METABOLISM OF CARBOHYDRATE

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 Introduction
 The most abundant biomolecules found in living organisms

 Some carbohydrates are covalently linked with a variety of other

molecules like lipids and proteins – glycolipids and glycoproteins
 Many of simpler carbohydrates have empirical formula of;

 Cn (H2O)n, where n ≥ 3

Function of carbohydrates
 The main source of energy for the body

 Storage form of energy

 Starch

 Glycogen
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 Excess carbohydrate is converted to fat
 Component of nucleic acids (DNA and RNA)

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Classification of carbohydrates
 Based on number of simple sugar, carbohydrates are classified as:
Monosaccharaides
 Molecules contain only one sugar groups

 Serves as building blocks of all carbohydrate

Fructose
 Widely present in fruit juice, honey, cane sugar..

 Used by the body as a source energy through glycolysis

Galactose
 Make the lactose of milk sugar

 Changed to glucose in the liver

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 Glucose
 The sugar of the body
 The sugar carried by the blood
 The principal one used by the tissues
 Source; fruit juice
Disaccharides
 When two monosaccharaides are combined together with
elimination of a water molecule forms disaccharides
Sucrose
Lactose
Maltose
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 Oligosaccharides
 When 3-9 monosaccharide's are joined forms oligosaccharides
Polysaccharides
 Contain above 10 simple sugars
 Divided into
 Homopolysaccharides
• Starch and glycogen which only made from glucose

 Heteropolysaccharides
• Glycosaminoglycan
• Glycoproteins

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 Isomerism of monosaccharaides
STEREOISOMERS
.
 Compounds having same structural formula, but differing in
arrangement of the groups around chiral carbon are known as
stereoisomers
 The carbon atom to which four different substituent groups
attached is called a chiral or asymmetric carbon atom

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 The second, third, fourth and fifth carbons of glucose are,
therefore, asymmetric
 Hexoses: glucose, galactose, mannose, etc. – are stereoisomers
of each other
They have same chemical formula C6H12O6

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 a molecule with n chiral centers can have 2n stereoisomers

Glyceraldehyde has 21 = 2

Aldohexoses, with four chiral centers, have 24 = 16

stereoisomers

 When the hydroxyl group on the reference carbon is

on the right, the sugar is the D isomer

on the left, it is the L isomer

 Reference carbon is carbon linked to four different groups and

furthest from carbonyl carbon
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.

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 Reducing sugar: if the anomeric carbon is not attached to any
other group  sugar is a reducing sugar
 Benedicts test identifies reducing sugar having free ketone or
aldehyde functional group
 Benedicts reagent contain
 Cupper Sulphate- Provides Cu2+ ions for reduction to Cu+
 Sodium citrate- Chelating agent
 Sodium carbonate- Provides alkaline pH

 Free aldehyde converts cupric to cuprous ions

 Cuprous ions gives brick red colour to solutions
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 Disaccharides
 Composed of two monosaccharide's linked together by glycosidic
bond
 The most common disaccharides are maltose, sucrose and lactose

Maltose
 Composed of two glucose units connected to each other by
glycosidic bond
 Maltose is a reducing sugar because it has one free anomeric
hydroxyl group

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 Sucrose
 Sucrose or cane sugar or common table sugar is a disaccharide of
glucose and fructose
 Sucrose does not contain free anomeric carbon hydroxyl group
and is non-reducing sugar

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 Lactose
 Lactose is a disaccharide that consists galactose joined to glucose
by a β-(14) glycosidic linkage
 The principal source of lactose is milk
 Lactose is a reducing sugar since it has free anomeric hydroxyl
group on glucose unit

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 GAGs are long, unbranched, heteropolysaccharide chains composed
of a repeating disaccharide unit
– Acidic sugar and amino sugar

 The Amino sugar is galactosamine with acetylated amino group

 The acidic sugar is glucuronic acid with negatively charged

carboxyl group
 Thus GAG are negatively charged in nature

 They are associated with small amount of protein, with 95%

carbohydrate forming proteoglycans
 GAG forms a ground substance called extracellular matrix

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 ECM is complex inter-digitating meshwork of proteins &
polysaccharides secreted by cells into spaces b/n them
 Helps organize cells into tissues

 The slippery properties of mucous secretions and vitreous humor of

the eye is due to presence of GAG

Glycoproteins
 Proteins with carbohydrate chains are attached

 They differ from proteoglycans of GAG by;

– Carbohydrate chains are short in glycoproteins
– Carbohydrates of glycoproteins do not have repeated disaccharides
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 Functions;
– Cell-surface antigenicity (blood group)
– All plasma proteins except albumin are glycoproteins

 The oligosaccharide may be attached to the protein through an N- or

O-glycosidic link
– N-linked sugar chain is attached to amino group of asparagine AA

– In O-linked the sugar is attached to OH-group of serine AA

 O-linked oligosaccharides on the surface of red blood cells help

provide the ABO blood group determinants

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 DIGESTION

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 In the digestive tract, dietary polysaccharides and disaccharides are
converted to monosaccharaides by glycosidase
 The monosaccharaides formed by glycosidases are transported
across the intestinal mucosal cells into the interstitial fluid and
subsequently enter the bloodstream
 Undigested carbohydrates enter the colon, where they may be
fermented by bacteria

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 The digestion of starch begins in the mouth, where chewing mixes
the food with saliva
 Saliva contain Salivary - amylase secreted by salivary glands
 It breaks -(1 4) bonds and convert polysaccharides into;
 Maltose and
 α-dextrin (smaller polysaccharides)

 Because of food remains for short time in the mouth, starch

digestion in the mouth is incomplete
 Since, as soon as food reaches stomach it will acidified
 Acid pH inactivates the action of this salivary amylase

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 Carbohydrate digestion in the small Intestine
 As acidic stomach contents reaches the duodenum, the low pH
stimulates the release of secretin
 Secretin simulates exocrine cells of Pancrease to release
bicarbonates which helps to raise pH
 Neutral pH is optimum for the action of pancreatic amylase

The pancreatic α-amylase

 Produces;

 Maltose, maltotriose and - limit dextrin (oligosaccharides)

 Further hydrolysis is carried out by intestinal brush border enzymes

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 The digestion of the disaccharides and digestion of maltose,
maltotriose and limit dextrins, occurs through disaccharidases
attached to the membrane surface of the brush border (microvilli) of
intestinal epithelial cells

Glucoamylase hydrolyze a-1,4 bonds of limit dextrin

Isomaltase hydrolyze isomaltase formed by Glucoamylase

Lactase hydrolyzes -1,4-bonds of lactose and produces glucose

and galactose
Sucrase converts sucrose into glucose and fructose
Maltase hydrolyze maltose to two molecules of glucose

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 Disorders of Carbohydrate Digestion
Lactose intolerance
 Lactose intolerance is a maldigestion syndrome due to the inability
to digest dietary lactose
 The patient experiences
 abdominal bloating
 abdominal cramps
 diarrhea and
 flatulence upon ingesting such food sources
 The inability to digest lactose could be due to the inherited or age-
dependent decline of lactase expression
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Cholera
 The cholera toxin, Choleragen that binds to receptor on the cell
surface of intestine called GM1 gangliosides
 Choleragen has two subunits called
– β-subunits that binds to GM1 ganglioside
– Catalytic A subunit that enters the cell

 The A subunit catalyzes the covalent modification of a Gαs protein:

 The α-subunit is modified by the attachment of an ADP-ribose

 This modification stabilizes the GTP-bound form of Gαs, trapping

the molecule in its active conformation
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 The active G protein, continuously activates protein kinase A

 PKA then;
– Phosphorylate chloride channel by then opens it
– Phosphorylate Na+-H+ exchanger and then inhibits its activity

 The net result of the phosphorylation is an excessive loss of NaCL

and the loss of large amounts of water into the intestine

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 Absorption
Absorption is takes place by:
Secondary active transport and facilitated transport
Active transport
 Glucose and galactose are absorbed by energy requiring
transporters
o called sodium dependent glucose transporter-1 (SGLT-1)

 Found in cell membrane of intestine

Facilitated absorption and transport

 Only fructose is absorbed by GLUT-5
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 Transport to the blood
Intestinal cells releases glucose in to blood by carrier
mechanism called glucose transporter-2(GLUT-2)

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 Energy for glucose transport
is provided indirectly, by the
active transport of Na+ out
of the cell
1= Na/K -ATPase
2= SGLT-1
3= GLUT-2

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 Glucose (Hexose) transporters
 Transporter proteins located in cell membrane called GLUT
transport hexose from blood stream to cells
GLUT-1 is located on;
 BBB and transport glucose into extracellular cerebrospinal fluid

GLUT-3 located on;

 Neurons
 Have low Km (high affinity) w/c allows neurons access to glucose
even when blood glucose is low

GLUT-1 is also located on;

 RBC
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 GLUT-2
 A high capacity and low affinity transporter
 Present on Liver, Kidney and β-cells of pancreas

GLUT-4 - transports glucose to

 Skeletal and cardiac muscles cells and Adipocytes

Insulin promotes rapid uptake of glucose by increasing number

of GLUT-4 on the cell membrane

GLUT-5 – transports Fructose in to

 Small intestine and
 Spermatozoa

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 Fate of Carbohydrates in Cell

 Glucose is a universal fuel for human cells

 Every cell uses glucose to obtain energy
 In tissues fructose and galactose are converted to intermediate of
glucose so, their fate is parallel to that of glucose
 After glucose is transported into cells, it is phosphorylated by a
hexokinase to form glucose 6-phosphate
 Glucose 6-phosphate can then enter a number of metabolic
pathways
 The three that are common to all cell types are:

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 Glycolysis
– Provide ATP
– Cell lack mitochondria oxidize glucose up to lactate

– Cells have mitochondria oxidize it up to CO 2 and H2O

Glycogen synthesis

Oxidation through hexose mono phosphate shunt to yield

– The reducing power (NADPH)
• For anabolic pathways and to prevent oxidative damage to cells

– Ribose sugar
• Used for the synthesis of nucleotides
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 Living organisms require a continual input of free energy for
three major purposes:
For muscle contraction
The active transport of molecules and ions
The synthesis of macromolecules from simple precursors

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 Glycolysis

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 Glycolysis is one of the principle pathways for generating ATP in
cells and is present in all cell types
 Glycolysis is a reactions in which a molecule of glucose is degraded
to yield two molecules of pyruvate and generation of ATP and
NADH
 From Greek Glykys means sweet/sugar, lysis means splitting
 The central role of glycolysis in fuel metabolism is related to its
ability to generate ATP with, and without, oxygen

 Aerobically
With the presence of oxygen and mitochondria

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 Anaerobically
With the absence of oxygen and mitochondria

 B/c it can run without involvement of O 2 and mitochondria it is called

anaerobic oxidation of glucose
 Glycolysis occurs in the cell cytoplasm of all tissues of the body

 Some cells only depend of glycolysis for ATP source;

 Due to lack of mitochondria;

Red blood cells (RBCs), Cornea, lens and some part of retina

 Due to reduced availability of O 2

Contracting muscles: Due to partial blocking of blood vessels by the

muscular contraction, there is a decrease in oxygen availability

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 Glycolysis occurs in ten steps:

The first five of glycolysis is preparatory (investment) phase

o 2 molecules of ATP are invested
o Glucose is converted into 2 molecules of Glyceraldehyde 3-P

The rest are called pay-off phase

o Chemical energy of glucose is conserved as ATP and NADH

Phosphorylation of glucose
 Glucose metabolism begins by phosphorylation of glucose to
glucose-6 phosphate
For the purpose of trapping glucose inside the cell
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 Phosphorylated glucose cannot easily pass through cell membrane
B/c it is too polar to pass hydrophobic cell membrane

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 There are two possible enzymes for this reactions

Glucokinase

If it is in the liver and B-cells of Pancrease

Have high Km (low affinity) and Vmax

Hexokinase

If it is in the Muscle and other tissues

Have low Km and Vmax

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 Cont…

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 Cont….

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 Generation of energy

Aerobic Anaerobic

Whole: 4 ATP, 2 NADH Whole=4 ATP

2x3=6ATP Net: 2 ATP
6+4=10
Net: 8ATP

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 Cori cycle
 Anaerobic glycolysis forms pyruvic acid, which is reduced to lactic
acid
 The increased NADH/NAD+ ratio will direct excess pyruvate into
lactate
 Lactate accumulations causes lactic acidosis
 Lactate released from cells is taken up by the liver, heart, and
skeletal muscle and oxidized back to pyruvate
 In the liver, the pyruvate is used to synthesize glucose
(gluconeogenesis), which is returned to the blood

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 The heart, use lactate released from other tissues as a fuel
 During an exercise such as bicycle riding, lactate released into the
blood from skeletal muscles in the leg might be used by resting
skeletal muscles in the arm
 In the brain, glial cells and astrocytes produce lactate, which is used
by neurons

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 Rappaport luebering cycle
 The RBCs have ability to form 2,3-disphosphogycerate (2,3-DPG)
 2,3-DPG decrease affinity of hemoglobin to oxygen, thus good
tissue oxygenation

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 Warburg effect
 Is dependency of cancer cells on anaerobic glycolysis at a much
higher rate than normal tissue, even when oxygen is available
 Cancer cells dependency on anaerobic glycolysis for ATP is due to;
– They lack the capillary network to supply sufficient oxygen
– Cancer cells grow more rapidly than the blood vessels that nourish
them; thus, as solid tumors grow, the oxygen concentration in their
environment falls

 So that cancers begin to experience hypoxia, a deficiency of oxygen

 Hypoxia enhances glycolysis by activating a transcription factor,
hypoxia-inducible transcription factor (HIF-1)
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 This increase in glycolysis by cancer cells is achieved by;
– Increases the expression of most glycolytic enzymes and the glucose
transporters GLUT1 and GLUT3 by HIF-1
– HIF-1 also increases the expression of vascular endothelial growth
factor (VEGF), that facilitate the growth of blood vessels that will
provide nutrients to cancer cells

 Anaerobic glycolysis generates lactic acid that is then secreted

 Lactic acid causes acidification of the tumor environment

 This acidification is important to:

Facilitate tumor invasion and inhibit the immune system from attacking
the tumor
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 Regulations
 The rate limiting enzyme of glycolysis is phosphofructokinase-I
 So most important control point for glycolysis is at this point

Activators of PFK-I Inhibitors of PFK-I

AMP-activate protein kinase B ATP
Fructose 2,6-bisphosphate Glucagon
Insulin Citrate-to prevent glycolysis during
the oxidation of fatty acid

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 Fructose-2,6-biP is produced by phosphorylation of fructose 6-
phosphate at the 2 position by phosphofructokinase-2
 It have two separate domains, a kinase and a phosphatase domain
– At kinase domain, fructose-6-P is phosphorylated to fructose-2,6-bisP and

– At phosphatase domain, fructose-2,6-bisP is hydrolyzed back to fructose-6-P

 In the liver PFK-II is phosphorylated near the amino terminal by

glucagon that decreases kinase and increases the phosphatase activity
 In the heart PFK-II is phosphorylated by norepinephrine and AMP
increases the kinase activity and increases fructose-2,6-bisP levels,
thereby contributing to the activation of glycolysis

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 Disease associated with glycolysis
Lactic acidosis
 Increased glycolysis and lack of oxygen

Hemolytic anemia
 Genetic deficiency of pyruvate kinase enzyme in the red blood
cells
 results in decreased ATP production in the RBC

 This affects specially Na+/k+-ATPase protein at cell membrane

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 Metabolism of other monosaccharide's
 Glycolysis is not exclusively for the catabolism of glucose

 many other carbohydrates enter the glycolytic sequence in course

of their metabolism

Metabolism of fructose
 Fructose is found as a free monosaccharide in many fruits, in
honey
 Fructose transport into cells is not insulin dependent unlike that
of glucose into certain tissues and, in contrast to glucose, fructose
does not promote the secretion of insulin
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 Some of the fructose in the cells is phosphorylated by hexokinase;

To fructose 6-phosphate
Found in muscle and adipose tissue
Affinity of hexokinase for fructose,, is extremely low
is important only when the fructose concentration is very high
 Most of the fructose is phosphorylated by the fructokinase;

To fructose 1-phosphate
Found in the liver, kidney, and intestine
Have high affinity for fructose

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 Metabolism of galactose
 Entry of galactose into peripheral cells is independent of insulin
 Galactose is phosphorylated at C-1 by the enzyme galactokinase
to form galactose 1-phosphate
 Galactose 1-phosphate is converted to glucose 1-phosphate by
the action of galactose 1-phosphate uridyl transferase
 The net reaction of the pathway is the ATP-dependent conversion
of galactose to glucose 1-phosphate
 The latter enters glycolytic sequence via glucose 6-phosphate

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 Polyol pathway
 An alternate mechanism for metabolizing a monosaccharide is to
convert it to a polyol (sugar alcohol)
 Synthesis of sorbitol: Aldose reductase reduces glucose, producing
sorbitol
 found in lens, retina, Schwann cells of peripheral nerves, liver,
kidney, placenta, RBC, and ovaries and seminal vesicles cells
 Oxidation of sorbitol to produce fructose by sorbitol
dehydrogenase
 In cells of the liver, ovaries, and seminal vesicles
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 Krebs cycle

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 The metabolism of glucose through glycolysis harvests only a fraction
of ATP available from glucose
 Most of the ATP generated in metabolism is provided by the aerobic
processing of glucose

 This process starts with the complete oxidation of glucose to CO 2 and

H2O

 Krebs cycle is the final common pathway for the oxidation of fuel
molecules; carbohydrates, fatty acids, and amino acids
– b/c all generate acetyl CoA, which is the substrate for the TCA cycle

 The reactions of Krebs cycle take place inside mitochondria

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 The citric acid cycle removes electrons from acetyl CoA and uses
these electrons to form NADH and FADH 2

 NADH and FADH2 generate ATP by electron-transport chain

 Pyruvate, formed in the cytosol, is transported into the mitochondrion

by a pyruvate carrier transporter
 Inside mitochondria, pyruvate is decarboxylated to Acetyl CoA by
pyruvate dehydrogenase complex
 The enzyme utilizes five coenzymes: Lipoic acid, FAD, NAD,
coenzyme A and thiamine pyrophosphate (TPP)

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• E1-pyruvate decarboxylase

• E2-dihydrolipoyl transacetylase

• E3-dihydrolipoyl dehydrogenase

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 The energy generated
Number of ATP or reduced Overall number of ATP formed
Coenzyme A formed
2NADH 2X3=6
6NADH 6X3=18
2 FADH 2X2=4
2 ATP 2
30 ATP

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 Regulations
 Krebs cycle is regulated at:

Pyruvate dehydrogenase
Isocitrate dehydrogenase
α- ketoglutarate dehydrogenase

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  The metabolic pathways donate electrons to NAD+ and FAD to
form energy rich reduced forms NADH and FADH
 These reduced forms intern donate their electron to electron
carriers collectively called ETC
 These electrons travel down the ETC, and combine with final
electron acceptor oxygen
 The ETC is the final common pathway by which electrons
derived from different fuels of the body flow to oxygen (O2)

 As electrons are passed down the ETC, they lose much of their
free energy
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 This energy is used to move protons a cross the inner
mitochondrial membrane from matrix to IMS
Creating a proton gradient that drives the production of ATP
from ADP and inorganic phosphate (P i)
 The flow of electrons along electron transport chain and
generation of ATP is called oxidative phosphorylation
 Electron transport chain is located in the inner mitochondrial
membrane
 Mitochondria contains inner and outer membrane separated by
intermembrane space
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 Outer membrane is freely permeable to ions and small
molecules because of porin channels
 Inner membrane is impermeable to small ions and molecules
such as ATP, ADP and pyruvate
 Mitochondrial matrix is the space enclosed by the inner
mitochondrial membrane
 It contains a gel-like solution in which several catabolic pathways
occur
Krebs cycle, Fatty acid oxidation, amino acid oxidation

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 The inner mitochondrial membrane contains five separate protein
complexes, called Complexes I, II, III, IV, and V
Complexes I–IV each contain part of the ETC
Complex I and III each pumps 4H+ and IV pumps 2H+
There is no pumping of protons at complex II
 These complexes accept or donate electrons to the relatively
mobile electron carriers:
Coenzyme Q and cytochrome c
 Each carrier in the ETC can receive electrons from an electron
donor and donate electrons to the next acceptor in the chain

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 Chemiosmotic hypothesis
 Explains how free energy generated by the transport of electrons
used to generate ATP from ADP+Pi

 These hypothesis stated that OXIPHOS occur in two steps

I. Generation of electrochemical gradient across the IMM

More positive charges outside and negative inside of the
membrane: electrical gradient
Outside is at lower PH than inside: pH gradient
II. Utilization of this gradient to fuel ATP synthesis by ATP synthase

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 ATP synthase has two subunit:

Fo; imbedded in the inner mitochondrial membrane

 Contains proton channe formed by 10 to 14 subunit to form C-ring

F1; contains catalytic activity of the ATP synthase

 Contains five polypeptide chains but only β-subunit involved in ATP

synthesis

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 Uncouplers
 When protons leak back into the matrix without going through the
ATP synthase pore, they dissipate the electrochemical gradient
across the membrane without generating ATP
 This phenomenon is called “uncoupling” oxidative phosphorylation

 It occurs with chemical compounds, known as Uncouplers, and it

occurs physiologically with uncoupling proteins called thermogenin
that form proton channels through the membrane
 Uncoupling of oxidative phosphorylation results in increased oxygen
consumption and heat production

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 Chemical Uncouplers, are lipid-soluble compounds that rapidly
transport protons from the cytosolic to the matrix side
– Dinitrophenol and aspirin in high dose

 Uncoupling proteins (UCPs) form channels through the inner

mitochondrial membrane that are able to conduct protons from the
intermembrane space to the matrix
 UCP1 (thermogenin) is associated with heat production in brown
adipose tissue

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 Membrane transporters

 NADH produced in the cytosol in glycolysis; cannot directly enter

the mitochondrial matrix
 b/c inner mitochondrial membrane lacks an NADH transporter

 Two electrons of NADH are transported from the cytosol into the
matrix using substrate shuttles:

Glycerol phosphate
Present in Brain and skeletal muscle

Malate-aspartate
Present in liver and heart muscle

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 Energy produced

 Transfer of 2e- from NADH to O2 pumps 10 protons to

intermembrane space
Complex I and III each pumps 4H+ and complex IV pumps 2H+

 But, transfer from FADH2 pumps 6 protons to intermembrane

space
Complex III pumps 4H+ and complex IV 2H+
4H+ generate 1 ATP, so that NADH generates 2.5 ATP and
FADH2 generates 1.5 ATP

From complete oxidation of glucose 38ATP are generated

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 GLYCOGEN METABOLISM

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 Glycogen is the storage form of glucose found in most types of cells.
It is composed of glucosyl units linked by -1,4 glycosidic bonds, with
-1,6 branches
 Blood glucose is can be obtained from diet, degradation of glycogen
and from gluconeogenesis
 Dietary source of glucose is sporadic so not reliable source for falling
level of blood glucose
 Gluconeogenesis is slow in responding to a falling blood glucose
level

Therefore, body developed mechanism to store glucose in rapidly

mobilizable form called glycogen
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 The two most sites of glycogen storage are found in the;

Liver and Skeletal muscle

 Liver glycogen stores:
Increase during Well-fed state
Decrease during fasting state or exersice
A first line of defence against falling level of blood glucose

 Muscle glycogen stores:

Increase during resting state
Decrease during exercising state of the muscle
Glycogen metabolism are regulated to meet the energy needs of the
muscle itself

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 Glycogen synthesis (Glycogenesis)

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 Glycogen is synthesized from molecules of α-D-glucose
 The process occurs in the cytosol and requires energy supplied by ATP
and uridine triphosphate (UTP)
 For glycogen synthesis, glucose first must be activated by reacting with
UTP and forms UDP-glucose
UDP-glucose is activated form of glucose donor
 Glycogen synthase can add glucose to only chains already containing
more than two glucosyl residues
 Thus, it requires a primer such as;

Protein called Glycogenin and

Fragment of Glycogen molecule
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 Glucose from UDP-glucose is accepted by primers by
autoglycosylations and forms α-1,4 linked glucose polymers
 Then, glycogen synthase come into play and extending the polymers

 When the chain reaches 11 glucose residues in length, a 6- to 8-

residue piece is cleaved by 4:6-transferase and reattached to a
glucosyl unit by an α-1,6 bond
 The other name of 4:6-transferase is branching enzyme

 Branching of glycogen serves two major roles;

– Increased sites for synthesis and degradation
– Enhancing the solubility of the molecule

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 Degradation of glycogen

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 The enzyme of glycogen breakdown is;

– Glycogen phosphorylase

• The key enzyme of glycogen degradation

– Debranching enzyme

 Glycogen phosphorylase
– Cleaves the α(1→4) glycosidic bonds between the glucosyl
residues by the addition of phosphates
• This process is called phosphorolysis

Glucose is released in the form of glucose 1-phosphate

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 glycogen phosphorylase become inhibited when four glucosyl
residues is remained after a branch point
– because the branching chain hinders a proper fit into the active site of
the enzyme

 After a branch point the action of Debranching enzyme come in to

play
 Debranching enzyme posses dual function:
As 4:4 transferase; shifts three of four glucosyl residues from one
outer branch to another
As α(1→6) glucosidase, removes a single glucosyl units that remain
at a branch point
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 Glucose is released from glycogen as glucose 1-phosphate and free
glucose
 Glucose 1-P is converted to glucose 6-P by phosphoglucomutase

Glucose 6-phosphate catalyzed by glucose 6-phosphatase to release free

glucose in the liver

Then this glucose is used for maintenance of blood glucose levels

Glycogen is an extremely important fuel source for skeletal muscle

when ATP demands are high

Glucose 6-phosphate in muscle is used as source of energy for

exercising muscle itself
– Because: Muscle doesn’t have glucose 6-phosphatase
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 Regulation
 Regulation of glycogen synthesis serves to prevent futile cycling
and waste of ATP
 Futile cycling refers to a situation in which a substrate is converted
to a product through one pathway, and the product converted back
to the substrate through another pathway
 Because the biosynthetic pathway is energy-requiring, futile cycling
results in a waste of energy
 Thus, glycogen synthesis is activated when glycogen degradation is
inhibited, and vice versa

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 Regulation of glycogen synthesis and degradation occurs at two
levels:
Hormonal regulations
 Glucagon and epinephrine: glycogenesis & glycogenolysis
 Insulin: glycogenesis and glycogenolysis

Allosteric regulations
 Glucose, ATP, glucose 6-phosphate
o Increase glycogenesis and decrease glycogenolysis

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 The regulation of skeletal muscle glycogen synthesis and
degradation differs from that in liver in several important respects:
– Glucagon has no effect on muscle, and thus glycogen levels in
muscle do not vary with the fasting/feeding state
– AMP is an allosteric activator of the muscle glycogen
phosphorylase, but not liver glycogen phosphorylase
• Muscle G. Phosphorylase has purine nucleotide binding site for AMP

– Ca2+ in muscle is released from the sarcoplasmic reticulum after

neural stimulation, and not from epinephrine-stimulated uptake
– Glucose is not a physiologic inhibitor of glycogen phosphorylase a
in muscle
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 Gluconeogenesis

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 Maintaining blood glucose level is important

 Because brain and red blood cells need continuous supply of glucose

 Liver glycogen depleted after about 30 hours of fasting

 Then, the only source of glucose at this time is gluconeogenesis

 Gluconeogenesis is synthesis of glucose from non carbohydrate

precursors lactate, pyruvate, amino acids and glycerol

 Non-carbohydrate precursors used to synthesize glucose are:

Lactate
Pyruvate,
Glucogenic amino acids and Glycerol
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 The only organs that can synthesize glucose by gluconeogenesis are;
Liver and
Renal cortex
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 Seven gluconeogenic reactions are reversible and are used in the
synthesis of glucose
 However, three of the reactions are irreversible
 Irreversible reaction of gluconeogenesis are the following;

Conversion of pyruvate to Phosphoenol pyruvate (PEP)

Dephosphorylation of fructose 1,6-bisphosphate
 catalyzed by Fructose 1,6-bisphosphatase

Hydrolysis of glucose 6-phosphate

 catalyzed by glucose 6-phosphatase
 Muscle lacks glucose 6-phosphatase and, therefore, cannot provide
blood glucose by gluconeogenesis
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 Pyruvate is converted to oxaloacetate by pyruvate carboxylase
 This reaction is occur in the mitochondria

 The other reaction of gluconeogenesis occur in the cytosol

 So that, gluconeogenesis can occur both in the cytosol and
mitochondria
 Oxaloacetate is then transported back to mitochondria
 OAA is first converted to malate to be transported to cytosol
 Because, IMM is not permeable to OAA
 Malate is converted to OAA in the cytosol
 Catalyzed by malate dehydrogenase enzyme
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 Regulation of gluconeogenesis
A. Hormonal regulation
Glucagon: Increase gluconeogenesis
Insulin: Inhibits gluconeogenesis

B. Allosteric regulation
Citrate and ATP: increase gluconeogenesis

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 Quiz-1 (11/17/2023/
1. Write two difference between glycogen stored in liver and
skeletal muscle
2. Write the raw materials to synthesize glucose
3. Why skeletal musce cannot produce free glucose from
glycogen?
4. A protein primer to initiate glycogen formation is
called_________

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 THANK YOU

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