Introduction to Carbohydrate Metabolism

Rev. Joseph Kwarteng

Faculty of Allied health Sciences
GCUC – Kumasi
Ghana
METABOLISM OF CARBOHYDRATES
 Introduction
• Usually carbohydrate metabolism consist of several pathways. Some of them are catabolic, few
are anabolic and one is amphibolic pathway. Further, most of the metabolic pathways of
carbohydrate metabolism either start with glucose or end with glucose. Hence, carbohydrate
metabolism means it is the metabolism of glucose.

• MEDICAL AND BIOLOGICAL IMPORTANCE OF GLUCOSE METABOLISM

1. Glucose is the major fuel for all types of cells in the body. Its oxidation produces energy.
2. Glucose consumption per day varies from one organ to another.
3. Some organs like brain prefers glucose as fuel than fat and protein. Brain consumes about 100
gm of glucose per day.
4. Rate of glucose oxidation is more in cancer cells. Hence, blocking glucose entry into cancer
cells can be a pharmacological technique for suppression of tumor growth.
5. Glucose is used for the formation of glycogen, pentoses, lactose and mucopoly saccharides.
6. Since brain is largely dependent on glucose for its energy needs glucose is synthesized from
glycogen or other non-carbohydrates during starvation/fasting or when food is in short supply .
GLYCOLYS
IS
(ATPs produced or consumed in each step and overall pathway)

(Feeder pathways)

(aerobic and anaerobic conditions)

 GLYCOLYSIS
• Defined as the ten (10) step catabolic pathway during which one
molecule of glucose is converted to two units of pyruvate and two (2)
ATP molecules.
• It is chemically represented by the equation:
Glucose + 2ATP 2 Pyruvate + 4ATP
• Glucose is the major metabolic fuel of mammals (except ruminants)
and a universal fuel of the fetus. It is the precursor for synthesis of all
the other carbohydrates in the body, including glycogen for storage;
Pentoses such as ribose and deoxyribose in nucleic acids; and
galactose in lactose of milk, in glycolipids, and in combination with
protein in glycoproteins and proteoglycans.
• Diseases associated with carbohydrate metabolism include diabetes
mellitus, galactosemia, glycogen storage diseases, and lactose
intolerance.
• Site of Glycolysis
Enzymes of glycolysis are present in the cytosol of most of the cells
present in the body.

• Source of Glucose
Dietary glucose formed from the digestion of dietary carbohydrates
enter liver through portal venous system after its absorption from the
intestine. Liver distributes glucose to all other organs (cells) of the
body.
• Dietary disaccharide are hydrolyzed into monosaccharide moieties
• Entry of the Glucose into the Cells and Tissues

• Glucose enters cells by facilitated transport.

1. Liver: Glucose enters liver cells by facilitated diffusion. It is an
insulin-independent transport mechanism for the transport of
glucose across liver cells.

2. Extra hepatic tissues:

Glucose enters adipocytes, erythrocytes, brain and skeletal muscle
by facilitated transport involving carrier molecule. The transport of
glucose across the membranes of these tissues by carrier is
dependent on insulin.
Overview of glycolysis
• Glycolysis is a near-universal pathway by which a glucose molecule is oxidized to
two molecules of pyruvate, with energy conserved as ATP and NADH.

• All ten glycolytic enzymes are in the cytosol, and all ten intermediates are
phosphorylated compounds of three or six carbons.

• In the preparatory phase of glycolysis, ATP is invested to convert glucose to

fructose 1,6-bisphosphate. The bond between C-3 and C-4 is then broken to yield
two molecules of triose phosphate.

• In the payoff phase, each of the two molecules of glyceraldehyde 3-phosphate

derived from glucose undergoes oxidation at C-1; the energy of this oxidation
reaction is conserved in the formation of one NADH and two ATP per triose
phosphate oxidized.
Two phases of glycolysis
 Preparatory Phase

Fig 14-2
 Reaction 1: phosphorylation

pg 526
Reaction 1: phosphorylation
 Hexokinase vs. glucokinase

Tissue-specific
isozymes.

Fig 15-14
 Reaction 2: isomerization

aldose ketose
Reaction 2: isomerization
Reaction 3: phosphorylation
Reaction 3: phosphorylation
Reaction 4: cleavage
Reaction 4: cleavage
Reaction 5: isomerization
Reaction 5: isomerization
Keeping Track of Carbons

G3P

glucose
Reaction 6: oxidation
Reaction 6: oxidation
Reaction 7: substrate level phosphorylation
Reaction 8: shift of phosphoryl group
Reaction 8: shift of phosphoryl group

Fig 14-3
~Fig 14-8
Reaction 9: dehydration
Reaction 10: substrate level phosphorylation
Importance of phosphorylated intermediates

1. Because the plasma membrane generally lacks transporters for phosphorylated sugars, the
phosphorylated glycolytic intermediates cannot leave the cell. After the initial phosphorylation,
no further energy is necessary to retain phosphorylated intermediates in the cell, despite the
large difference in their intracellular and extracellular concentrations.

2. Phosphoryl groups are essential components in the enzymatic conservation of metabolic

energy. Energy released in the breakage of phosphor-anhydride bonds (such as those in ATP) is
partially conserved in the formation of phosphate esters such as glucose 6-phosphate. High-
energy phosphate compounds formed in glycolysis (1,3-bisphosphoglycerate and
phosphoenolpyruvate) donate phosphoryl groups to ADP to form ATP.

3. Binding energy resulting from the binding of phosphate groups to the active sites of enzymes
lowers the activation energy and increases the specificity of the enzymatic reactions. The
phosphate groups of ADP, ATP, and the glycolytic intermediates form complexes with Mg 2+, and
the substrate binding sites of many glycolytic enzymes are specific for these Mg 2+ complexes.
Most glycolytic enzymes require Mg2+ for activity.
 Summary
During glycolysis, some of the energy of the
Energy glucose molecule is conserved in ATP, while
much remains in the product, pyruvate.
investment
The overall equation for glycolysis is:

Glucose + 2NAD + 2ADP + 2Pi

Cleavage 2 pyruvate + 2NADH + 2H + + 2ATP + 2H2O

Energy The ATP yield from glycolysis under

Harvest anaerobic conditions (2 ATP per molecule of
glucose) is much smaller than that from the
complete oxidation of glucose to CO2 under
aerobic conditions (30 or 32 ATP per glucose;
 Efficiency

The direct oxidation of glucose will cost the cell more interms of
O2 and energy. However, this cost burden is reduced when done
through the pyruvate intermediate as shown in above equations.
 Feeder Pathways for supply
of other monosaccharides
into the glycolytic pathway

 All carbohydrates
enter glycolysis

 In muscle, often
via hexokinase

glycerol

Glycerol 3-P
Fig 14-9
FATE OF PYRUVATE IN ANAEROBIC/HYPOXIC CONDITIONS
 Under anaerobic conditions, pyruvate from glycolysis are reduced (fermented) to
 lactic acid in humans and animals (lactic acid accumulate in muscles and cause
fatigue/exhaustion) OR
 ethanol in bacteria and fungi.
FATE OF PYRUVATE IN AEROBIC CONDITIONS
 Under aerobic conditions, pyruvate from glycolysis is further oxidized to yield
acetaldehyde which is complemented to Coenzyme A to yield a complex called Acetyl
CoA (A-CoA).

 The Acetyl-CoA enters into the TCA cycle and consequently oxidative phosphorylative
pathway.
Energetics of Glycolysis
Generation and consumption of ATP in anaerobic and aerobic glycolysis is given below.
In aerobic glycolysis:

1. Number of ATPs generated by phosphoglycerate kinase 2

2. Number of ATPs generated by Pyruvate kinase 2
3. Number of ATPs generated by respiratory chain oxidation
of 2 NADH produced in reaction 6 6
4. Number of ATPs consumed in reaction 1 and 3 –2
Net = 8

In anaerobic glycolysis, 2 NADH produced in reaction 6 are used to convert pyruvate to

lactate. Hence, ATP is not generated. Therefore, the net ATP production in anaerobic
glycolysis is only 2 (8 – 6 = 2). Thus, oxidation of glucose to pyruvate (aerobic
glycolysis) generates 8 ATP molecules whereas oxidation of glucose to lactate
(anaerobic glycolysis) generates 2 ATP molecules.
 Medical and Biological Importance of Glycolysis
1. Glycolysis provides energy to cells. Anaerobic glycolysis meets energy requirement
of rapidly contracting skeletal muscle.

2. Since heart is mainly aerobic organ, myocardial ischemia decreases glycolytic ability
of cardiac muscle. As a result energy or ATP production in heart is affected.

3. Deficiency of enzymes of glycolysis (pyruvate kinase) causes haemolytic anemia.

This is because erythrocytes gets their energy from glycolysis.

4. Deficiency of muscle phosphofructo kinase -1 (PFK-1) causes decreased muscular

performance and fatigue.

5. Dietary fructose and galactose are also metabolized by this pathway.

Contd.

6. Glycolysis has amphibolic role also. It provides precursors for the formation of lipids
and aminoacids. For example, pyruvate is converted to alanine by transamination and
dihydroxy acetone phosphate serves as precursor for triglyceride formation.

7. Two glycolytic intermediates pyruvate and glyceraldehydes-3-phosphate are used for

the synthesis of cholesterol, thiamine and pyridoxine in tuberculosis, malaria and
gastritis causing organisms.

8. Glycolysis is the major energy source for rapidly growing malerial parasite in R.B.C.
Lactate is the end product of glycolysis in malerial parasite. LDH of parasite is
different from human enzyme. Unlike human LDH parasite enzyme is not subjected to
inhibition by substrate pyruvate. This allows rapid formation of lactate from pyruvate
and fast energy production.

9. In brain tumors lactate production is 10 times more

 Fructose intolerance
Hereditary fructose intolerance results from a defect in fructose
breakdown in the liver, usually in aldolase.
 REGULATION OF GLYCOLYSIS

 Usually metabolic pathways are regulated by altering activities of few enzymes of

that pathway.

 Glycolysis is under allosteric and hormonal control. Hexokinase, phosphofructo

kinase – 1, and pyruvate kinase are regulatory enzymes of glycolysis. Their activities
are allosterically controlled. Furthermore, glucokinase, phosphofructokinase-1 and
pyruvate kinase are under hormonal control also.

 While allosteric control is fast and immediate, hormonal control is slow and takes a
long time to achieve.
Allosteric Regulation of
glycolysis

Irreversible steps are

regulated:
Hexokinase/Glucokinase

Phosphofructokinase I

Pyruvate Kinase
1) Allosteric regulation of glycolysis

 Phosphofructokinase-1 is the major regulatory enzymes of glycolysis.

It is an allosteric enzyme and catalyzes rate limiting reaction of
glycolysis. It is inhibited by ATP and citrate. AMP and fructose-6-
phosphate are activators of this enzyme.

 Pyruvate kinase is the second regulatory enzyme. It is inhibited by

ATP and phosphoenolpyrvate.

 Glucose - 6-phosphate inhibits activity of hexokinase. So, when ATP

(energy) concentration is high glycolysis is inhibited and decrease in
ATP level increases rate of glycolysis.
 Control of Hexokinase

Glucose + ATP  G6P + ADP

Feedback inhibition by G6P.

Tissue-specific isozymes.
 Control of PFK-1

Many allosteric effectors; e.g., ATP.

H+,
 Control of PFK-1

ATP is an
allosteric inhibitor of
PFK-1.

Two binding sites:

substrate and
allosteric site.
 Control of pyruvate kinase

PEP + ADP  pyruvate + ATP

Control of pyruvate kinase
2) Hormonal regulation of glycolysis
 On a slightly longer time scale, glycolysis is regulated by the hormones
glucagon, epinephrine, norepinephrine, corticosteroids, and insulin, and
by changes in the expression of the genes for several glycolytic
enzymes.

 Insulin increases rate of glycolysis by increasing concentration of

glucokinase, phosphofructokinase-1 and pyruvate kinase.
Que: Discuss the hormonal control of glycolysis
Que: State three main hormones
and discuss how they interplay to
regulate glycolysis in cells.
 Poisons that inhibit the glycolytic pathway.
1. Iodoacetate (IA) , iodoacetamide (IAA), Arsenate, and heavy metals like Mercury
(Hg2+) , Silver (Ag+ ), etc.

These inhibit glycolysis by inactivating the enzyme glyceradehyde – 3 – phosphate

dehydrogenase.

They bind irreversible to the sulhydryl groups (-SH) of the enzyme proteins thereby
deforming the 3-D conformation of the enzyme active site. They thus decrease
muscular energy production causing general weakness and consequently death.

Are both used as rodent poison.

iodo.gif
 2. During detoxification in the liver and kidney, the fluoroacetate can be converted to
fluorocitrate – another poison.

The fluorocitrate also inhibit two enzymes namely:

a. phosphofructokinase – 1 (PFK-1) during glycolysis
b. Aconitase - during the TCA cycle.

In view of this, fluoroacetate is referred to as a “suicidal inhibitor” and as rodent poison.

3. Enolase is inibited by fluoride.

Medical Importance

1. Inhibition of glycolysis by fluoride is exploited for accurate estimation of blood

glucose level. If fluoride is not added to blood the glucose concentration in the blood
decreases due to consumption of glucose by erythrocytes. Hence, inaccurate low
blood glucose value is obtained on analysis.

2. 2,3 – bis Phosphoglycerate Cycle

It is involved in the synthesis of 2, 3-bis phosphoglycerate from 1, 3-bis
phosphoglycerate in erythrocytes. Because of this energy yielding reaction catalyzed
by phosphoglycerate kinase is bypassed. The formation of 2, 3-bis phosphoglycerate
from 1, 3-bisphosphoglycerate is catalyzed by bisphosphoglycerate mutase (Fig. 9.2b).
It is also called as Rapoport-Leubering cycle.
Importance
3. In the erythrocytes 2, 3-BPG aids unloading of oxygen by oxyhaemoglobin.
4. Due to the diversion of 1, 3-BPG to 2, 3-BPG production, energy yield of glycolysis is less in erythrocytes.
REVIEW QUESTION
1. Define glycolysis. Name types of glycolysis. Detail any one process along
with energetics.

2. How dietary fructose and galactose are utilized in the body? Write about
inherited diseases associated with their utilization.

3. Describe inherited diseases of carbohydrate metabolism.

4. Write normal blood glucose level. Name its sources. How it enters cells?
Outline its fate inside cell.

5. Write significance of glycolysis.

CASES IN BIOCHEMISTRY
1. A child was brought to hospital with vomiting, dizziness and sweating. The child
developed all these problems and diarrhoea only after consumption of fruits, fruit
juices or sweets made from jaggery and sugar. The child mother informed on
questioning that the child was normal on breast feeding. On examination his weight
was found to be below normal and had liver enlargement. His blood glucose level was
below normal but reducing substances were found in urine. Write your diagnosis.

2. A 10-year old boy with an history of reeling sensation and sweating was brought to
hospital. Physical examination showed swelling in the abdomen, liver enlargement
and normal heart. Glycogen isolated from liver biopsy specimen had normal
structure. Blood glucose level was below normal, uric acid and lipid levels were
elevated. Discuss your diagnosis.