Chapter 2

Carbohydrate
 Introduction

Carbohydrates are the sugars and their derivatives; the

name comes from their empirical formulae with carbon
atoms and the elements of water in the ratio 1:1 (CH2O).

In polysaccharides and disaccharides, monosaccharides are

linked together by glycosidic bonds to form glycosides.
The glycosidic bond fixes the configuration on carbon atom 1
of the first monosaccharide into one form so that it no longer
mutarotates.
 Introduction Classification

Saccharides

Monosaccharides Disaccharides Oligosaccharides Polysaccharides

Starch,
Trioses, tetroses, Lactose, O-linked N-linked cellulose,
Derived
pentoses, hexoses maltose, oligosacchari oligosacchari pectin,
monosaccharides
cellobiose des des amylopectin,...

Glycosides, sugar phosphates,

gluconic acid and glucuronic
acid, amino sugars, vit C
 Classification
Introduction
Monosaccharides

Monosaccharide: trioses, tetroses, pentoses, hexoses

Ribose (pyranose form) Ribose (furanose form)

Glyceraldehyde

Glucose
 Classification
Introduction
Disaccharides
 Classification
Introduction
Polysaccharides

In animals, excess glucose is stored as a large branched

polysaccharide called glycogen whereas in most plants the
storage form of glucose is the polysaccharide called
starch. Bacteria and yeasts store glucose as yet another
type of polysaccharide called dextran. Cellulose is a
structural polysaccharide used to make plant cell walls.

The 𝛼1–4 linkages in the straight chain and 𝛼1–

6 branchpoint linkages in glycogen.
 Introduction Functions

• Storage substance of potential energy. About 60% of the total energy required of man
is provided by the breakdown of carbohydrates.
• Glucose is the sole form of energy for the brain and other nervous tissue
• Structural component: monosaccharides make up nucleic acids, coenzymes. Hyaluronic acid
is the viscous substance in the matrix of the connective tissue, heparin prevents the clotting
of bloods, glucuronic acids act as detoxifying agents, glycosides are components of steroid
hormones.
• Regulation of fat metabolism: when carbohydrates are restricted in the diet there is more rapid
metabolization of fats, leading to the accumulation of incompletely oxidised intermediate
products leading to ketosis => uncontrolled diabetes mellitus
 Introduction Stereoisomers

Stereoisomers (also called optical isomers)

D- or L-?

Glucose Fructose Galactose

 Introduction Ring structures

• The aldehyde or ketone group can react with a hydroxyl group to form a covalent bond.
• OH group at C-1 lies below the plane of the ring => 𝛼-D-glucose
• OH group at C-1 lies below the plane of the ring => 𝛽-D-glucose
 Digestion, absorption and storage of carbohydrates

Hormones regulate distribution of carbohydrate:

Insulin, released in response to high glucose

levels, stimulates fat and glycogen storage.

Glucagon, released from the pancreas when

blood glucose is low, stimulates release of
glucose from the liver and of fatty acids from fat
cells. Insulin and glucagon have opposing effects.

Other hormones (epinephrine, stress hormones)

release to respond to hypoglycemia, exercises
and physiologic stress
Digestion, absorption and storage of carbohydrates
Digestion, absorption and storage of carbohydrates

Absorb: the glucose transporter for this movement is the facilitated diffusion type.
 Digestion, absorption and storage of carbohydrates
https://www.youtube.com/watch?v=LW_3Ji0mlEc

GLUT (Sodium independent)

Active transport and facilitative
diffusion Ping-pong mechanism
 Digestion, absorption and storage of carbohydrates

GLUT4: insulin dependent

Digestion, absorption and storage of carbohydrates

https://www.youtube.com/watch?v=LW_3Ji0mlEc

S-GLUT (sodium–glucose transporter)

Secondary active transport
S-GLUT is coupled with Na+/K+ ATPase
pump
The energy stored in the sodium gradient is
then used by the SGLT to transport glucose
against its concentration gradient into the
cell. Glucose is co-transported with
sodium, utilizing the energy released
during the sodium movement.
 Digestion, absorption and storage of carbohydrates

Storage:
In humans, the glycogen reserves of liver, which are used to supply glucose to the blood for
utilization by other tissues, especially the brain and erythrocytes, are exhausted after about 24
hours without food.
The liver can, however, convert amino acids into glucose, a process called gluconeogenesis, which
releases the glucose into the bloodstream, and thus provide brain and erythrocytes with the fuel
they can metabolise.

Muscle also has large glycogen reserves which are used to provide energy for ATP production,
needed in muscle contraction, but it only serves the muscle. Free glucose cannot be produced
from glycogen in muscle and so is not released from it into the circulation, as happens with the
liver.

Brain and in erythrocytes store free glucose

 Digestion, absorption and storage of carbohydrates

Glycogen synthesis
 Digestion, absorption and storage of carbohydrates

Glycogen synthesis • Primarily occurs in the muscle and liver

• From glucose -> G6P -> G1P
• 3 enzymes: UDP-glucose pyrophosphorylase, glycogen synthase,
and branching enzyme
1. UDP-glucose pyrophosphorylase catalyses the synthesis of UDP-glucose from UTP and glucose 1-
phosphate:
 Digestion, absorption and storage of carbohydrates

Glycogen synthesis
1. UDP-glucose pyrophosphorylase catalyses the synthesis of UDP-glucose from UTP and glucose 1-phosphate
2. Glycogen synthase now transfers the glucosyl residue from UDP-glucose to the C4 OH group at the
nonreducing end of a glycogen molecule, forming an 𝛼1–4 glycosidic bond. Glycogen synthase
continues extending the existing chain

UDP-glucose
 Digestion, absorption and storage of carbohydrates

Glycogen synthesis
1. UDP-glucose pyrophosphorylase catalyses the synthesis of UDP-glucose from UTP and glucose
1- phosphate
2. Glycogen synthase now transfers the glucosyl residue from UDP-glucose to the C4 OH group at the
nonreducing end of a glycogen molecule, forming an 𝛼1–4 glycosidic bond. Glycogen synthase
continues extending the existing chain
3. Branching enzyme [amylo-(1–4→1–6) transglucosylase]: breaks one of the 𝛼1–4 bonds and
reattaches these by creating an 𝛼1–6 bond
 Digestion, absorption and storage of carbohydrates

Glycogen breakdown
Occurs in the liver
Glycogen breakdown occurs at the non- reducing end.
Instead of cleaving (lysing) glucose with water, it
cleaves it with phosphate (phosphorolysis). The
enzyme is called glycogen phosphorylase

G-1-P

Glucose-6-phosphatase
G-6-P Glucose
 Metabolism of glucose (Glycolysis)

• Occurs in the cytoplasm of

prokaryotes and eukaryotes.
• Role: produces energy (both directly
and by supplying substrate for the citric
acid cycle and oxidative
phosphorylation), produces
intermediates for biosynthetic
pathways.
• Glycolysis converts one molecule of
TCA cycle
glucose into two molecules of pyruvate
[which are then converted to acetyl
coenzyme A (CoA) ready for entry into
the citric acid cycle].
Metabolism of glucose (Glycolysis)
Metabolism of glucose (Glycolysis)
Stage 1:
- Traps glucose inside the cell and no ATP is formed
- Lowers intracellular (unphosphorylated) glucose
concentration to allow further uptake by facilitative
diffusion through GLUTS

1st step:
2nd step:

25
3rd step:

• Symmetrical phosphorylation to set up cleavage to 3-carbon sugar

• F-1,6-BP is committed to become pyruvate and yield energy
• This process uses the energy of ATP

26
4th step:

27
4th step:

28
4th step:

Acid catalysis protonates the carbanion

29
4th step:

Product Release is the slow step

30
5th step:

His 95
Glu 165

31
Metabolism of glucose
(Glycolysis)
NAD+
1st step:

33
2nd step

1,3-BP Is a high-energy compound

Can donate the phosphate group to ADP to make ATP
‘kinase’ is an enzyme that transfer phosphate group

34
 3rd step:

- Acid/base catalysis
- One of the active-site histidines is post-translationally
modified to phospho-histidine.
- Phospho-histidine donates its phosphate to 3-
phosphoglycerate at the C2-oxygen before retrieving
the phosphate from the 3-carbon oxygen.

35
 4th step:

5th step:
•Phosphoenolpyruvate (PEP) is a high-energy
compound => can donate the phosphate group
to ADP to make ATP
•Loss of phosphate from PEP yields an enol
that tautomerizes into ketone.
•Tautomerization
• effectively lowers the concentration of
the reaction product
• drives the reaction toward ATP formation

36
Metabolism of glucose (Glycolysis)

The net reaction in the transformation of glucose into pyruvate:

Metabolism of glucose (Glycolysis)

Aerobic Anaerobic
39
 Tricarboxylic acid/ Krebs cycle/ citric acid cycle

Pyruvate dehydrogenase oxidises the pyruvate (using

NAD+ which is reduced to NADH) to form acetyl CoA
and CO2.
The intermediates in the cycle provide precursors for
many biosynthetic pathways:

8 electrons donated by the acetyl group end up in

3NADH and 1FAD

1 GTP is formed
 Tricarboxylic acid/ Krebs cycle/ citric acid cycle

Both FAD and NAD+ are electron-accepting coenzymes

FAD is able to accept single electrons NAD+ accepts a pair of electrons
Single electrons are transferred independently from 2 E.g: in the oxidation of the alcohols
different atoms to ketones
E.g: double-bond formation (succinate to fumarate)
 Glycolysis is tightly controlled:

Glycolysis catalysed by hexokinase,

phosphofructokinase, and pyruvate kinase are
irreversible, and each of them serves as a
control sites.

• When glucose 6 phosphate increases =>

inhibit hexokinase
• PFK inhibition => hexokinase
inhibition PFK controls the rate of
glycolysis

• High concentration of ATP inhibits these

3 enzymes
=> glycolysis slows down
 Metabolism of fructose

Fructose is an abundant sugar in the human diet; sucrose is

a disaccharide which when hydrolysed yields fructose and
glucose
There are two pathways for the metabolism of fructose:
• In muscle and adipose tissue, fructose can be
phosphorylated by hexokinase (which is capable of
phosphorylating both glucose and fructose) to form
fructose 6-phosphate which then enters glycolysis.
• In liver, the cells contain mainly glucokinase instead of
hexokinase and this enzyme phosphorylates only
glucose. Thus in liver, fructose is metabolised instead
by the fructose 1-phosphate pathway

(Fructose 1-phosphate pathway)

 Metabolism of galactose
The hydrolysis of the disaccharide lactose (in milk) yields galactose and glucose. Galactose and
glucose are epimers that differ in their configuration at C-4 => the entry of galactose into glycolysis
requires an epimerisation reaction (galactose–glucose interconversion pathway)
 Glucose synthesis (Glyconeogenesis)

• Gluconeogenesis is the synthesis of glucose from noncarbohydrate sources and is crucial

for providing glucose, especially to the brain and erythrocytes.
• It becomes essential during periods of fasting or intense exercise when glycogen stores are
depleted.
• The substrate for gluconeogenesis is pyruvate
• Amino acids from protein breakdown and glycerol from fat breakdown are key substrates
for gluconeogenesis during starvation.
• Gluconeogenesis occurs primarily in the liver with minimal activity in the kidneys, while very
little occurs in the brain or muscles.
• Enzymes involved in gluconeogenesis are compartmentalised within liver cells, with
specific locations for key enzymes like pyruvate carboxylase and glucose 6-phosphatase.
Glucose synthesis (Glyconeogenesis)
ATP
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ADP luco 6-pho ph
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ADH + {2 ADH+H
Jr irreversible steps,
'
allosteric enzyme
2 ADP 2 ADP Fru unfavored G overcome b,
ATP ,6-pho phate
2 ATP 2)ATP

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ADP pho pha
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(2 2-Pho phogly rate --- Dih dro ace on
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(2,Pyruvat
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)
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 Regulation of glycolysis

The enzymes that involved in glycolysis are allosterically

controlled

• AMP level rises => stimulates 3 enzymes

• ATP level rises => inhibits 3 enzyme
• Glucose-6-phosphate is high => inhibits hexokinase
Glycolysis and gluconeogenesis are reciprocally regulated

When energy is needed:

• High level of AMP => stimulates PFK, inhibits F 1,6-BP
=> stimulates glycolysis, inhibits gluconeogenesis
• High level of ATP and citrate indicate energy
abundance => inhibit PFK, stimulate F 1,6-BP =>
inhibit glycolysis, stimulates gluconeogenesis
• Pyruvate kinase is inhibited by ATP and alanine
during energy abundance
Glycolysis and gluconeogenesis are reciprocally regulated

In the fasting state:

Glucagon stimulates protein kinase =>
phosphorylation of the bifunctional enzyme
=> FBPase 2 is activated, PFK2 is inhibited =>
glycolysis is inhibited, gluconeogenesis is
stimulated

After a meal:
Insulin stimulates protein phosphatase,
dephosphorylation of the bifunctional
enzyme => FBPase 2 is inhibited, PFK2 is
activated => glycolysis is stimulated,
gluconeogenesis is inhibited
Glycolysis and gluconeogenesis are reciprocally regulated

Hormones and secondary message

• The intracellular second messenger of glucagon

and adrenaline is cyclic AMP (cAMP)
• cAMP is the allosteric activator of protein kinase (PKA)

50
 Regulation of glycogen synthesis and degradation

Allosterically controlled
• During muscle contraction, glucose
6- phosphate levels are low =>
glycogen synthase is inhibited, and Phosphorylated Dephosphorylated
phosphorylase is most active => inactive active
glycogen degradation occurs, and
glycogen synthesis is inhibited
• In resting muscle: ATP and glucose 6-
phosphate levels rise, phosphorylase
b is inhibited => turns off glycogen
degradation, and activates The nonhormonal ‘routine’ allosteric controls on
glycogen synthase glycogen metabolism in muscle
 Regulation of glycogen synthesis and degradation

Calcium control of glycogen metabolism

• Similar to protein kinase, Ca2+ phosphorylates phosphorylase kinase, activates
phosphorylase and stimulates glycogen degradation.
• Ca2+ released during muscle contraction activates.
 Regulation of glycogen synthesis and degradation

• Glucagon: raises blood sugar levels, stimulates the breakdown (glycogenolysis) of glycogen in the
liver into glucose, which is then released into the bloodstream.
• Adrenaline: stimulates the release of glucose by promoting glycogenolysis, providing a quick
energy source for the body during stressful situations.
• Both hormones have cyclic AMP as second messenger.
 Regulation of glycogen synthesis and degradation

Insulin activates glycogen synthase

• Insulin binds to its receptor => triggers PKB

• PKB phosphorylates and deactivates
glycogen synthase kinase 3 (GSK3)
• When GSK3 is inactive, it cannot phosphorylate
glycogen synthase => glycogen synthase is inactive
=> Less glucose is converted into glycogen
 The Cori cycle

• The Cori Cycle involves the conversion of lactate back to pyruvate in the liver, which
then undergoes gluconeogenesis to produce glucose.
• The glucose is released into the bloodstream, making it available for uptake by skeletal muscles
and other tissues, completing the cycle.
 Diabetes

https://www.youtube.com/watch?v=XfyGv-xwjlI

Diabetes mellitus is categorised into two major sub-types and the causes associated remains differential
•Type – I: The immune system mistakenly attacks the β cells of pancreas where genes play a vital role.
•Type – II: Interplay of genetics and lifestyle factors plays a vital role. Being obese or overweight increases
the associated risks.

Insulin decreases the level of blood glucose either

a) By inhibiting the production of glucose from liver by glycogenolysis and gluconeogenesis, or
b) By increasing the uptake of glucose by liver, muscle and fat tissue.

Glucagon is secreted by α cells of pancreas when the concentration of glucose is low. Glucagon acts by
a) Antagonising the effect of insulin by enhancing the processes like glycogenolysis and gluconeogenesis
in liver.
b) In addition to glucagon, cortisol and catecholamines also increases the plasma glucose levels
 Diabetes

1. Insulin secretagogues: increasing

the secretion of insulin from pancreas
by binding to sulfonylurea receptor
(SUR) of ATP sensitive potassium
channel on pancreatic β cells
(Tolbutamide, Chlorpropamide,
Glibenclamide,

2. Biguanides: increase inulin

receptor activity (Metformin)

3. Insulin sensitisers: Peroxisome

proliferator activated receptor
agonists (PPARs). PPARγ agonists are
generally thiazolidinedione (glitazones)
 Diabetes

4. Alpha-glucosidase
inhibitor: Voglibose and Miglitol
 Diabetes

5. Incretin mimetics (GLP-1

agonists and DPP-IV inhibitors)
• GLP-1 agonists: Exenatide
• DPP-IV
inhibitor: Sitagliptin, Vildagliptin,
Saxagliptin
 Diabetes

6. Sodium glucose co-

transporter 2
antagonists/ inhibitors
• prevents reabsorption of
glucose and enhances the
excretion of glucose in
urine
• e.g: Canagliflozin, Dapagliflo
zin, Empagliflozin,

PCT: proximal convoluted