequesters more Ca ++ .
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B) Phlorhizin (plant glycoside) inhibits
glucose reabsorption by the kidney tubules
and causes experimental glucosuria

▪ Competitive inhibitor of SGLT1 and SGLT2

C ) Some antibiotics, such as streptomycin, are glycosides.

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 2. Oligosaccharides
Disaccharides
▪ Contain two MSs joined together by O-glycosidic linkage.

▪ The most common glycosidic linkage is between C1 of one and C4 of

the other MS to form 1→4

▪ The linkage can be /β

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❖ Maltose (malt sugar):
• Consists of an -glucose units (-1,4-glucosidic linkage)
• It is hydrolyzed into two glucose (maltase / HCl )
• It is produced by enzymatic (amylase) hydrolysis of dietary starch and
glycogen
CH2OH
O H
H
H
4 1
OH H
OH
O
CH2OH CH2OH
H OH
H
O H H
O H -D-Glucose CH2 6
H O
4 1 4 H 1 H H
OH H OH H Isomaltose H
OH 4 1
OH  O OH H
H OH H OH
OH OH
-D-Glucose -D-Glucose H OH
Maltose -D-Glucose

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❖Lactose (milk sugar):

➢ It is formed of -galactose and glucose (-1,4-glycosidic linkage).

➢ It is hydrolyzed by lactase (-galactosidase) or by HCl

CH2OH CH2OH
O  O
OH H H
H H
4 1 O 4 1
OH H OH H
H H OH
H OH H OH
-D-Galactose -D-Glucose

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❖Sucrose:
▪ It is the major cane and beet sugar, commonly named as table sugar.
▪ It is formed of -glucose linked to -fructose (--1,2-glycosidic
linkage).
▪ hydrolyzed by the intestinal sucrase enzyme or by HCl, to produce
fructose and glucose.
CH2OH
O 1
H H HOH2C O H
H
4 1   2
OH H H OH
OH O CH2OH
H OH OH H
-D-Glucose -D-Fructose
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 3. Polysaccharides
• These are high molecular weight polymers of monosaccharides and
are the major form of CHOs occurring in nature.

• classified into two categories:

– homopolysaccharides that are composed of one type of D-
monosaccharide or their derivatives.

– heteropolysaccharides that are composed of more than one type of

D-monosaccharides and their derivatives.

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 A) Homopolysaccharides

I. Glycogen

▪ Polymer of glucose molecules

➢ linked through
▪ -1,4 and
▪ -1,6-glucosidic linkages

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II. Cellulose

▪ Consists of long linear chains

of -glucose with -1,4-
glucosidic linkage

▪ a major constituent of plant

cell walls and plant fibers

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❑ Benefits of dietary fibers:
➢ dietary fibers prevents constipation by giving stool its bulkiness and
increasing peristalsis.

➢ The soluble fibers also slow the stomach emptying and attenuate the post-
prandial rise in blood glucose that spares insulin.

➢ Adsorbs toxins (bile acids and cholesterol) and prevents their absorption.
▪ lowering blood cholesterol

➢ its fermentation by large intestinal bacteria gives volatile fatty acids

(particularly, butyric acid) that are strong anticancer agents against
colorectal cancer
▪ These large intestinal bacteria also synthesize some water-soluble vitamins.
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 III. Dextran
• It is a highly branched meshwork glucosan composed of -glucose units
linked by ,1-4, ,1-3 and ,1-6-glucosidic linkages.

❑ Therapeutic Applications of Dextran:

➢ Dextran 70, used to treat hypovolemia

➢ Dextran ferrous sulfate is a suitable form for IM

(Fe++ deficiency anemia)

➢ Sodium dextran sulfate is an anticoagulant

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 B) Heteropolysaccharides
▪ mixture of several types of monosacchrides and/or their derivatives

➢ could be unbranched or branched .

▪ They provide protection, shape, and extracellular support for cells,

tissues, and organs for organisms starting from bacteria to the
extracellular matrix of different tissues.

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• They are of two types:
– non-nitrogenous , that do not contain sugaramines.
Eg. Plant gums, Pectins, Agar...
– nitrogenous, that contain sugaramines.
Eg. Glycoproteins, Glycosaminoglycans

▪ The terminal monosaccharide in the oligosaccharide parts of the

glycoprotein on the surface of RBCs determines blood group (ABO)

▪ Glucosamine derivative is part of many structural polymers, including those

of the bacterial cell wall.
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 Mucopolysaccharidosis
❑ Failure to recycle the mucopolysaccharides due to genetically inherited
deficiency of various lysosomal enzymes results in several serious disorders
known as mucopolysaccharidoses .

➢ MPS are examples of the lysosomal

storage diseases with accumulation
of a specific mucopolysaccharide
within cells.

❖ Clinical Characteristics
•Skeletal deformities
•Mental retardation
•Cardiac dysfunction
•Hepatosplenomegali
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 Metabolism of Carbohydrate

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 Digestion of Carbohydrates
• About 60% of the human diet consists of CHO.

• Most of the CHOs in the food stuffs are complexed with proteins,
lipids or even nucleic acids to form the cellular matrix of the ingested
food.

• The separation and then breakdown of these foodstuffs into simpler

metabolizable forms constitutes the process of digestion

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❖ The dietary CHOs can be divided into three groups:

A) Ready-to-absorb

B) Digestible

C) Non-digestible

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 Absorption Of Carbohydrates

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• The monosaccharides are absorbed through the epithelial cells into
the blood stream and are delivered to the liver by the portal vein,
chiefly in the form of hexoses (glucose, fructose, mannose and
galactose) and as pentose sugars (ribose).

• Monosaccharide's absorbed to the liver is converted into glucose.

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 By Oman Ph. 50
7/22/2021
 Factors affecting rate of absorption
➢ Primarily determined by the time of contact between the food bolus and the
intestinal mucosal cells, thus factors slowing down the movement of bowels
would increase absorption and vice-versa.
A. Hormones
➢ T3 and T4: Na+-K+ ATPase units ; absorption of CHOs.

➢ Aldosterone: Absorption of hexoses is linked with the Na+, therefore in

case of adrenocortical deficiency the absorption is impaired.
Intestinal absorption of CHOs is not influenced by insulin
B. Vitamins
• Deficiency of thiamine, pyridoxine and pantothenic acid leads to diminished
absorption.
By Oman Ph. 51
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 Glycemic Index (GI) of a food
❑ An indication of how rapidly blood Glc levels rise after
consumption of certain types of diet.

❑ The glycemic response to ingested foods depends on:

▪ The GI of the foods

▪ fiber & fat content of the food and

▪ method of preparation of the food

▪ Whole-wheat white bread is the reference CHO with a GI of 100

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 Glucose Transporters

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 Disorders of CHO Digestion and Absorption
Lactose intolerance
▪ is a maldigestion/malabsorption syndrome due to the inability to
digest and/or absorb dietary lactose from non-fermented dairy
products and pharmaceutical preparations
❖ The patient experiences:
▪ abdominal cramps
▪ abdominal bloating (flatulence)
▪ diarrhea and nausea, upon ingesting such food sources

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➢ Can be the result of:
• Primary deficiency of lactase
– An inherited or age-dependent decline of enzyme expression
• Secondary to an injury to the intestinal mucosa
▪ Eg: of intestinal diseases: Colitis, kwashiorkor, gastroenteritis &
excessive alcohol consumption

• The lactose that is not absorbed is

– Converted by colonic bacteria to lactate, butyric acid, CH4, CO2 & H2 gas.

– Osmotic effect of the lactose & lactate in the bowel lumen diarrhea

a breath test will be +ve for H2, and, feces will have an acidic pH and
contain
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By Oman Ph.
59
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❖ Management
• Avoiding milk or
• Tablets like Lactaid, contain lactase

– Lactase-treated milk
– -galactosidase therapy

• True fermented food products such

as yogurt and many cheeses (especially aged ones)
have had their lactose degraded during fermentation.

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 Glycolysis
• Glycolysis is the process of breaking
down glucose into
– 2 Pyruvate or
– 2 Lactate.

• It is employed by all tissues to provide

– energy (ATP) and
– intermediates for other metabolic pathways

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 • It is a unique pathway, since it
can:
– utilize O2 if available
(aerobically), or
– function anaerobically

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 IC site and tissue distribution
• It occurs in the cell cytosol of all tissues of the body
• Glycolysis is especially important in:
– RBCs
– lack of mitochondria
– Cornea, lens & some parts of retina
– limited blood supply & lack of mitochondria
– Kidney (medulla), testicles, leukocytes & white muscle fibers
– relatively few mitochondria & a limited supply of oxygen
– Contracting muscles  oxygen
– Cancer cells  rate of glycolysis is high than normal cells  Why?
– lack of an extensive capillary network & smaller numbers of mitochondria
– Brain & gastrointestinal tract  Bynormally
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 Biological and Metabolic Importance of Glycolysis
• Glucose oxidation to produce ATP
• It provides pyruvic acid needed for Krebs' cycle
• It provides intermediate that link with fat metabolism
• It provides intermediate that link with AA metabolism
eg: G-3-P to serine and pyruvate to alanine and vice versa
• In connection with PPP (pentoses), gluconeogenesis and with
glycogene ; G-6-P
• It produces 2,3-DPG that is important in tissue oxygenation
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 The overall reaction, under aerobic glycolysis
(Glucose→2 Pyruvate)

Glucose + 2 NAD+ + 2 Pi + 2 ADP

2Pyruvate + 2NADH + 2 H+ + 2 ATP +2H2O

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 The overall reaction, under anaerobic glycolysis
(Glucose→2 Lactate)

Glucose + 2 ADP + 2 Pi

2 Lactate + 2 ATP + 2 H2O + 2H+

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 Oxidation of Extra-mitochondrial NADH

Glycerophosphate shuttle

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 Energy yield from glycolysis
❖ Under anaerobic conditions:
– Total ATP invested in the activation phase = 2 ATP
– Total ATP gained = 4 ATP
– Net ATP gained = 2 ATP

❖ Under aerobic conditions:

– Total ATP invested in the activation phase = 2 ATP
– Total ATP gained = 4 ATP
– Net ATP gained = 2 ATP and 2 NADH (5/3 ATP)
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 Lactate formation in muscle
▪ In exercising skeletal muscle, skeletal
NADH production exceeds the muscle

oxidative capacity of the ETC

▪ NADH/NAD+ ratio, favoring

reduction of pyruvate to lactate.

▪ Therefore, during intense exercise, lactate accumulates in muscle,

causing a drop in the intracellular pH, potentially resulting in cramps.

▪ Much of this lactate eventually diffuses into the bloodstream, and can
be used by the liver and kidneyByto
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Oman Ph. glucose 74
 Regulation of Glycolysis
❖ Regulation of glycolysis targets the key regulatory enzymes:
▪ HK/GK
▪ Phosphofructokinase-1, the most important rate-limiting site
▪ Pyruvate-kinase
• The pathway responds to the regulation by:
• metabolic intermediates
Local control; to benefit the cell
• energy status of the cell

• hormones Global control; for the benefit of the whole organism

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 I-Local control

By Oman Ph. 76
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 II- Global control; Hormonal Regulation of Glycolysis

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 Rapaport-Lubering Cycle

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 Pyruvate kinase affects the fetus RBCs Hg affinity

• In the fetus, RBCs contain PK-M2 with higher activity that rapidly
consumes glycolytic intermediates with the result that 1,3-DPG is not
available for conversion into 2,3-DPG.

• The low 2,3-DPG level in fetal RBCs increases hemoglobin affinity for O2
compared to that of maternal erythrocytes

• This enables fetal RBCs to extract O2 from mother's blood.

• At birth, the newborn RBCs express low activity of M-type isoenzyme

causing accumulation of 1,3-DPG that facilitates the synthesis of 2,3-DPG,
which lowers hemoglobin-O2 affinity.
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 Arsenate inhibit energy production by glycolysis
• Arsenate prevent net ATP production
by glycolysis, without inhibiting the
pathway itself.

G3PDHN

PGK

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Erythrocyte Pyruvate Kinase Deficiency Resulting in Hemolytic Anemia

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 Diseases Associated with Impaired Glycolysis

❖ Lactic acidosis: Elevated concentrations of lactate in the plasma.

❖ Accumulation of lactate depletes the blood alkali reserve leading to

hyperlactemia and lactic acidosis (blood pH <7.2)

▪ MI / CHF
▪ Pulmonary embolism
▪ Uncontrolled hemorrhage
▪ Thiamine deficiency disease (Beriberi)
▪ Consumption of large amounts of alcohol
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 Alcohol Metabolism
• In the human body, ethanol is mainly
metabolized (90%) by cytosolar
hepatic NAD-dependent alcohol
dehydrogenases reversibly into
acetaldehyde.

• ~10% of the ingested ethanol is

oxidized through hepatic catalase in
the peroxisome and microsomal
cytp450s system that uses NADPH
and O2 without generating energy.

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• NADH/NAD ratio is the prime
cause of the toxic effects of acute
and chronic alcohol ingestion:
– Lactic acidosis
– Hypoglycemia
• acetyl-CoA
– Fatty liver
– Alcoholic ketoacidosis
• AMP, Purine
– Hyperuricemia

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 Citric acid
Tricarboxylic Acid, TCA
H. Krebs
Krebs
Cycle

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❖Pyruvate
 is at a crossroads in metabolism
 It may be converted in one step to:
▪ Acetyl CoA (PDHC) , TCA cycle or FA
▪ Lactate (LDH)
▪ Alanine (ALT)
▪ Oxaloacetate (PC), Gluconeogenesis

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 Entry of pyruvate into Mitochondria

PDH

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 Pyruvate Dehydrogenase (PDH) Complex
PDH Complex :
 serves as a bridge between glycolysis and the TCA cycle
 Oxidative decarboxylation of pyruvate to acetyl-CoA
 One of several α-ketoacid dehydrogenases;

α-ketoglutarate dehydrogenase
- In the TCA cycle
α-ketoacid dehydrogenases
- Associated with the catabolism of leucine, isoleucine & valine
 Its irreversibility explains in part;
why acetyl-CoA can not yield a net synthesis of glucose?
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 PDH complex functions as a unit consisting of 3 principal enzymes:
▪ Pyruvate decarboxylase /pyruvate dehydrogenase (E1)
▪ Dihydrolipoyl transacetylase (DHLTA; E2)
▪ Dihydrolipoyl dehydrogenase (DHLD; E3)
 Five coenzymes are required for PDH complex activity:
▪ TPP
▪ CoA & lipoamide lipoic acid bound in amide linkage to
protein
▪ FAD & NAD+
 Vitamins required for their synthesis are:
Thiamin, Pantothenic acid, Riboflavin & Niacine
 Deficiencies in any of these vitamins have obvious effects on energy
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metabolism
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Overall Reaction of Oxidative Decarboxylation of Pyruvate to Acetyl-CoA by the PDH Complex

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PDH Complex 94
 Regulation of PDH Complex

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 Arsenate and Mercury
 deficiency of thiamine (Vit-B1 )
 Inhibits the PDH Complex
▪ Energy depletion neural symptom

▪ Different targets of an arsenic poisoning

– Glycolytic pathway
– PDH Complex
– α-KGDH Complex of TCA cycle

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 Regulation of the TCA cycle
pyruvat

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The total yield of ATP from the oxidation of one acetyl-coA
is summarizes as follows:

3NADH 3NAD+ (3*2.5=7.5 ATP)

1FADH2 1FAD (1*1.5=1.5ATP)
1GTA=1ATP
Total =10ATP/acetyle CoA
Or =20ATP/Glucose

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▪ Total energy yield from full oxidation through:
– Glycolysis

– PDH complex

– TCA cycle

– ETC-OP

C6H12O6 + 6O2 + 32/30 GDP + 32/30 Pi 6CO2 + 6H2O + 32/30 ATP

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 28/26

CH O +
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6O2 + 32/30 ADP + 32/30 Pi
By Oman Ph.
6CO2 + 6H2O + 32/30 ATP 101
The total yield of ATP from the oxidation of glucose; Glycolysis and TCA Cycle

7/22/2021 By Oman Ph. 102

 Toxicity of Fluoroacetate - A Suicide Substrate

7/22/2021 By Oman Ph. 103

 Biological Importance of Krebs' Cycle

 Energy production
 It is a major source of succinyl-CoA which is used for:
▪ Synthesis of hemoglobin and other porphyrins
▪ Ketolysis: For activation of ketone bodies

❖It is an amphipathic pathway :

▪ Gluconeogenesis
▪ Transamination and Deamination Particularly in the liver
▪ Lipogenesis

7/22/2021 By Oman Ph. 104

Anaplerotic
Rxn’s of TCA
cycle

7/22/2021 By Oman Ph. 105

 Anaplerotic Reactions

Reaction Tissue(s)/organism(s)

Pyruvate + HCO-3 + ATP  OAA + ADP + Pi [PC] Liver, kidney

PEP + CO2 + GDP  OAA + GTP [PEPCK] Heart, skeletal muscle

Higher plants, yeast,

PEP + HCO-3  OAA + Pi [PEP Carboxylase]
bacteria

Pyruvate + HCO-3 + NAD(P)H  Malate + NAD(P)+ [Malic Enzyme] Widely distributed in

Eukaryotes & Prokaryotes

7/22/2021 By Oman Ph. 106

Pentose Phosphate Pathway (PPP)
or
Hexose Monophosphate Shunt (HMS)
 Introduction
• It is an alternative minor pathway for
glucose oxidation

• It is a cytosolic pathway present in all

cells

• No ATP is directly consumed or produced Glucose

in the cycle Glucose-6-P

▪ The pathway includes:

– three irreversible oxidative reactions
– a series of reversible sugar–P
interconversions

7/22/2021 108
By Oman Ph.
7/22/2021 By Oman Ph. 109
7/22/2021 By Oman Ph. 110
 Regulation of PPP
• The regulated step is G-6-P-DHN

– Strongly inhibited by NADPH

– Insulin upregulates expression of the gene for G-6-P-DHN
– The pathway increases in the well fed state

7/22/2021 By Oman Ph. 111

❑ The NADPH-producing oxidative
portion of the PPP is particularly
important:
– In biosynthesis of FAs (liver,
mammary glands, and adipose)

– Synthesis of steroid hormones

(placenta, ovaries, testes, and
adrenal cortex)

– Reduced glutathione
(erythrocytes)
7/22/2021 By Oman Ph. 112
❖ The non-oxidative reactions of the PPP
occur in all cell types synthesizing
nucleotides and nucleic acids.

➢ Rapidly dividing cells require more

ribose -5-P than NADPH.

▪ Because the reactions are reversible,

they can be entered from glycolytic
intermediates (F-6-P and G-3-P) if
ribose is needed and G6PDHN is
inhibited.
7/22/2021 By Oman Ph. 113
Production of ROS and the body protection mechanism
• ROS are formed from the partial reduction of O2.
• These compounds are formed continuously as by-products of aerobic
metabolism, through reactions with drugs and environmental toxins,
or when the level of antioxidants is diminished, all creating the
condition of oxidative stress.
• The highly reactive oxygen intermediates can cause serious chemical
damage to DNA, proteins, and unsaturated lipids, and can lead to cell
death.
• These ROS have been implicated in a number of pathologic processes,
including reperfusion injury, cancer and inflammatory disease.
7/22/2021 By Oman Ph. 114
 ROS…
• The cell has several protective mechanisms that minimize the
toxic potential of these compounds.
• Reduced glutathione (GSH), present in most cells, can
chemically detoxify H2O2
• This reaction, catalyzed by the selenium-requiring Glutathione
peroxidase, forms oxidized glutathione (GSSG), which no
longer has protective properties.
• The cell regenerates GSH in a reaction catalyzed by
glutathione reductase, using NADPH as a source of reducing
equivalents.
• Thus, NADPH indirectly provides e-s for the reduction of
H2O2
7/22/2021 By Oman Ph. 115
 Role of NADPH for Erythrocyte
• Erythrocytes are totally dependent
on the PPP for their supply of
NADPH
– Used to maintain reducing
GSH.
– Since they do not have an
alternate source for this
essential coenzyme.
• ROS damage macromolecules
(DNA, RNA, and protein) and
ultimately lead to cell death.

7/22/2021 By Oman Ph. 116

Glutathione is a tripeptide composed
of glutamate, cystein, glycine.

Reduced glutathione (GSH)

maintains the normal reduced
state of the cell.

Reduced glutathione (GSH)

7/22/2021 By Oman Ph. 117
• Additional enzymes (SOD and catalase), catalyze the conversion of toxic
oxygen intermediates to harmless products.

7/22/2021 By Oman Ph. 118

• NADPH is also essential for
normal RBC structure and
keeping hemoglobin in Fe++
state.

7/22/2021 By Oman Ph. 119

 Deficiency of G6PD in RBC
• Cells unable to produce NADPH that is essential
for the maintenance of the reduced glutathione
pool.

• The cells most affected are the RBCs, because

they do not have additional sources of NADPH.

• G6PD deficiency is an X-linked genetic disease

characterized by hemolytic anemia.

• Neonatal jaundice (increased production of

unconjugated bilirubin) appearing 1–4 days after
birth.

• Dark or black urine

7/22/2021 By Oman Ph. 120
▪ G6PD deficiency is the most common disease-producing enzyme
abnormality in humans;
– affecting more than 400 million individuals worldwide.

▪ Most G6PD‐deficient individuals are asymptomatic

• Only in combination with certain environmental factors (sulfa antibiotics,

herbicides, antimalarials, fava beans) do clinical manifestations occur.

7/22/2021 By Oman Ph. 121

 Interesting

– The growth Plasmodium falciparum (malaria parasite) fails in G6PD

deficient individuals.

– The relative resistance of the G6PD patients to infection with

Plasmodium falciparum may be due to the rapid turnover of the
weakened RBCs membranes to the degree that these cannot sustain
the parasitic life cycle long enough for productive growth.

• RBCs are the host cell for the parasite.

7/22/2021 By Oman Ph. 122

 Drugs that should be avoided in G6PD deficiency patients
Drug Name Therapeutic Use
Aspirin Antipyretic and antiinflammatory
Dapsone Antimicrobial for treatment of leprosy
Flutamide Antiandrogen for treatment of prostate cancer
Mafenide blue Topical antimicrobial
Methylene Blue Antidote for drug induced methemoglobinemia
Nalidixic acid Antibiotic used for urinary tract infections
Nitrofurantoin Antibiotic used for urinary tract infections
Phenazopyridine Analgesic for treatment of dysuria
Primaquine Antimalarial agent
Rasburicase Adjunct to antineoplastic agents
Sulfacetamide Antibiotic (Ophthalmic and topical preparations)
Sulfamethoxazole Antibiotic used in combinations (Bactrim, Septra)
Sulfanilamide
7/22/2021 Antifungal agent
By Oman Ph. 123
 Role of NADPH for Immune system

▪ NADPH provides the reducing equivalents for phagocytes (Neutrophils) in

the process of eliminating invading microorganisms.

• NADPH oxidase uses O2 and NADPH e- to produce O2-, which, in turn, can
be converted to H2O2 by SOD.

• Genetic deficiencies in NADPH oxidase cause chronic granulomatous

disease (CGD) characterized by severe, persistent infections

7/22/2021 By Oman Ph. 124

7/22/2021 By Oman Ph. 125
❑ NADPH is required for the synthesis of NO
▪ causes vasodilation

▪ acts as a neurotransmitter

▪ prevents platelet aggregation, and

▪ helps mediate macrophage bactericidal

activity

7/22/2021 By Oman Ph. 126

7/22/2021 By Oman Ph. 127
 Fructose Metabolism

• Dietary sources of fructose include; sucrose, honey and fruits, and from the
high-fructose corn syrup

• Absorption of fructose into intestinal mucosa and other types of cells is

carried out by facilitated diffusion using GLUT5 fructose transporter

• Eventually it is converted into glucose, glycogen, TAG (in liver).

7/22/2021 By Oman Ph. 128

 Fructolysis

7/22/2021 By Oman Ph. 129

 Fructose and diabetes
• Fructokinase is not affected by fasting or insulin
– fructose metabolism bypasses PFKI step that is insulin-regulated.

• This explains why fructose disappears from blood of diabetic patients at a

normal rate.

• Thus, fructose seems to be more easily metabolized than glucose in diabetic

patients.

• Therefore, IV fructose infusion is helpful in hospitalized diabetic patients or

in diabetic coma and ketoacidosis.
7/22/2021 By Oman Ph. 130
 Inherited Abnormalities of Fructose Metabolism

7/22/2021 By Oman Ph. 131

 GLUCONEOGENESIS

7/22/2021 By Oman Ph. 132

 Gluconeogenesis
➢ Gluconeogenesis, the synthesis of ‘NEW’ glucose, from non-CHOs.

• Non-CHO sources of glucose:

➢Lactate produced from (RBC & Exercising muscle)
➢Glucogenic amino acids derived from muscle protein
➢Glycerol released from adipose tissue TAG
➢Others  Pyruvate & Propionic acid

7/22/2021 By Oman Ph. 133

• The daily glucose consumption of the adult brain is
approximately 75% (120 -150 g) of the whole body requirements
(160 - 190g).

• The body stores are 210 g (190 g from liver glycogen and 20
grams in body fluids) enough for a day.

• In a longer period of starvation, glucose must be formed from

non-carbohydrate sources for survival.
7/22/2021 By Oman Ph. 134
❖Sources of blood glucose:
 Diet  Glycogenolysis  Gluconeogenesis
▪ Glycogenolysis can be turned on rapidly in response to
➢Hormonal stimulation
▪ Gluconeogenesis is turned on with a slower response
- Reaching maximal activity over a period of hours (at
about 8 hr’s)
- It becomes the primary source of our blood glucose

7/22/2021 By Oman Ph. 135

❖ Tissues distribution

A) Liver (80%)

▪ The major organ contributing to blood glucose

▪ Liver is unique in that it has the capacity to convert 3-C precursors into
glucose

B) Kidney Cortex (20%)

▪ Kidney medulla consumes most of glucose produced by the kidney

cortex.
By Oman Ph. 136
7/22/2021
 Biological Importance of Gluconeogenesis
▪ There is always a basal requirement of glucose
▪ Gluconeogenesis supplies body cells with glucose
➢Becomes fully active as stores of glycogen are depleted
▪ is the way by which NH3 and lactate (muscular contraction &
RBCs) is detoxicated.

7/22/2021 By Oman Ph. 137

❖ Gluconeogenesis requires both a source of:
▪ Energy & Carbons  for formation of glucose
• Energy  provided by metabolism of fatty acids
• Carbon skeletons  provided from three primary sources

7/22/2021 By Oman Ph. 138

 Pathway of Gluconeogenesis

▪ It is essentially the reverse of glycolysis, except

➢At the three irreversible rxn’s that by different enzyme(s) to be
reversed.
➢Seven of the steps in glycolysis are reversible, catalyzed by the same
enzymes used in glycolysis
➢Involving both mitochondrial, cytosolic & ER enzymes
➢Starting point of the pathway will be differ based on its precursors:

7/22/2021 By Oman Ph. 139

❖ Three of the reactions of glycolysis are irreversible and must be
.
circumvented by four alternative reaction

▪ GK G-6-phosphatase

▪ PFKI F-1-6-bis phosphatase

▪ PK PC/PEPCK

7/22/2021 By Oman Ph. 140

7/22/2021 By Oman Ph. 141
7/22/2021 By Oman Ph. 142
 ▪Gluconeogenesis is fairly efficient
➢The liver can make a kilogram of glucose per day by
gluconeogenesis
✓Actually does so in poorly controlled, hyperglycemic diabetic
patients

▪ Gluconeogenesis from pyruvate is also moderately expensive,

✓Requiring a net expenditure of 6 moles of ATP & 2NADH

✓This ATP and NADH is provided by oxidation of fatty acids

By Oman Ph. 143
7/22/2021
❖ Avidin
–A protein in egg whites with a b barrel
structure, tightly binds biotin

–The strong avidin-to-biotin affinity

➢Excess consumption of raw eggs
can cause:
»Fasting hypoglycemic

7/22/2021 By Oman Ph. 144

 ❖Hydrolysis of Glc 6-phosphatase
in to Glucose & Pi

▪ Several ER proteins play a role in the

generation of glucose from glucose 6-
phosphate.
– T1: G-6-P into ER
– T2 : Pi
– T3: glucose

7/22/2021 By Oman Ph. 145

 Gluconeogenesis From Amino acids
❖The source of pyruvate and oxaloacetate is mainly AA

❖Most AAs are glucogenic:

»Alanine is converted into pyruvate by ALT
»Aspartate is converted into oxaloacetate by AST
»Glutamine and Glutamate into α-ketoglutarate by glutamate
dehydrogenase

7/22/2021 By Oman Ph. 146

Interaction between Glucose-Alanine and Cori’s cycle with Gluconeogenesis

7/22/2021 By Oman Ph. 147

 Gluconeogenesis From TAG
▪ Only the glycerol component of TAG
• Acetyl CoA & even C-chain number
FAs:
–Can’t serve as substrates for net
gluconeogenesis
• Odd C-chain number & branched-
chain fatty acids
- Yield propionyl CoA
- Which can serve as a minor
precursor for gluconeogenesis
Propionyl
7/22/2021
CoA methylmalonyl CoA Succinyl CoA
By Oman Ph. 148
❖ Glycolysis & Gluconeogenesis are both spontaneous;

▪If both pathways were simultaneously active in a cell

➢ It would constitute a "futile cycle" that would waste energy
➢ Glycolysis:
Glucose + 2 NAD+ + 2 ADP + 2 Pi

2 pyruvate + 2 NADH + 2 ATP

➢ Gluconeogenesis:
2 pyruvate + 2 NADH + 4 ATP + 2 GTP

Glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi

7/22/2021 By Oman Ph. 149
 Regulation of Gluconeogenesis
▪ Although gluconeogenes is occurs during fasting
➢it is also stimulated:
• During prolonged exercise
• By a high-protein diet
• Under conditions of stress
➢The factors that promote the overall flow of carbon from
pyruvate to glucose include:
• The availability of substrate &
• Changes in the activity or amount of certain key enzymes
7/22/2021 By Oman Ph. 150
 Regulatory Enzymes of Gluconeogenesis in Liver

Enzymes Mechanism (Allosteric Effectors)

PC Activated by acetyl CoA

•Induced by glucagon, epinephrine,

PEPCK glucocorticoids
•Repressed by insulin
Inhibited by F2,6P, AMP
F-1,6-bisphosphatase
Induced during fasting

G-6-phosphatase
7/22/2021 Induced
By Oman Ph. during fasting 151
Effect of Elevated Glucagon
on the IC [Fru 2,6-BP] in the
Liver

7/22/2021 By Oman Ph. 152

 Blood Glucose Homeostasis

• Between meals
– blood Glc is derived primarily from
hepatic glycogen
• During the day
– depending on the frequency of
snacking,
– Glycogenolysis &
– Gluconeogenesis
• Late in the night or in early morning
gluconeogenesis
– becomes the primary source of
7/22/2021 By Oman Ph. 153
blood Glc
 Sources of Blood Glucose in: Fed, Fasting, & Starved States
7/22/2021
•Note that the scale changes
By Oman Ph.
from hours to days. 154
 GLYCOGEN METABOLISM

7/22/2021 By Oman Ph. 155

Introduction
➢ Glycogen:
– A highly branched homopolysaccharide
– Formed of -glucose units linked by:

• 14 glucosidic linkage along the main chain

• 16 glucosidic linkage at the branching point

7/22/2021 By Oman Ph. 156

➢ In humans, glycogen is found primarily in the:
• Liver & skeletal muscle;
• It may represent up to:
– 10% of the weight of liver
– 1% of the weight of muscle

➢ Glycogen is stored in large cytosolic granules;

• Glycogen granules are:
– Complex aggregates of glycogen
– Enzymes that synthesize & degrade it
– machinery for regulating
these enzymes
7/22/2021 By Oman Ph. 157
 Function of Glycogen
➢ In muscle:
• A quick source of energy for anaerobic metabolism
• Can be exhausted in less than an hour during vigorous activity
➢ In Liver:
• Serves as a reservoir of glucose for other tissues;
• When dietary glucose is not available (b/n meals or during a fast)
–Releasing glucose to maintain blood glucose conc.
• Liver glycogen can be depleted in 12 to 24 hr’s

7/22/2021 By Oman Ph. 158

 Glycogenesis (Glycogen Synthesis)
➢The synthesis of glycogen from glucose
➢Very small amount of glycogen synthesis & storage in the CNS
– This is why it is completely dependent on blood glucose
➢ Sources of glucose
• For liver glycogen:
– Blood glucose, Other hexoses, glucose from gluconeogenesis
• For muscle glycogen:
– Blood glucose only

7/22/2021 By Oman Ph. 159

 Steps of Glycogenesis
❑ Gluocse → Gluocse-6-P
• by GK/HK
❑ Activation of Glc-1-P to UDP-Glc
• by UDP-Glc pyrophosphorylase & pyrophosphatase
 Glucose-1-phosphate + UTP → UDP-glucose + Ppi
• by UDP-Glc pyrophosphorylase
 PPi + H2O → 2 Pi
• by pyrophosphatase
❑Transfer of glucose to glycogen primer;  (14) and (16) linkage;
• by Glycogen synthase and branching
7/22/2021 By Oman Ph.
enzyme 160
 How is a New Glycogen Molecule Initiated?
❑ Glycogen primer:
▪ usually a preformed (1→4) polyglucose chain, or branch
having at least eight glucose residues,
▪ Glycogenin
– The 1st step in the synthesis of a new glycogen molecule is the
transfer of a Glc residue from:
» UDP-Glc to the -OH group of serine/Tyrosine194 of glycogenin
» Catalyzed by the intrinsic Glucosyltransferase

7/22/2021 By Oman Ph. 161

➢Glycogenin:
– Initiates glycogen synthesis
– Is also an enzyme that catalyzes attachment of a glucose molecule to one of
its own tyrosine residues.
7/22/2021 By Oman Ph. 162
 Glycogen Synthase
❑ Transfer of the glucose moiety of UDP-glucose to the hydroxyl at C4
of the terminal residue of a glycogen chain

»to form an (1→ 4) glycosidic linkage:

Glycogen(n residues) + UDP-glucose →Glycogen(n +1 residues) + UDP
➢cannot make the (1→6) bonds found at the branch
points of glycogen

7/22/2021 By Oman Ph. 163

 Glycogen Synthase

7/22/2021 By Oman Ph. 164

 Branching Enzyme
• Also called:
• Amylo (1→4) to (1→6) transglycosylase or
• Glycosyl-(4→6)-transferase
• Makes branch points of glycogen
• Catalyzes transfer of a terminal fragment of 6 or 7 Glc residues
» from the none reducing end of a glycogen branch having at least 11
residues
» to the C6-OH group of a Glc residue at a more interior position of the
same or another glycogen chain
• Branch point should be at least 4 residues from the previous branch point
in the same chain
7/22/2021 By Oman Ph. 165
7/22/2021 By Oman Ph.
166
❖Branching of glycogen serves two major roles;
▪ Increased sites for synthesis &degradation,
• Permitting rapid release of glucose 1-phosphate for muscle activity
▪ Enhancing the solubility of the molecule

➢Endurance athletes require a slower, more sustained release of Glc 1-P;

• Formation of branch points in glycogen is slower than the addition of Glc units to a linear
chain.
• Some endurance athletes practice carbohydrate loading:
– Exercise to exhaustion (when muscle glycogen in largely depleted)
– Followed by a high carbohydrate meal,
❖which results in:
✓Rapid glycogen synthesis, with fewer branch points than normal.

7/22/2021 By Oman Ph. 167

 Glycogenolysis (Glycogen Breakdown)
–It is the process of glycogen catabolism (or breakdown) into:
– Glucose  to blood, in the liver Or,
– Glucose-6-phosphate  in the skeletal muscles
– It is Not the reverse of glycogenesis;  it is a separate pathway
– In skeletal muscle and liver,
• Glucose units of the outer branches of glycogen enter;
– Glycolytic pathway or to blood through the action of 4 enzymes:
✓ Glycogen phosphorylase
✓ Debranching enzyme
✓ Phosphoglucomutase and glucose-6-Phosphatase
7/22/2021 By Oman Ph. 168
 Steps of Glycogenolysis
–Sequential removal of terminal glucose residues
– By glycogen phosphorylase
–Debranching
– By Bifunctional debranching enzyme
» Transferase activity Glycosyl (4→4) transferase
» (1→6) glucosidase activity
– Once branches are transferred & the glucosyl residue at C-6 is hydrolyzed
» Glycogen phosphorylase activity can continue
–Glucose 1-phosphate is converted to glucose 6-phosphate
» By Phosphoglucomutase
7/22/2021 By Oman Ph. 169
 CH2OH
H O H
H
OH H
OH OPO32−

H OH
glucose-1-phosphate

➢ Glycogen Phosphorylase:
▪ Phosphorolytic cleavage of the (1→4) glycosidic linkages of glycogen

▪ Releasing glucose-1-phosphate as reaction product

Glycogen(n residues) + Pi → Glycogen (n–1 residues) + Glucose-1-phosphate

7/22/2021 By Oman Ph.
170
 ➢Glycogen Phosphorylase:
▪ Homodimeric enzyme
▪ Subject to allosteric control;
➢Its transitions between
✓ Relaxed (active) &
✓Tense (inactive) conformations

➢A glucose analog, N-acetylglucosamine (GlcNAc):

▪ is adjacent to PLP at the active site in the crystal structure shown above
7/22/2021 By Oman Ph. 171
 ➢A class of drugs developed
• For treating the hyperglycemia of
diabetes:
✓Chloroindole-carboxamides;
▪ Inhibit liver Phosphorylase
allosterically
✓These inhibitors bind at the
dimer interface
▪ Stabilizing the inactive
(tense) conformation

By Oman Ph. 172

7/22/2021
7/22/2021 By Oman Ph.
173
 Debranching enzyme :
▪ By bifunctional enzyme:
 Transferase activity; (1→4) to (1→4) glucantransferase
– Transfers 3 Glc residues from a 4-residue limit branch to the end of
another branch
– Diminishing the limit branch to a single Glc residue
 (1→6) Glucosidase activity:
– Catalyzes hydrolysis of the  (1→6) linkage, yielding free glucose
The major product of glycogen breakdown is;
Glucose-1-phosphate, from Phosphorylase activity

7/22/2021 By Oman Ph. 174

 Glycogen Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-1-P Glucose-6-P Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.

➢Glucose-6-phosphate:
➢ May enter Glycolysis or
➢ Mainly in liver be dephosphorylated for release to the blood
➢ Liver Glucose-6-phosphatase catalyzes the following,
Glc-6-phosphate + H2O → Glucose + Pi
➢ Essential to the liver's role in maintaining blood glucose:
7/22/2021
▪ Most other tissues lackBythis
Oman Ph.
enzyme 175
 Glycogen Synthesis
UTP UDP + 2 Pi
glycogen(n) + glucose-1-P glycogen(n + 1)

Glycogen Phosphorylase Pi

➢Both synthesis & breakdown of glycogen are spontaneous

–If both pathways were active simultaneously in a cell, there would be a
–Futile Cycle
–With cleavage of one ~P bond per cycle (in forming UDP-glucose).
–To prevent such a futile cycle,
–Glycogen Synthase and Glycogen Phosphorylase are
–Reciprocally regulated by:
7/22/2021 •Allosteric effectors & Phosphorylation
By Oman Ph. 176
 Regulation of Glycogenolysis & Glycogenesis
➢The principal enzymes controlling glycogen metabolism:
–Glycogen phosphorylase & Glycogen synthase

–Regulated by:

• Allosteric mechanisms

• Covalent modifications  due to reversible:

– Phosphorylation & dephosphorylation of enzyme protein

» In response to hormone action

7/22/2021 By Oman Ph. 177
❑ Glycogenolysis is activated in response to:
• Both acute & chronic stress
–The stress may be:
• Physiologic  e.g. in response to:
» Increased blood Glc utilization during prolonged exercise
• Pathologic  e.g. as a result of:
» Blood loss
• Psychological  e.g. in response to:
» Acute or chronic threats
178
7/22/2021 By Oman Ph.
 Allosteric mechanisms

7/22/2021 By Oman Ph. 179

 Covalent Modifications; Hormonal Regulation
❑Regulation by covalent
modification (phosphorylation and
dephosphorylation):
▪ Insuline: glycogenesis

▪ Glucagon & Epinephrine: glyogenolysis

7/22/2021 By Oman Ph. 180

7/22/2021 By Oman Ph. 181
7/22/2021 By Oman Ph. 182
 Activation of muscle glycogen phosphorylase during exercise
183
7/22/2021 By Oman Ph.
 Hormones involved in control of Glycogenolysis

Effect on
Hormone Source Initiator
Glycogenolysis

Glucagon pancreatic α-cells Hypoglycemia Rapid activation

Acute stress,
Epinephrine adrenal medulla Rapid activation
Hypoglycemia

Cortisol adrenal cortex Chronic stress Chronic activation

Insulin pancreatic β-cells Hyperglycemia Inhibition

7/22/2021 By Oman Ph. 184
 Regulation of Liver Glycogen Stores

State Regulators Response of Tissue

Blood: Glucagon 
Glycogen degradation 
Fasting Insulin 
Glycogen synthesis 
Tissue: cAMP 

Blood: Glucagon 
Insulin  Glycogen degradation 
Carbohydrate meal Glucose  Glycogen synthesis 
Tissue: cAMP 
Glucose 

Blood: Epinephrine  Glycogen degradation 

Exercise and stress Tissue: cAMP  Glycogen synthesis 
Ca2+ -calmodulin 
7/22/2021 By Oman Ph. 185
 Regulation of Muscle Glycogen Stores

State Regulators Response of Tissue

Glycogen synthesis 
Fasting (rest) Blood: Insulin 
Glucose transport 

Glycogen synthesis 
Carbohydrate meal (rest) Blood: Insulin 
Glucose transport 

Blood: Epinephrine 
Glycogen synthesis 
Tissue: AMP 
Exercise Glycogen degradation 
Ca2+ -calmodulin 
Glycolysis 
cAMP 
7/22/2021 By Oman Ph. 186
 Glycogen Storage Diseases
❖ Glycogen storage disease

• is a generic term to describe a group of inherited disorders

• characterized by deposition of an abnormal type or quantity of

glycogen in the tissues.

–Glycogen storage diseases are genetic enzyme deficiencies.

7/22/2021 By Oman Ph. 187

 A) Type I (von Gierke’s disease)
➢ Deficiency:
✓ G-6-phosphatase (Type Ia)
✓ G-6-P translocase (Type Ib)
▪ G-6-P = high :  GS
 GP
o Accumulation of glycogen=>Hepatomegaly
▪ Low blood glucose= Glucagon => Gluconeogesis end with high amount of G-6-P, but
unable to be converted in to glucose
▪ Renomrgally
➢ Failure: Glycogenolysis and Gluconeogenesis
➢ Sevier fasting hypoglycemia
➢ Dislipdemia
➢ Lactic acidosis
➢ Hyperuricemia => (Gout)
7/22/2021 By Oman Ph. 188
 B) Type IV (Andersen’s disease)
• deficiency of the liver branching enzyme
• accumulation of abnormal glycogen with fewer branching points and
longer outer branches
– Activation Immune system
• Cirrhosis
▪ Liver transplantation seems to be the only successful treatment

7/22/2021 By Oman Ph. 189

 C) Type V (McArdle’s disease)
• partial or total lack of muscle glycogen phosphorylase:

• Glycogen is accumulated in the skeletal muscles in an abnormally

high amount (2.5-4.1%)

• Blood lactate did not increase after exercise

• muscle cramps and damage occurs leading to myoglobinuria during

exercise
7/22/2021 By Oman Ph. 190
7/22/2021 By Oman Ph. 191