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 Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial
ASBASJSM COLLEGE OF PHARMACY
COLLEGE OF PHARMACY (AN AUTONOMOUS COLLEGE) BELA
s (An Autonomous College)
BELA (Ropar) Punjab

Name of Unit Carbohydrate Metabolism and Biological Oxidation

Subject /Course name Biochemistry
Subject/Course ID BP203T
Class: B.Pharm. Semester II
Course coordinator Mrs. Manpreet Kaur/ Mrs. Amandeep Kaur
Mobile No. 9592378971/ 8427898869
Email id manipreet663@gmail.com/kauraman9929@gmail.com

Learning Outcome of Module 02

LO Learning Outcome Course Outcome Code
LO1 To learn about Properties of Carbohydrates. BP203.1
LO2 To gain knowledge about the biological roles of BP203.1
Carbohydrates.
LO3 To Learn about metabolism of Carbohydrate. BP203.2
LO4 To learn about Properties of Amino acid BP203.1

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Content Table
Topic
 Carbohydrate Metabolism: Glycolysis and citric acid cycle- Pathway, energetics

and significance.

 HMP Shunt and its significance; Glucose-6-Phosphate dehydrogenase deficiency.

 Glycogen metabolism pathways and glycogen storage diseases.

 Gluconeogenesis- Pathway and its significance.

 Hormonal regulation of blood glucose level and Diabetes mellitus.

 Biological Oxidation: Electron transport chain and its mechanism.

 Oxidative phosphorylation and its mechanism and substrate phosphorylation.

 Inhibitors ETC and oxidative phosphorylation/ uncouples.

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CARBOHYDRATE METABOLISM

 Glucose is the major form of sugar moiety present in blood and other body fluids. The
digestion of food carbohydrates, such as starch, sucrose, and lactose produces the
monosaccharides glucose, fructose and galactose, which pass into the blood stream. The
study of synthesis (Anabolism) and degradation (Catabolism) of biomolecules is
biochemically termed as metabolism.

Anabolism + Catabolism = Metabolism

 Since glucose is the most important carbohydrate existing in physiological amounts in the
body and is easily absorbed from the diet, the metabolism of carbohydrate resolves itself to
the study of the metabolism of glucose and its main derivatives.
 The monosaccharides galactose and fructose are converted to glucose in the liver. All the
monosaccharides are completely absorbed in the small intestine.
 The glucose in the circulating blood and tissue fluids is drawn upon by all the cells of the
body and used for the production of energy. Normally carbohydrate metabolism supplies
more than half of the energy requirements of the body. In fact the brain largely depends
upon carbohydrate metabolism as a source of energy and quickly ceases to function
properly when the blood glucose level falls much below normal.
 The major function of carbohydrate in metabolism is to serve as fuel and get oxidised to
provide energy for other metabolic processes. The metabolic intermediates are used for
various biosynthetic reactions. For this purpose, carbohydrate is utilized by the cells
mainly in the form of glucose.
 A major part of dietary glucose is converted to glycogen for storage in liver. Glucose is
degraded in the cell by way of a series of phosphorylated intermediates mainly via two
metabolic pathways.
1. Glycolysis
2. Tricarboxylic acid cycle

GLYCOLYSIS
Oxidation of glucose to pyruvate is called glycolysis. It was first described by Embden-
Meyerhof and Parnas. Hence it is also called as Embden-Meyerh of pathway. Glycolysis
occurs virtually in all tissues. Erythrocytes and nervous tissues derive the energy mainly from
glycolysis. This pathway is unique in the sense that it can proceed in both aerobic (presence

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of O2) and anaerobic (absence of O2) conditions. All the enzymes of glycolysis are found in
the extra mitochondrial soluble fraction of the cell, the cytosol.
The overall equation for glycolysis from glucose to lactate is as follows:

Reactions of glycolytic pathway

Series of reactions of glycolytic pathway which degrades glucose to pyruvate are

represented below. The sequence of reactions occurring in glycolysis may be considered
under four stages.

Stage I: This is a preparatory phase. Before the glucose molecule can be split, the rather
asymmetric glucose molecule is converted to almost symmetrical form, fructose 1, 6-
diphosphate by donation of two phosphate groups from ATP.
1. Uptake of glucose by cells and its phosphorylation:
Glucose is freely permeable to liver cells, intestinal mucosa and kidney tubules where
glucose is taken up by 'active' transport. In other tissues insulin facilitates the uptake of
glucose. Glucose is phosphorylated to form glucose 6-phosphate. The enzyme involved in
this reaction is glucokinase or hexokinase. This reaction is irreversible.

2. Conversion of glucose 6-phosphate to fructose 6-phosphate:

Glucose 6-phosphate is converted to fructose 6-phosphate by the enzyme phosphogluco
isomerase.

3. Conversion of fructose 6-phosphate to fructose 1, 6 diphosphate:

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Fructose 6-phosphate is phosphorylated irreversibly at 1 position catalyzed by the enzyme
phosphofructokinase to produce fructose1, 6-diphosphate.
Stage II:
Actual splitting of fructose 1, 6 diphosphate: Fructose 1, 6 diphosphate is split by the
enzyme aldolase into two molecules of triose phosphates, an aldotriose-glyceraldehyde 3-
phosphate and one ketotriose-dihydroxy acetone phosphate. The reaction is reversible.
There is neither expenditure of energy nor formation of ATP.

Interconversion of triose phosphates: Both triose phosphates are interconvertible.

Stage III: It is the energy yielding stage. Reactions of this type in which an aldehyde
group is oxidised to an acid are accompanied by liberation of large amounts of potentially
useful energy.
Oxidation of glyceraldehyde 3-phosphate to 1, 3-bisphosphoglycerate: Glycolysis
proceeds by the oxidation of glyceraldehyde 3-phosphate to form 1,
3−bisphosphoglycerate. The reaction is catalyzed by the enzyme glyceraldehyde 3-
phosphate dehydrogenas.

Conversion of 1, 3-bisphosphoglycerate to 3-phosphoglycerate: The reaction is catalyzed

by the enzyme phosphoglycerate kinase. The high energy phosphate bond at position-1 is
transferred to ADP to form ATP molecule.

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Stage IV: It is the recovery of the phosphate group from 3-phosphoglycerate. The two
molecules of 3- phosphoglycerate, the end product of the previous stage, still retains the
phosphate group, originally derived from ATP in Stage I.
Conversion of 3-phosphoglycerate to 2-phosphoglycerate: 3-phosphoglycerate formed
by the above reaction is converted to 2-phosphoglycerate, catalyzed by the enzyme
phosphoglycerate mutase.

Conversion of 2-phosphoglycerate to phosphoenol pyruvate: The reaction is catalyzed

by the enzyme enolase, the enzyme requires the presence of either Mg2+ or Mn2+ ions for
activity.

Conversion of phosphoenol pyruvate to pyruvate: Phosphoenol pyruvate is converted to

pyruvate, the reaction is catalysed by the enzyme pyruvate kinase. The high energy
phosphate group of phosphoenol pyruvate is directly transferred to ADP, producing ATP.
The reaction is irreversible.

Summary of glycolysis

During glycolysis NAD+ is reduced to NADH. At the same time, glyceraldehyde 3-

phosphate is oxidized to 1, 3-bisphosphoglycerate. To conserve the coenzyme NAD+,
NADH must be reoxidized. Under anaerobic conditions this is done when pyruvic acid is
converted to lactic acid. In the presence of oxygen, NADH can be oxidized to NAD+ with
the help of the respiratory enzymes.

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ANAEROBIC PHASE
In the absence of O2, reoxidation of NADH at glyceraldehyde 3-phosphate dehydrogenase
stage cannot take place in respiratory chain. But the cells have limited coenzyme. Hence
to continue the glycolysis NADH must be reoxidized to NAD+. This is achieved by
reoxidation of NADH by conversionof pyruvate to lactate (without producing ATP).

It is to be noted that in the reaction catalyzed by glyceraldehyde 3-phosphate

dehydrogenase, therefore, no ATP is produced.
In the anaerobic phase oxidation of one glucose molecule produces 4 - 2 = 2 ATP.

Energy yield per glucose molecule oxidation

During glycolysis ATP molecules are used and formed in the following reactions (aerobic
phase).
Reactions Catalyzed ATP used ATP formed

Stage I:

1. Glucokinase (for phosphorylation) 1

2. Phosphofructokinase I (for phosphorylation) 1

Stage II:
3. Glyceraldehyde 3-phosphate dehydrogenase 6
(oxidation of 2 NADH in respiratory chain)

4. Phosphoglycerate kinase (substrate level phosphorylation) 2

Stage IV:
2
5. Pyruvate kinase (substrate level phosphorylation)

Total 2 10

Net gain 08

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Schematic diagram of glycolytic pathway

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TRICARBOXYLIC ACID CYCLE (TCA CYCLE)
This cycle is the aerobic phase of carbohydrate metabolism and follows the anaerobic
pathway from the stage of pyruvate and is called as citric acid cycle or TCA cycle. The
name citric acid cycle stems from citric acid which is formed in the first step of this
cycle. This cycle is also named "Kerbs cycle" after H.A. Krebs, an English biochemist
who worked on it.
Under aerobic conditions, pyruvate is oxidatively decarboxylated to acetyl coenzyme A
(active acetate) before entering the citric acid cycle. This occurs in the mitochondrial
matrix and forms a link between glycolysis and TCA cycle.
This reaction is catalysed by the multienzyme complex known as pyruvate dehydrogenase
complex.

Schematic Diagram of Krebs Cycle

Reactions of the citric acid cycle: There are eight steps in the cycle and the reactions are as
follows.
1. Formation of citrate: The first reaction of the cycle is the condensation of acetyl CoA with

oxaloacetateto form citrate, catalyzed by citrate synthase. This is an irreversible reaction.

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2. Formation of isocitrate via cis aconitate: The enzyme aconitase catalyzes the reversible
transformation of citrate to isocitrate, through the intermediary formation of cis aconitate.

3. Oxidation of isocitrate to α-ketoglutarate and CO2: In the next step, isocitrate

dehydrogenase catalyzes oxidative decarboxylation of isocitrate to form α-ketoglutarate.

4. Oxidation of α-keto glutarate to succinyl CoA and CO2: The next step is another
oxidative decarboxylation, in which a-ketoglutarate is converted to succinyl CoA and CO2
by the action of the α- ketoglutarate dehydrogenase complex. The reaction is irreversible.

5. Conversion of succinyl CoA to succinate: The product of the preceding step,

succinyl CoA is converted to succinate to continue the cycle. GTP is formed in
this step (substrate level phosphorylation) and the enzyme that catalyzes this
reversible reaction is called succinyl CoA synthetase or succinic thiokinase.

6. Oxidation of succinate to fumarate: The succinate formed from succinyl CoA is oxidized
to fumarate by the enzyme succinate dehydrogenase.

7. Hydration of fumarate to malate: The reversible hydration of fumarate to malate is

catalyzed by fumarase.

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8. Oxidation of malate to oxaloacetate: The last reaction of the citric acid cycle is, NAD
linked malate- dehydrogenase which catalyses the oxidation of malate to oxaloacetate.

Energy yield from TCA cycle: If one molecule of the substrate is oxidized through
NADH in the electron transport chain three molecules of ATP will be formed and through
FADH2, two ATP molecules will be generated. As one molecule of glucose gives rise to
two molecules of pyruvate by glycolysis, intermediates of citric acid cycle also result as
two molecules.

Vitamins play key roles in the citric acid cycle:

Four of the B vitamins are essential in the citric acid cycle and therefore in energy-yielding
metabolism:
1. Riboflavin, in the form of flavin adenine dinucleotide (FAD), a cofactor in the α-
ketoglutarate dehydrogenase complex and in succinate dehydrogenase.
2. Niacin, in the form of nicotinamide adenine dinucleotide (NAD), the coenzyme for
three dehydrogenases in the cycle — isocitrate dehydrogenase, α-ketoglutarate

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dehydrogenase and malate dehydrogenase.
3. Thiamin (vitamin B1), as thiamin diphosphate, the coenzyme for decarboxylation in
the α-ketoglutarate dehydrogenase reaction.
4. Pantothenic acid, as part of coenzyme A, the cofactor attached to ―active‖
carboxylic acid residues such as acetyl-CoA and succinyl-CoA.
The Citric Acid Cycle Takes Part in Fatty Acid Synthesis: Acetyl-CoA, formed from
pyruvate by the action of pyruvate dehydrogenase, is the major building block for long-
chain fatty acid synthesis in nonruminants. (In ruminants, acetyl-CoA is derived directly
from acetate.) Pyruvate dehydrogenase is a mitochondrial enzyme and fatty acid
synthesis is a cytosolic pathway, but the mitochondrial membrane is impermeable to
acetyl- CoA. Acetyl-CoA is made available in the cytosol from citrate synthesized in the
mitochondrion, transported into the cytosol and cleaved in a reaction catalyzed by
ATP-citrate lyase.

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HMP shunt pathway

Although glycolysis and citric acid cycle are the common pathways by which animal
tissues oxidise glucose to CO2 and H2O with the liberation of energy in the form of ATP,
a number of alternative pathways are also discovered. The most important one is Hexose
Monophosphate Shunt Pathway (HMP shunt). The pathway occurs in the extra
mitochondrial soluble portion of the cells.
It has two major functions:

I. The formation of NADPH for synthesis of fatty acids and steroids

II. The synthesis of ribose for nucleotide and nucleic acid formation.

The fundamental difference between NADPH and NADH (reduced nicotinamide adenine
dinucleotide) is that NADH is oxidised by the respiratory chain to generate ATP whereas
NADPH serves as a hydrogen and electron donor in reductive biosynthesis, for example
in the biosynthesis of fatty acids and steroids.
Glucose, fructose and galactose are the main hexoses absorbed from the gastrointestinal
tract, derived principally from dietary starch, sucrose and lactose respectively. Fructose
and galactose are converted to glucose, mainly in the liver.
The overall equation of the hexose phosphate pathway is

and the net result is the production of NADPH, a reductant for biosynthetic reactions
and ribose 5-phosphate, a precursor for nucleotide synthesis.
Oxidative reactions of the hexose mono-phosphate pathway:
Step 1:
Glucose 6-phosphate in the presence of NADP+ and the enzyme glucose 6-phosphate
dehydrogenase, forms 6-phospho glucono-δ -lactone. The first molecule of NADPH+ is
produced in this step.

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Step 2:
The 6-phospho glucono- δ-lactone is unstable and the ester spontaneously hydrolyses to
6- phosphogluconate. The enzyme that catalyses the reaction is lactonase.

Step 3:
6-phospho gluconate further undergoes dehydrogenation and decarboxylation by 6-
phosphogluconate dehydrogenase to form the ketopentose, D-ribulose 5-phosphate.
This reaction generates the second molecule of NADPH.

Step 4:
The enzyme phosphopentose isomerase converts ribulose 5-phosphate to its aldose
isomer, D-ribose 5-phosphate.

GLUCONEOGENESIS

The synthesis of glucose from non-carbohydrate precursors is known as

gluconeogenesis.

The major site of gluconeogenesis is liver.

It usually occurs when the carbohydrate in the diet is insufficient to meet the demand
in the body, with the intake of protein rich diet and at the time of starvation, when
tissue proteins are broken down to amino acids.

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Substrates for Gluconeogenesis
Gluconeogenic precursors are molecules that can be used to produce a net synthesis of
glucose. They include the intermediates of glycolysis and the citric acid cycle. Glycerol,
lactate, and the α-keto acids obtained from the deamination of glucogenic amino acids are
the most important gluconeogenic precursors.
1. Glycerol: Glycerol is released during the hydrolysis of triacylglycerols in adipose
tissue and in the liver. Glycerol is phosphorylated by glycerol kinase to glycerol
phosphate, which is oxidized by glycerol phosphate dehydrogenase to
dihydroxyacetone phosphate as an intermediate of glycolysis.
2. Lactate: It is released into the blood by exercising skeletal muscle, and by cells that
lack mitochondria, such as red blood cells. In the Cori cycle, glucose is converted by
exercising muscle to lactate, which diffuses into the blood. This lactate is taken up by
the liver and reconverted to glucose, which diffuse into the circulation.
3. Amino acids: Amino acids derived from hydrolysis of tissue proteins are the major
sources of glucose during fasting.

Gluconeogenesis and glycolysis

Gluconeogenesis and glycolysis are opposing metabolic pathways and share a number of
enzymes. In glycolysis, glucose is converted to pyruvate and in gluconeogenesis
pyruvate is converted to glucose. However gluconeogenesis is not exact reversal of
glycolysis.
There are three essentially irreversible steps in glycolysis which are

In gluconeogenesis these three reactions are bypassed or substituted by the following news
ones.

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Reactions of gluconeogenesis

1. The formation of phosphoenol pyruvate begins with the carboxylation of pyruvate at the
expense of ATP to form Oxalo acetate.

Oxalo acetate is converted to phosphoenolpyruvate by phosphorylation with GTP,

accompanied by a simultaneous decarboxylation.

2. Fructose 6-phosphate is formed from fructose 1, 6-diphosphate by hydrolysis and the

enzyme fructose 1, 6 diphosphatase catalyses this reaction.

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3. Glucose is formed by hydrolysis of glucose 6-phosphate catalysed by glucose 6-
phosphatase.

Gluconeogenesis of amino acids

Amino acids which could be converted to glucose are called glucogenic amino acids. Most
of the glucogenic amino acids are converted to the intermediates of citric acid cycle either by
transamination or deamination.
Gluconeogenesis of Propionate:

Propionate is a major source of glucose in ruminants, and enters the main gluconeogenic
pathway via the citric acid cycle after conversion to succinyl CoA.

Gluconeogenesis of Glycerol

At the time of starvation glycerol can also undergo gluconeogenesis. When the

triglycerides are hydrolysed in the adipose tissue, glycerol is released. Further metabolism
of glycerol does not take place in the adipose tissue because of the lack of glycerol kinase
necessary to phosphorylate it. Instead, glycerol passes to the liver where it is
phosphorylated to glycerol 3-phosphate by the enzyme glycerol kinase.

This pathway connects the triose phosphate stage of glycolysis, because glycerol 3-
phosphate is oxidized to dihydroxy acetone phosphate in the presence of NAD+ and
glycerol 3-phosphate dehydrogenase.

This dihydroxy acetone phosphate enters gluconeogenesis pathway and gets converted to
glucose. Liver and kidney are able to convert glycerol to blood glucose by making use of
the above enzymes.

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Gluconeogenesis of lactic acid (Cori cycle)
The liver and skeletal muscles exhibit a special metabolic cooperation as far as
carbohydrates are concerned by the way of a cycle of conversions known as Cori cycle.

Cori cycle

In this cycle liver glycogen may be converted into muscle glycogen and vice versa
and the major raw material of this cycle is lactate produced by the active skeletal
muscles.
At the time of heavy muscular work or strenuous exercise, O2 supply is inadequate in
active muscles but the muscles keep contracting to the maximum. Hence, glycogen
stored up in the muscle is converted into lactic acid by glycogenolysis followed by
anaerobic glycolysis and thus lactate gets accumulated in the muscle. Muscle tissue
lacks the enzyme glucose 6-phosphatase hence it is incapable of synthesizing
glucose from lactic acid and the conversion take place only in the liver.
Lactate diffuses out of the muscle and enters the liver through blood. In the liver
lactate is oxidised to pyruvate which undergoes the process of gluconeogenesis
resulting in the resynthesis of glucose.
The glycogen may be once again converted to glucose (glycogenolysis) and may be
recycled to the muscle through the blood. The process of gluconeogenesis
completes the cycle by converting glucoseonce again to muscle glycogen.

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DIABETES MELLITUS

Diabetes mellitus is an important disorder of carbohydrate metabolism. However, fat and

protein metabolism are also affected in diabetic condition. Diabetes means excretion of
excessive volume of urine and mellitus means sweet. So the word diabetes mellitus refers
to chronic excretion of large volume of urine containing glucose.
Diabetes mellitus, caused by a deficiency in the secretion or action of insulin, is a
relatively common disease. Insulin is an endocrine hormone which is secreted by β-cells
of islets of Langerhans of pancreas. The abnormality in glucose metabolism is indicative
of diabetes or a tendency towards the condition. Diabetes mellitus is really a group of
diseases in which the regulatory activity of insulin is defective.
There are two major clinical classes of the disease:

1. Type-I or insulin dependent diabetes mellitus (IDDM), this disease begins early in the
life and quickly becomes severe.
2. Type - II or non-insulin dependent diabetes mellitus (NIDDM), this disease is slow to
develop, milder and often goes unrecognized.
Type one requires insulin therapy and careful, life-long control of the balance between
glucose intake and insulin dose. The decreased or defective production of insulin is
characterized by the following symptoms.
i.Decreased permeability of the cell membrane for glucose resulting in the accumulation of
glucose in the blood. This condition is known as hyperglycemia. Glucose concentration
increases as high as 500 mg/100 ml of blood.
ii.Polyuria: This means excretion of increased quantity of urine. This is to excrete the
additional quantity of glucose in urine (glucosuria).
iii.Polydipsia: The excessive thirst which leads to increased consumption of water. This
condition is known as polydipsia. This is to replace the volume of water excreted due
to polyuria.
iv.Polyphagia: Excessive appetite leads to polyphagia and increased intake of food. This is
to replace the lost nourishment. The diabetic has voracious appetite, but inspite of over
eating; they lose weight and become lean and emaciated.
v.As glucose is not enough for energy production, increased mobilisation of fat from
adipose tissue occurs. But the metabolism of fat is incomplete resulting in the
production of large amounts of the intermediary products of fat metabolism namely
ketone bodies (e.g. Acetoacetate and β-hydroxybutarate). This condition is known as
'ketosis' and excess ketone bodies cause severe acidosis, ultimately resulting in 'coma'.

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Deposition of lipids in the walls of the blood vessels resulting "atherosclerosis".

Biochemical measurements on the blood and urine are essential in the diagnosis and
treatment of diabetes, which causes profound changes in metabolism. A sensitive
diagnostic criterion is provided by the glucose tolerance test (GTT).

Classification of antidiabetic drugs: Antidiabetic drugs can be classified into two

categories:

1. Insulin injections: Mostly used on serious cases of diabetes.

2. Oral hypoglycaemic agents: These agents are the group of drugs that may be taken
singly or in combination to lower the blood glucose in type 2 diabetes. Type 2 diabetes
can be due to increased peripheral resistance to insulin or to reduced secretion of
insulin. Oral hypoglycaemic should be used together with changes in diet and lifestyle
to achieve good glycaemic control and it is customary to monitor such changes for
three months before considering medication.

Oral hypoglycaemic agents are not usually used in type 1 diabetes, but metformin may
be of use in overweight type 1 diabetics.
The following groups of oral hypoglycaemics are currently available:

Biguanides derivatives: Metformin; Sulphonylureas derivatives: glimepiride;

Postprandial glucose regulators: Repaglinide and Nateglinide;

Thiazolidinediones derivatives: Pioglitazone and Rosiglitazone and Acarbose:

which acts by inhibiting intestinal alpha glucosidases, which delays the absorption
and digestion of sucrose and starch.

Glucose Tolerance Test (GTT) or Oral Glucose Tolerance Test (OGTT)

A Glucose Tolerance Test in medical practice is the administration of glucose to determine

how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin
resistance, and sometimes reactive hypoglycemia. The glucose is most often given orally so
technically is terms as an oral glucose tolerance test (OGTT)

Preparation and cautions

The patient is instructed not to restrict carbohydrate intake in the days or weeks before
the test. The test should not be done during an illness, as results may not reflect the
patient's glucose metabolism when healthy. A full adult dose should not be given to a

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person weighing less than 43 kg (94 lb).
Procedure for OGTT

The patient should have been fasting for the previous 8-14 hours (water is allowed).
Then the patient has given a glucose solution to drink about 1.75 grams per kilogram
of body weight, to amaximum dose of 75 g. It should be drunk within 5 minutes.
Blood is drawn at intervals for measurement of glucose (blood sugar), the
intervals and number of samples varies according to the purpose of the test.
If renal glycosuria (sugar excreted in the urine despite normal levels in the blood) is
suspected, urine samples may also be collected for testing along with the fasting and 2
hour blood tests.

Interpretation of OGTT results

Fasting plasma glucose should be below 6.1 mmol/l (110 mg/dl). Fasting levels between
6.1 and 7.0 mmol/l (110 and 126 mg/dl) are borderline ("impaired fasting glycaemia"),
and fasting levels repeatedly at or above 7.0 mmol/l (126 mg/dl) are diagnostic of diabetes.
The 2 hour glucose level should be below 7.8 mmol/l (140 mg/dl). Levels between this
and 11.1 mmol/l (200 mg/dl) indicate, "Impaired Glucose Tolerance." A glucose level
above 11.1 mmol/l (200 mg/dl) at 2 hours confirms a diagnosis of diabetes.

REGULATION OF GLUCONEOGENESIS

The regulation of gluconeogenesis is determined primarily by the circulating level of

glucagon, and by the availability of gluconeogenic substrates.
A. Glucagon

This pancreatic islet hormone stimulates gluconeogenesis by three mechanisms.

Changes in allosteric effectors: Glucagon lowers the level of fructose 2, 6-

bisphosphate, resulting in activation of fructose 1, 6- bisphosphatase and
inhibition of phosphofructokinase , thus favoring gluconeogenesis over glycolysis.
Covalent modification of enzyme activity: Glucagon, via an elevation in
cyclic AMP (cAMP) level and c AMP- dependent protein kinase activity,
stimulates the conversion of pyruvate kinase to its inactive (phosphorylated) form.
This decreases the conversion of PEP to pyruvate, which has the effect of diverting
PEP to the synthesis of glucose.
Induction of enzyme synthesis: Glucagon increases the transcription of the
PEP- carboxykinase gene, thereby increasing the availability of this enzyme's

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activity as levels of its substrate rise during fasting.
[Note by: Insulin causes decreased transcription of the mRNA for this enzyme.]

B. Substrate availability

The availability of gluconeogenic precursors, particularly glucogenic amino acids,

significantly influences the rate of hepatic glucose synthesis. Decreased levels of insulin
favor mobilization of amino acids from muscle protein and provide the carbon skeletons
for gluconeogenesis.
C. Allosteric activation by acetyl CoA

Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during

fasting. As a result of excessive lipolysis in adipose tissue, the liver is flooded with fatty
acids. The rate of formation of acetyl CoA by β-oxidation of these fatty acids exceeds the
capacity of the liver to oxidize it to CO2 and H2O. As a result, acetyl CoA accumulates
and leads to activation of pyruvate carboxylase.
[Note: Acetyl CoA inhibits pyruvate dehydrogenase. Thus, this single compound can
divert pyruvate toward gluconeogenesis and away from the TCA cycle]

GLYCOGEN METABOLISM
Glycogen is a branched polymer of α-D-glucose.
The main stores of glycogen in the body are found in skeletal muscle and liver,
although most other cells store small amounts of glycogen for their own use.
The function of muscle glycogen is to serve as a fuel reserve for the synthesis of
adenosine triphosphate (ATP) during muscle contraction. That of liver glycogen is to
maintain the blood glucose concentration, particularly during the early stages of a fast.
Approximately 400 g of glycogen make up one to two percent of the fresh weight of
resting muscle, and approximately 100 g of glycogen make up to ten percent of the
fresh weight of a well-fed adult liver.

Structure of glycogen: Glycogen is a branched-chain homopolysaccharide made

exclusively from α-D- glucose. The primary glycosidic bond is an α(1→4) linkage.
After an average of eight–ten glucosyl residues, there is a branch containing an
α(1→6) linkage. A single molecule of glycogen can have a molecular mass of up to
108 daltons.
Liver glycogen stores increase during the well-fed state, and are depleted during a
fast. Muscle glycogen is not affected by short periods of fasting (a few days) and is
only moderately decreased in prolonged fasting (weeks).

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Glycogen biosynthesis:

The process of biosynthesis of glycogen from glucose is known as glycogenesis.

The process occurs in the cytosol, and requires energy supplied by ATP for the
phosphorylation of glucose and uridine triphosphate (UTP).
Glycogenesis is a very essential process since the excess of glucose is converted and
stored up as glycogen which could be utilised at the time of requirement. In the
absence of this process the tissues are exposed to excess of glucose immediately after
a meal and they are starved of it at other times.
The following are the various reactions of glycogenesis are as follows:

Step 1

Glucose is phosphorylated to glucose 6-phosphate, a reaction that is common to the first

reaction in the pathway of glycolysis from glucose. This reaction is catalysed by
hexokinase in muscle and glucokinase in liver in the presence of ATP.

Step 2

Glucose 6-phosphate is then reversibly converted to glucose 1-phosphate in a reaction

catalysed by enzyme phosphogluco mutase. This process requires Mg2+ and a small
amount of glucose 1, 6-diphosphate as coenzyme.

Step 3

The glucose 1-phosphate is then activated by the energy produced by the hydrolysis of
uridine triphosphate (UTP) in the presence of uridine diphosphate glucose
pyrophophosrylase. This is a key reaction in glycogen biosynthesis.

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Step 4

UDP-glucose is the immediate donor of glucose residues in the reaction catalyzed by

glycogen synthase, which promotes the transfer of the glucose residue from UDP-
glucose to a non-reducing end of a branched glycogen chain.

Step 5

When the chain has become long with more than 8 glucose units, a second enzyme,
namely branching enzyme amylo 1-4 to 1-6 transglycosylase acts on the glycogen.
Glycogen thus formed may be stored in liver, muscles and tissues.
If no other synthetic enzyme acted on the chain, the resulting structure would be a linear
(unbranched) molecule of glucosyl residues attached by α(1→4) linkages. Such a
compound is found in plant tissues, and is called amylose. In contrast, glycogen has
branches located, on average, eight glucosyl residues apart, resulting in a highly branched,
tree-like structure that is far more soluble than the unbranched amylose. Branching also
increases the number of nonreducing ends to which new glucosyl residues can be added.

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DEGRADATION OF GLYCOGEN (GLYCOGENOLYSIS)

When the blood sugar level falls (Hypoglycemia), glycogen stored in the tissues
specially glycogen of liver and muscles may be broken down and this process of
breakdown of glycogen is called glycogenolysis.
When glycogen is degraded, the primary product is glucose 1-phosphate, obtained by
breaking α (1→4) glycosidic bond. In addition, free glucose is released from each α
(1→6)-linked glucosyl residue.

A. Shortening of chains

Glycogen phosphorylase sequentially cleaves the α(1→4) glycosidic bonds between the
glucosyl residues at the nonreducing ends of the glycogen chains by simple
phosphorolysis until four glucosyl units remain on each chain before a branch point. The
resulting structure is called a limit dextrin, and phosphorylase cannot degrade it any
further.
B. Removal of branches

Branches are removed by the two enzymic activities of a single bifunctional protein, the
debranching enzyme. First, oligo-α (1→4)→α(1→4)-glucan transferase removes the
outer three of the four glucosyl residues attached at a branch. It next transfers them to the
nonreducing end of another chain, lengthening it accordingly. Thus, an α(1→4) bond is
broken and an α(1→4) bond is made, and the enzyme functions as a 4:4 transferase.
Then the remaining single glucose residue attached in an α(1→6) linkage is removed
hydrolytically by amylo-α(1→6)-glucosidase activity, releasing free glucose.

The glucosyl chain is now available again for degradation by glycogen phosphorylase
until four glucosyl units from the next branch are reached.
C. Conversion of glucose 1-phosphate to glucose 6-phosphate

Glucose 1-phosphate, produced by glycogen phosphorylase, is converted in the cytosol to

glucose 6- phosphate by phosphoglucomutase.
In the liver, glucose 6-phosphate is translocated into the endoplasmic reticulum (ER) by
glucose 6- phosphate translocase. There it is converted to glucose by glucose 6-
phosphatase—the same enzyme used in the last step of gluconeogenesis.
In the muscle, glucose 6-phosphate cannot be dephosphorylated because of a lack of
glucose 6- phosphatase. Instead, it enters glycolysis, providing energy needed for muscle
contraction.

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D. Lysosomal degradation of glycogen

A small amount (one–three percent) of glycogen is continuously degraded by the

lysosomal enzyme, α(1→4)-glucosidase (acid maltase). The purpose of this pathway is
unknown. However, a deficiency of this enzyme causes accumulation of glycogen in
vacuoles in the lysosomes, resulting in the serious glycogen storage disease type II
(Pompe disease).

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GLYCOGEN STORAGE DISEASES (GSD)

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) Glycogen storage
disease (GSD, also glycogenosis and dextrinosis) is the result of defects in the
processing of glycogen synthesis or breakdown within muscles, liver, and other cell
types
Glycogen is a major source of energy for the body. It is stored in the form of
glycogen in both the liver and muscles and later released with the help of enzymes.
Persons affected by GSD have an inherited defect in one of the enzymes responsible
for forming or releasing glycogen as it is needed by the body during exercise and/or
between meals.
Types of Glycogen Storage Disease
1. Type 0 - glycogen synthase deficiency:

The enzyme glycogen synthase is needed for the body to make glycogen. A deficiency
results in very low amounts of glycogen stored in the liver. A person between meals can
develop very low blood sugar levels, known as hypoglycemia.
2. Type I - Von Gierke Disease:
It is also known as glucose-6-phosphatase deficiency, in which the body cannot break
down glycogen for energy.
Gycogen is stored in the liver and muscles and is normally broken down into glucose
when you do not eat. It occurs when the body lacks the protein (enzyme) that releases
glucose from glycogen. This causes abnormal amounts of glycogen to build up in certain
tissues. When glycogen is not broken down properly, it leads to low blood sugar.
Von Gierke disease is inherited, which means it is passed down through families. If both
parents carry the defective gene related to this condition, each of their children has a 25%
chance of developing the disease.
3. Glycogen Storage Disease Type II:
It is also known as Pompe disease or acid maltase deficiency.

It is an inherited disorder caused by the buildup of a complex sugar called glycogen in

the body's cells. The accumulation of glycogen in certain organs and tissues,
especially muscles, impairs their ability to function normally.
Three types of Pompe disease,

i. The classic form of infantile-onset Pompe disease begins within a few months of birth.
Infants with this disorder typically experience muscle weakness (myopathy), poor
muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects. Affected

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infants may also fail to gain weight and grow at the expected rate (failure to thrive) and
have breathing problems. If untreated, this form of Pompe disease leads to death from
heart failure in the first year of life.
ii. The non-classic form of infantile-onset Pompe disease usually appears by age 1. It is
characterized by delayed motor skills (such as rolling over and sitting) and progressive
muscle weakness. The heart may be abnormally large (cardiomegaly), but affected
individuals usually do not experience heart failure. The muscle weakness in this
disorder leads to serious breathing problems, and most children with non-classic
infantile-onset Pompe disease live only into early childhood.
iii. The late-onset type of Pompe disease may not become apparent until later in childhood,
adolescence, or adulthood. Late-onset Pompe disease is usually milder than the
infantile-onset forms of this disorder and is less likely to involve the heart. As the
disorder progresses, breathing problems can lead to respiratory failure take place.
4. Glycogen Storage Disease Type IV:
It is also known as Andersen disease or brancher enzyme deficiency.
Deficient activity of the glycogen-branching enzyme is the cause of GSD Type IV. It
results in accumulation of abnormal glycogen in the liver, muscle and other tissues.

5. Glycogen Storage Disease Type V:

It is also known as McArdle Disease.
It cause due to myophosphorylase deficiency.
It is a rare metabolic disorder which causes muscle pain in everyday activities and
exercise. If activity is prolonged despite the pain then muscle damage ensues with
the risk of muscle breakdown and kidney failure.

6. Glycogen Storage Disease Type VI:

It is also known as Hers disease.

It cause due to liver phosphorylase deficiency.

7. Glycogen Storage Disease Type VII:

It is also known as Tarui disease.
It cause due to muscle phosphofructokinase deficiency.
The phosphofructokinase enzyme which is needed to facilitate the breakdown of
glycogen into energy in muscle. This results in reduced amount of energy available to
muscles during exercise.

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The body breaks down muscle when trying to attain energy, which causes symptoms
such as muscle pain, cramping, fatigue and tenderness. With the breakdown of muscle
and the release of the red protein myoglobin, red-brown urine may be seen.
The enzyme deficiency is due to abnormalities in the muscle phosphofructokinase
gene. GSD VII is inherited as an autosomal recessive genetic disorder.

8. Glycogen Storage Disease Type IX:

- It cause due to liver glycogen phosphorylase kinase deficiency.
- In most individuals apart from liver enlargement there are few other problems.
There is usually no tendency to low blood sugar, the liver becomes smaller with age
and children grow normally.

Summary of Glycogen storage disease (GSD, also glycogenosis and dextrinos

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HORMONE CONTROL OF CARBOHYDRATE METABOLISM

Introduction:

The metabolism of carbohydrates is regulated by a variety of hormones and other molecules.

Some of these have already been mentioned in previous sections. The proper functions of the
body are dependent on precise control of the glucose concentration in the blood. The normal
fasting level of glucose in the blood is 70-90 mg/100 ml.
If the concentration of glucose in blood is too high (above 120 mg/100 mL) a condition known
as hyperglycemia results. Hyperglycemia may temporarily exist as a result of eating a meal
rich in carbohydrates.
If the concentration of glucose is too low (below 70 mg/100 ml) a condition of hypoglycemia
exists. Hypoglycemia is characterized by general weakness, trembling, drowsiness, headache,
profuse perspiration, rapid heart beat, and possible loss of consciousness.
INSULIN:
Insulin, a polypeptide, is secreted from the pancreas in response to a hyperglycemia condition
which usually results shortly after ingesting a meal. The major effect of insulin is to promote
the transport of sugar across the cell membrane of fat and muscle cells. In addition, insulin
promotes anabolic processes such as increasing the rate of synthesis for glycogen
(glycogenesis), fatty acids, and proteins. Insulin inhibits the catabolic processes such as the
breakdown of glycogen and fat.
A deficiency of insulin (hypoinsulinism) results in a permanent hyperglycemic condition
known as diabetes mellitus. If little or no insulin is present, glucose cannot be utilized
properly by the cells and accumulates in the blood. Fatty acid metabolism is also upset. For
this reason, a detailed study of diabetes mellitus must wait until the next chapter.
Hyperinsulinism (too much insulin) leads to the hypoglycemic condition. Excessive amounts
of glucose are removed from the blood. Severe hypoglycemia may result when a diabetic
injects too much insulin. A severe insulin shock may result in a coma since glucose does not
reach the brain. A diabetic usually carries a glucose rich food, such as candy, to provide a
quick supply of glucose to replenish depleted glucose levels caused by too much insulin.
A functional type of hypoglycemia results in some individuals from an over stimulation of
insulin. The causes of hypoglycemia are not completely understood, but it occurs in some
people after eating heavily sugared food such as heavily sugared cereal and/or coffee and
sweet rolls. The initial high glucose levels over stimulates the pancreas to produce too much
insulin

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GLUCAGON:

If one hormone, insulin, controls the excess of glucose in the blood by stimulating synthesis
of glycogen, then other hormones must respond to low levels of glucose. The liver is more
responsive to glucagon, a peptide also secreted by the pancreas.
Glucagon increases glucose levels in the blood by stimulating the breakdown of glycogen
(glycogenolysis) in the liver into glucose which leaves the liver cells and enters the blood
stream. The method of hormone stimulation is a complex cascade effect. The exact sequence
has been worked out in the most detail for epinephrine (adrenalin) although glucagon works
in a similar fashion.

BIOLOGICAL OXIDATION
Biological oxidation-reduction reaction
Oxidation-reduction (or "redox") reactions are a very large class of chemical reactions in
which both oxidation and reduction necessarily occur.

An oxidation is defined as loss of electrons in the course of a chemical reaction. If a species

gains electrons, it is undergoing a reduction. Since electrons are "conserved" in a chemical
reaction (they are not created or destroyed), one chemical species' loss is another's gain. Thus,
a reduction cannot occur with a corresponding oxidation, and vice-versa. The term "redox"
also nicely encapsulates how inextricably tied together oxidation and reduction are in reality.

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Other terminology used in discussing redox chemistry: A chemical species that gets reduced
is acting as an oxidizing agent, or oxidant, while the species undergoing oxidation is acting
as the reducing agent, or reductant.

Oxidation state (or oxidation number) is a bookkeeping device employed by chemists to

help them classify and understand chemical reactions. The simplest way to interpret
oxidation number is to think of it as the number of electrons lost or gained by an atom
(compared to its neutral, uncombined form) when it reacts to form ions or molecules.
Consider first the case of ions. For monatomic ions, such as Na+ or Cl−, the oxidation
number is the same as the charge, +1 and −1, for the sodium cation and chloride anion,
respectively. In molecules and polyatomic ions, oxidation states for atoms are calculated by
comparing the number of valence electrons in the neutral atom with a count of the
surrounding bonding and nonbonding electrons in the Lewis structure. In this respect, it
is similar to determining formal charge of an atom in a Lewis structure. A general rule in
determining an oxidation number of an atom in a complete Lewis structure, is any
differences in electronegativity between covalently bonded atoms is treated as if the bond is
actually ionic. That means both electrons are counted as belonging to the more
electronegative atom.
In computing formal charge, electrons in covalent bonds are treated as equally shared,
despite differences in electro negativity. But like formal charge, the sum of the oxidation
numbers for each atom in a formula or Lewis structure for a molecular or ionic species must
sum to the net charge of that formula or Lewis structure (zero for a molecule). We will soon
see that assignment of oxidation numbers and following how they change in a chemical
reaction allows us to recognize redox reactions and determine the stoichiometry of the
electron transfer occurring.
It is easy to recognize any reaction featuring an uncombined, neutral element as a redox

reaction. examples are

CH4(g) + 2 O2(g) → CO2(g) + 2 H2O(l)

Fe(s) + O2(g) → Fe2O3(s)

2 Na(s) + Cl2(g) → 2 NaCl

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ELECTRON TRANSPORT CHAIN
Definition
The electron transport chain is a cluster of proteins that transfer electrons through a
membrane within mitochondria to form a gradient of protons that drives the creation of
adenosine triphosphate (ATP). ATP is used by the cell as the energy for metabolic
processes for cellular functions.
During the process, a proton gradient is created when the protons are pumped from the
mitochondrial matrix into the intermembrane space of the cell, which also helps in
driving ATP production. Often, the use of a proton gradient is referred to as the
chemiosmotic mechanism that drives ATP synthesis since it relies on a higher
concentration of protons to generate ―proton motive force‖. The amount of ATP
created is directly proportional to the number of protons that are pumped across the
inner mitochondrial membrane.
The electron transport chain involves a series of redox reactions that relies on protein
complexes to transfer electrons from a donor molecule to an acceptor molecule. As a
result of these reactions, the proton gradient is produced, enabling mechanical work to
be converted into chemical energy, allowing ATP synthesis. The complexes are
embedded in the inner mitochondrial membrane called the cristae in eukaryotes.
Enclosed by the inner mitochondrial membrane is the matrix, which is
where necessary enzymes such as pyruvate dehydrogenase and pyruvate
carboxylase are located. The process can also be found in photosynthetic eukaryotes in
the thylakoid membrane of chloroplasts and in prokaryotes, but with modifications.
By-products from other cycles and processes, like the citric acid cycle, amino acid
oxidation, and fatty acid oxidation, are used in the electron transport chain. As seen in
the overall redox reaction, energy is released in an exothermic reaction when electrons
are passed through the complexes; three molecules of ATP are created.

2 H+ + 2 E+ + ½ O2 → H2O + ENERGY
Phosphate located in the matrix is imported via the proton gradient, which is used to
create more ATP. The process of generating more ATP via the phosphorylation of ADP
is referred to oxidative phosphorylation since the energy of hydrogen oxygenation is
used throughout the electron transport chain. The ATP generated from this reaction go
on to power most cellular reactions necessary for life.

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Mechanism of ETC
In the electron transfer chain, electrons move along a series of proteins to generate an
expulsion type force to move hydrogen ions, or protons, across the mitochondrial
membrane. The electrons begin their reactions in Complex I, continuing onto Complex
II, traversed to Complex III and cytochrome c via coenzyme Q, and then finally to
Complex IV. The complexes themselves are complex-structured proteins embedded in
the phospholipid membrane. They are combined with a metal ion, such as iron, to help
with proton expulsion into the intermembrane space as well as other functions. The
complexes also undergo conformational changes to allow openings for the
transmembrane movement of protons.
These four complexes actively transfer electrons from an organic metabolite, such as
glucose. When the metabolite breaks down, two electrons and a hydrogen ion are
released and then picked up by the coenzyme NAD+ to become NADH, releasing a
hydrogen ion into the cytosol.

The NADH now has two electrons passing them onto a more mobile molecule,
ubiquinone (Q), in the first protein complex (Complex I). Complex I, also known as
NADH dehydrogenase, pumps four hydrogen ions from the matrix into the
intermembrane space, establishing the proton gradient. In the next protein, Complex II
or succinate dehydrogenase, another electron carrier and coenzyme, succinate is
oxidized into fumarate, causing FAD (flavin-adenine dinucleotide) to be reduced to
FADH2. The transport molecule, FADH2 is then reoxidized, donating electrons to Q
(becoming QH2), while releasing another hydrogen ion into the cytosol. While
Complex II does not directly contribute to the proton gradient, it serves as another
source for electrons.

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Complex III, or cytochrome c reductase, is where the Q cycle takes place. There is an
interaction between Q and cytochromes, which are molecules composed of iron, to
continue the transfer of electrons. During the Q cycle, the ubiquinol (QH2) previously
produced donates electrons to ISP and cytochrome b becoming ubiquinone. ISP and
cytochrome b are proteins that are located in the matrix that then transfers the electron
it received from ubiquinol to cytochrome c1. Cytochrome c1 then transfers it to
cytochrome c, which moves the electrons to the last complex. (Note: Unlike
ubiquinone (Q), cytochrome c can only carry one electron at a time). Ubiquinone then
gets reduced again to QH2, restarting the cycle. In the process, another hydrogen ion is
released into the cytosol to further create the proton gradient.
The cytochromes then extend into Complex IV, or cytochrome c oxidase. Electrons are
transferred one at a time into the complex from cytochrome c. Theelectrons, in addition
to hydrogen and oxygen, then react to form water in an irreversible reaction. This is the
last complex that translocates four protons across the membrane to create the proton
gradient that develops ATP at the end. As the proton gradient is established, F1F0 ATP
synthase, sometimes referred to as Complex V, generates the ATP. The complex is
composed of several subunits that bind to the protons released in prior reactions. As
the protein rotates, protons are brought back into the mitochondrial matrix, allowing
ADP to bind to free phosphate to produce ATP. For every full turn of the protein, three
ATP is produced, concluding the electron transport chain.

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Oxidative phosphorylation
Definition
Oxidative phosphorylation (UK or electron transport-linked phosphorylation) is the
metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing the
chemical energy of molecular oxygen, which is used to produce adenosine triphosphate
(ATP). In most eukaryotes, this takes place inside mitochondria. Almost all aerobic
organisms carry out oxidative phosphorylation. This pathway is so pervasive because the
energy of the double bond of oxygen is so much higher than the energy of the double bond
in carbondioxide or in pairs of single bonds in organic molecules observed in alternative
fermentation processes such as anaerobic glycolysis.

Overview:

The electron transport chain is a series of proteins embedded in the inner mitochondrial
membrane. In the matrix, NADH and FADH2 deposit their electrons in the chain (at the first
and second complexes of the chain, respectively). The energetically "downhill" movement of
electrons through the chain causes pumping of protons into the intermembrane space by the first,
third, and fourth complexes.
Finally, the electrons are passed to oxygen, which accepts them along with protons to form
water.
The electron transport chain is a series of proteins and organic molecules found in the inner
membrane of the mitochondria. Electrons are passed from one member of the transport
chain to another in a series of redox reactions. Energy released in these reactions is captured
as a proton gradient, which is then used to make ATP in a process called chemiosmosis.
Together, the electron transport chain and chemiosmosis make up oxidative
phosphorylation.

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Substrate-level phosphorylation

Substrate-level phosphorylation is a metabolic reaction that results in the formation of

ATP or GTP by conversion of a higher energy substrate (whether phosphate group
attached or not) into lower energy product and a using some of the released chemical
energy, the Gibbs free energy, to transfer a phosphoryl (PO3) group to ADP or
GDP from another phosphorylated compound. Unlike oxidative phosphorylation,
oxidation and phosphorylation are not coupled in the process of substrate-level
phosphorylation, and reactive intermediates are most often gained in the course of
oxidation processes in catabolism. Most ATP is generated by oxidative phosphorylation in
aerobic or anaerobic respiration while substrate-level phosphorylation provides a quicker,
less efficient source of ATP, independent of external electron acceptors. This is the case
in human erythrocytes, which have no mitochondria, and in oxygen-depleted muscle.
Adenosine triphosphate is a major "energy currency" of the cell. The high energy bonds
between the phosphate groups can be broken the power a variety of reactions used in all
aspects of cell function. Substrate-level phosphorylation occurs in the cytoplasm
of cells during glycolysis and in mitochondria either during the Krebs cycle or
by MTHFD1L , an enzyme interconverting ADP + phosphate + 10- formyltetrahydrofolate
to ATP + formate + tetrahydrofolate (reversibly), under both aerobic and anaerobic
conditions. In the pay-off phase of glycolysis, a net of 2 ATP are produced by substrate-
level phosphorylation.

GLYCOLYSIS

The first substrate-level phosphorylation occurs after the conversion of 3-

phosphoglyceraldehyde and Pi and NAD+ to 1,3-bisphosphoglycerate via
glyceraldehyde 3-phosphate dehydrogenase. 1,3-bisphosphoglycerate is then
dephosphorylated via phosphoglycerate kinase, producing 3-phosphoglycerate and ATP
through a substrate-level phosphorylation.

The second substrate-level phosphorylation occurs by dephosphorylating

phosphoenolpyruvate, catalyzed by pyruvate kinase, producing pyruvate and ATP.

During the preparatory phase, each 6-carbon glucose molecule is broken into two 3-carbon

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molecules. Thus, in glycolysis dephosphorylation results in the production of 4 ATP.
However, the prior preparatory phase consumes 2 ATP, so the net yield in glycolysis is 2
ATP. 2 molecules of NADH are also produced and can be used in oxidative
phosphorylation to generate more ATP.

Mitochondria
ATP can be generated by substrate-level phosphorylation in mitochondria in a pathway
that is independent from the proton motive force. In the matrix thereare three reactions
capable of substrate-level phosphorylation, utilizing either phosphoenolpyruvate
carboxykinase or succinate-CoA ligase,or monofunctional C1-tetrahydrofolate synthase.

Phosphoenolpyruvate carboxykinase

Mitochondrial phosphoenolpyruvate carboxykinase is thought to participate in the transfer

of the phosphorylation potential from the matrix to the cytosol and vice versa. However, it
is strongly favored towards GTP hydrolysis, thus it is not really considered as an important
source of intra-mitochondrial substrate- level phosphorylation.
Succinate-CoA ligase
Succinate-CoA ligase is a heterodimer composed of an invariant α-subunit and a substrate-
specific ß-subunit, encoded by either SUCLA2 or SUCLG2. This combination results in
either an ADP-forming succinate-CoA ligase or a GDP- forming succinate-CoA ligase.
The ADP-forming succinate-CoA ligase is potentially the only matrix enzyme generating
ATP in the absence of a proton motive force, capable of maintaining matrix ATP levels
under energy-limited conditions, such as transient hypoxia.
Monofunctional C1-tetrahydrofolate synthase
This enzyme is encoded by MTHFD1L and reversibly interconverts ADP + phosphate +
10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate.

Other mechanisms
In working skeletal muscles and the brain, Phosphocreatine is stored as a readily available
high-energy phosphate supply, and the enzyme creatine phosphokinase transfers a
phosphate from phosphocreatine to ADP to produce ATP. Then the ATP releases giving
chemical energy. This is sometimes erroneously considered to be substrate-level
phosphorylation, although it isa transphosphorylation.

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Importance of substrate-level phosphorylation in anoxia

During anoxia, provision of ATP by substrate-level phosphorylation in the matrix is

important not only as a mere means of energy, but also to prevent mitochondria from
straining glycolytic ATP reserves by maintaining the adenine nucleotide translocator
in ‗forward mode‘ carrying ATP towards thecytosol.

Oxidative phosphorylation
An alternative method used to create ATP is through oxidative phosphorylation, which
takes place during cellular respiration. This process utilizes the oxidation of NADH to
NAD+, yielding 3 ATP, and of FADH2 to FAD, yielding 2 ATP. The potential energy
stored as an electrochemical gradient of protons (H+) across the inner mitochondrial
membrane is required to generate ATP from ADP and Pi (inorganic phosphate molecule),
a key difference from substrate- level phosphorylation. This gradient is exploited by ATP
synthase acting as a pore, allowing H+ from the mitochondrial intermembrane space to
move down its electrochemical gradient into the matrix and coupling the release of
free energy to ATP synthesis. Conversely, electron transfer provides the energy required to
actively pump H+ out of the matrix.

Uncouplers of oxidative phosphorylation

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the
electron transport and phosphorylation reactions and thus inhibit ATP synthesis without
affecting the respiratory chain and ATP synthase. Uncouplers inhibit ATP synthesis by
preventing this coupling reaction in such a fashion that the energy produced by redox
reactions cannot be used for phosphorylation. Uncouplers include DNP, valinomycin, and
CCCP. Most of them are hydrophobic weak acids that act by protonophoric action and
activities.

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the

electron transport and phosphorylation reactions and thus inhibit ATP synthesis without
affecting the respiratory chain and ATP synthase (H(+)- ATPase). Miscellaneous
compounds are known to be uncouplers, but weakly acidic uncouplers are representative
because they show very potent activities. The most potent uncouplers discovered so far are

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the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in
vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid
dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are
required. Weakly acidic uncouplers are considered to produce uncoupling by their
protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting
these effects, the stability of the respective uncoupler anions in the hydrophobic membrane
is very important. High stability is achieved by delocalization of the polar ionic charge
through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic
uncouplers is characteristic of the highly efficient membrane targeting action of a
nonsite-specific type of bioactive compound.

One example of an ‗uncoupler‘ of oxidative phosphorylation is DNP (2,4-dinitrophenol).

2,4-Dinitrophenol (DNP), C6H4N2O5, is a cellular metabolic poison. It uncouples

oxidative phosphorylation by carrying protons across the mitochondrial membrane,
leading to a rapid consumption of energy without generation of ATP.

In living cells, DNP acts as a proton ionophore, an agent that can shuttle protons (hydrogen
ions) across biological membranes. It defeats the proton gradient across mitochondrial
membrane, collapsing the proton motive force that the cell uses to produce most of its ATP
chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as
heat.

DNP is often used in biochemistry research to help explore the bioenergetics of chemiosmotic
and other membrane transport processes.

The HMP shunt represents an alternative pathway for the breakdown of glucose. Briefly
describe the main products produced by this pathway and it‘s biological significance.

The main product are Ribose-5-P, NADPH and Intermediates of the glycolytic pathway.
HMP shunt represents an alternate degradative pathway for the breakdown of glucose, and
it provides a link between glycolysis and nucleotide metabolism and fatty acid.
Biological significance of Ribose-5-P is that serves as the precursor to various nucleotides
(ATP, NAD, NADP, coenzyme A) and nucleic acids (DNA) within our cells.
Biological significance of NADPH: represents the major source of reducing power for
biosynthetic reactions within cells, particularly the synthesis of fatty acids. It follows that the

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HMP shunt is active in tissues specialized for the synthesis of fatty acids or steroids.
Biological significance of Intermediates of the glycolytic pathway: the demand for NADPH in
the cell is usually far greater than the demand for ribose-5-P, thus the second phase of this
pathway is devoted to recycling the 5-carbon skeletons into intermediates of the glycolytic
pathway so that the cell can harness the energy that is present in these molecules.

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Very Short Questions (2marks)

1) Define Glucose Tolerance Tests (GTT).
2) What is Galactosemia?
3) What are Glycogen storage diseases?
4) Define glycogenesis.
5) Define glycogenolysis.

Short Questions (5marks)

1) Describe Cori‘s Cycle along with its significance.

2) Explain the amphibolic role of TCA cycle.
3) Explain the pyruvate dehydrogenase complex.
4) Name the irreversible enzymes of glycolysis and key enzymes of gluconeogenesis.
5) Write the Significance of HMP shunt pathway.
6) Write a short note on Electron Transport chain.

Long Questions (10marks)

1) Describe in detail EM Pathway along with its energetics and regulation.

2) Describe TCA cycle along with regulation and it‘s energetic. Add a note on its Amphibolic
role.
3) Explain the HMP shunt pathway and its significance.
4) Describe glycogen metabolism along with its regulation.
5) Explain the digestion and absorption of carbohydrates.
6) Describe various mechanisms for regulation of blood glucose.
7) Enumerate the gluconeogenic substrates and describe the reactions of gluconeogene

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