METABOLISM OF CARBOHYDRATES

Topics:
✓ Glycolysis
✓ TCA cycle
✓ Glycogen metabolism
✓ Regulation of blood glucose level
✓ Disease related to abnormal metabolism of carbohydrate.
Metabolism: It refers to all the chemical reactions occurring in the living system in a well organized and integrated manner.
Metabolism is broadly divided in two categories: Catabolism and Anabolism.
1. Catabolism: The degradative process involve in the breakdown of complex molecules to simpler ones with the release of
energy.
2. Anabolism: It is biosynthetic reaction which involves the formation of complex molecules from simple ones.
* The term amphi-bolism is used for the reactions which are both catabolic and anabolic. E.g. Krebs Cycle (Citric Acid
Cycle)
Catabolism: The purpose of catabolism is to collect ATP required for the synthesis of complex molecules. It occurs in three
stages:
a) Conversion of complex molecules in to its simpler units like polysaccharides are converted to monosaccharides, lipids to
free fatty acid and glycerol, proteins to amino acids etc.
b) Formation of simple intermediates: the simpler units in stage 1 gets converted to simple intermediates such as pyruvate
and acetyl CoA. At this stage, the intermediates cannot be identified as carbohydrates, lipids or proteins.
c) Final oxidation of acetyl CoA: Oxidation of CoA in Krebs Cycle releases CO2 and also NADH and FADH2. This NADH
and FADH2 finally gets oxidized to liberate large quantity of energy in the form of ATP.
Anabolism: the anabolic reaction depends on supply of energy. The anabolic and catabolic pathways are irreversible and
occurs independently.
The biochemical reactions are of mainly four types:
1. Oxidation-reduction
2. Group transfer
3. Rearrangement and isomerization
4. Make and break of carbon-carbon bonds
 METABOLISM OF CARBOHYDRATES
Carbohydrates are major source of energy for living cells which are synthesized by plants during photosynthesis from
carbon-dioxide and water on absorption of light. Thus light is ultimate source of energy for all biological processes.
Glucose acts as basic unit of source of energy synthesized from non-carbohydrate precursors and stored as glycogen. The
other monosaccharides involved in carbohydrate metabolism are fructose, galactose and mannose.
The fasting blood glucose level in normal individual is 70-100 mg/dl of blood. Liver plays an important role in monitoring
blood glucose levels.
Major pathways of carbohydrate metabolism:
1. Glycolysis: Embden-Mayerhof-Parnas pathway (EMP Pathway). Oxidation of glucose to pyruvate and lactate.
2. Citric acid Cycle: Krebs cycle or tricarboxylic acid cycle(TCA Cycle). Oxidation of Acetyl CoA to CO2.
3. Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources.
4. Glycogenesis: Formation of glycogen from glucose.
5. Glycogenolysis: Breakdown of glycogen in to glucose.
6. Hexose monophosphate shunt: Pentose phosphate pathway or direct oxidative pathway. Oxidation of glucose.
7. Uronic acid pathway: Glucose converted to glucuronic acid.
8. Galactose metabolism: Conversion of galactose to glucose and synthesis of lactose.
9. Fructose metabolism: oxidation of fructose to pyruvate.
10. Amino sugar and mucopolysaccharide metabolism: Synthesis of amino sugars for the formation of
mucopolysaccharides and glycoproteins.

❖ GLYCOLYSIS: It is defined as the sequence of reactions converting glucose or glycogen to pyruvate or lactate, with the
production of ATP. It is the universal pathway in the living cells.
Salient features:
1. Occurs in all cells of the body. The enzyme for this pathway is present in cytoplasm of the cells.
2. It is both aerobic and anaerobic process. Pyruvate and lactate are the end products in both the processes respectively.
3. It is the major pathway for ATP synthesis in the tissues which lack mitochondria like cornea, erythrocytes, lens etc.
4. This process is essential for brain which is dependent on glucose for energy.
5. The intermediate products of glycolysis are useful for the synthesis of amino acids and fats.
Reactions of glycolysis: the pathway has three phases:
1. Energy investment phase or priming stage:
• In this phase, glucose is phosphorylated to glucose 6-phosphate by enzyme hexokinase or glucokinase. It is an
irreversible reaction dependant on ATP.
• Glucose 6-phosphate then isomerises to form fructose 6-phosphate in the presence of enzyme phospho-hexose
isomerase.
• Again fructose 6-phosphate is phosphorylated to fructose 1,6-biphosphate by phosphofructokinase.
2. Splitting phase:
• The six carbon fructose 1,6-biphosphate spilt in to two three carbon compounds, glyceraldehyde 3-phosphate and
dihydroxy acetone phosphate by enzyme aldolase.
• Isomerization of dihydroxy acetone phosphate to glyceraldehyde 3-phosphate also occurs in this step i.e. formation of 2
molecules of glyceraldehyde 3-phosphate.
3. Energy generation phase:
• Glyceraldehyde 3-phosphate is converted to 1,3-bisphosphoglycerate by enzyme dehydrogenase.
• This step involves formation of NADH+. In aerobic process, NADH passes through electron transport chain and 6 ATP
are produced.
• The enzyme phosphoglycerate kinase acts on 1,3-bisphosphoglycerate resulting in ATP synthesis.
Note:
• Glycolysis in erythrocytes leads to lactate production because mitochondria which is center for aerobic oxidation is absent.
• Brain, retina, skin, GI tract etc. derive their most of the energy through glycolysis.
• In glycolysis, under anaerobic condition, 2 ATP are synthesized while in aerobic condition, 7 ATP are synthesized.
• The inhibition of glycolysis by oxygen is known as Pasteur effect. It was discovered by Louis Pasteur.

❖ CITRIC ACID CYCLE/TCA CYCLE/ KREBS CYCLE: It involves oxidation of acetyl CoA to CO2 and H2O. About
65-70% of the ATP is synthesized in this cycle. It is regarded as central metabolic pathway and is final common oxidative
pathway for carbohydrates, fats and amino acids. It is the most important central pathway connecting almost all the
individual metabolic pathways either directly or indirectly.
• The enzymes for TCA cycle are present in mitochondrial matrix.
• It involves the combination of two carbon acetyl CoA with a four carbon oxaloacetate to produce a six carbon tricarboxylic
acid, citrate.
• It is an open cycle in which many compounds enter as reactant and leave as by-products.
Reactions of citric acid cycle:
Step 1. Formation of citrate: Condensation of acetyl CoA and oxaloacetate by enzyme citrate synthase to form citrate.
Step 2. and 3. Citrate is isomerized to isocitrate by enzyme aconitase. This isomerization occurs in two steps where cis-
aconitase is formed as intermediate product. This step is reversible accordingly.
Step 4. and 5. Formation of α-ketoglutarate by enzyme iso-citrate dehydrogenase having an intermediate oxalo-succinate. In
this step, formation of oxalo-succinate is reversible and NADH is formed while, formation of α-ketoglutarate is irreversible
and liberation of CO2 occurs.
Step 6. Conversion of α-ketoglutarate to succinyl CoA by enzyme alpha-ketoglutarate dehydrogenase complex. Formation of
NADH and liberation of CO2 also occurs in this step.
Step 7. Formation of succinate: Succinyl CoA is converted to succinate by succinate thiokinase. Here, phosphorylation of
GDP to GTP or ADP to ATP occurs. Also a molecule of CoA is released.
Step 8. Conversion of succinate to fumarate: oxidation of succinate by succinate dehydrogenase forms fumarate. This reaction
produces FADH2.
Step 9. Formation of malate: The enzyme fumarase converts fumarate to malate with the addition of H2O. This step is
reversible.
Step 10. Conversion of malate to oxaloacetate: Malate is oxidised to oxaloacetate by enzyme malate dehydrogenase. Synthesis
of NADH occurs in this step. Also oxaloacetate is regenerated which can combine with another molecule of acetyl CoA and
continue the cycle.
Summary of TCA cycle: Acetyl CoA + 3NAD+ + FAD + GDP + Pi +2H2O →2CO2 +3NADH +3H+ +FADH2 +GTP +CoA.
Note: *However there is no direct participation of O2 in TCA cycle but still this cycles operates only under aerobic conditions
because of its connection with electron transport chain where NAD+ and FAD are regenerated in the presence of O2.
Role of Vitamins in TCA cycle: B-complex vitamins are essential for Krebs cycle
1. Thiamine (as TPP) as a coenzyme for alpha-ketoglutarate dehydrogenase.
2. Riboflavin (as FAD) as a coenzyme for succinate dehydrogenase.
3. Niacin (as NAD+) as electron acceptor at 3 steps in TCA cycle.
4. Panthothenic acid (as CoA) attached to acetyl CoA and succinyl CoA.
5. Vitamin like compound, Lipoic acid also participates in TCA cycle.
Regulation of Citric acid cycle: Three enzymes, citrate synthase, isocitrate dehydrogenase and ꭤ-ketoglutarate
dehydrogenase regulate citric acid cycle.
1. Citrate synthase: inhibited by ATP, NADH, acetyl CoA and succinyl CoA.
2. Iso-citrate dehydrogenase: activated by ADP and inhibited by ATP and NADH.
3. ꭤ-ketoglutarate dehydrogenase: inhibited by succinyl CoA and NADH.
*Citric acid cycle is amphibolic in nature. It provides various intermediates for the synthesis of many compounds needed for
the body.
*It is actively involved in gluconeogenesis, transamination and deamination.
*Oxaloacetate and α-ketoglutarate respectively serves as precursor for synthesis of aspartate and glutamate which in turn
required for the synthesis of non-essential amino acids, purines and pyrimidine.
*Succinyl CoA is used for the synthesis of porphyrins and heme.

❖ GLYCOGEN METABOLISM: Glycogen is storage form of glucose in animals as starch in plants. Stored mostly in liver
and muscles. Glycogen is stored as granules in cytosol where most of the enzymes for glycogen synthesis and breakdown
are present.
Functions of Glycogen:
- Liver glycogen maintains blood glucose level
- Muscle glycogen serves as reserve for ATP supply during muscle contraction.

➢ GLYCOGENESIS: Synthesis of glycogen from glucose in the cytoplasm and requires ATP & UTP.
1. Synthesis of UDP-glucose (Uridine diphosphate glucose): the enzyme hexokinase (in liver) and glucokinase (in muscles)
convert glucose to glucose 6-phosphate. Phosphoglucomutase converts G-6-phosphate to G-1-phosphate, this further
converted to UDP-glucose by enzyme phosphorylase and then UTP.
2. Requirement of primer to initiate glycogenesis: a small fragment of glycogen acts as primer for glycogen synthesis. In the
absence of glycogen, a protein glycogenin performs the same function.
3. Glycogen synthesis by glycogen synthase: the enzyme glycogen synthase is responsible for formation of 1,4-glycosidic
linkages.
4. Formation of branches in glycogen: Glycogen is a branched tree like structure. The formation of branches occurs by
enzyme glucosyl 4-6 transferase.
➢ GLYCOGENOLYSIS: Degradation of stored glycogen in liver and muscles. Glycogen is degraded by breaking α-1,4-
and α-1,6- glycosidic bonds.
1. Action of glycogen phosphorylase: The α-1,4- glycosidic bonds are cleaved by glycogen phosphorylase to yield glucose
1-phosphate. This process is called phosphorolysis.
2. Action of debranching enzyme: debranching enzyme have two enzyme activities on single polypeptide, hence it is called
bifunctional enzyme. The branches of glycogen are cleaved by this enzyme. Other enzymes like glucosyl transferase and
α-1,6-glucosidase also involved in the reaction.
3. Formation of glucose 6-phosphate and glucose: Glucose 1-phosphate in step 1 gets converted to glucose 6-phosphate by
enzyme phosphoglucomutase. The liver, kidney and intestine contains enzyme glucose 6-phosphatase that cleaves
glucose 6-phosphate to free glucose molecule. Therefor liver is the major glycogen storage organ to provide glucose in
to the circulation which is to be utilized by various tissues.

Note:
*Acid maltase or α-1,4-glucosidase is a lysosomal enzyme that degrades small quantity of glycogen. Deficiency of this
enzyme results in glycogen accumulation causing Pompe’s disease.
*Glycogenesis and glycogenolysis are respectively controlled by enzymes glycogen synthase and glycogen phosphorylase.
Body controls the glycogen metabolism in such a way that when substrate availability and energy levels are high, glycogen
is synthesized. On the other hand when glucose concentration and energy levels are low, glycogen breakdown is enhanced.
*An elevated level of glucagon or epinephrine level increases glycogen degradation whereas elevated level of insulin results
in increased glycogen synthesis.
❖ REGULATION OF BLOOD GLUCOSE LEVEL: Glucose is the basic carbohydrate currency of body. About 18 gm
of free glucose is present in the body which is sufficient to fulfill the energy requirement of the body for an hour. Liver
produces about 180-220 gm of glucose/24 hrs by stored glycogen. The fasting blood glucose level is approx. 70-
100mg/dl of blood.

Sources of blood glucose:

1. Dietary source: dietary carbohydrate is digested and absorbed as monosaccharides like glucose, fructose, galactose etc.
The fructose and galactose also gets converted to glucose and then enter blood.
2. Gluconeogenesis: the degraded products of glycogen, fats and proteins like lactate, free glycerol and amino acid
respectively are good precursors for glucose synthesis. Gluconeogenesis continuously add glucose to blood.
Gluconeogenesis is the predominant source of glucose in late night but during day time, this process is less active.
3. Glycogenolysis: degradation of glycogen in liver produces free glucose. Glucose is primarily derived from
glycogenolysis during the meals.
4. Kidney plays an important role in homeostasis of blood glucose. Glucose is continuously filtered, reabsorbed and
returned to blood. The tubules of kidney can reabsorb glucose at a rate of 350mg/minute.
5. Hormone like insulin lowers the blood glucose level while other hormones like glucagon, epinephrine, thyroxine etc. do
the opposite action.
6. Growth hormone and ACTH also regulates blood glucose and their net effect is hypoglycaemic.
*Homeostasis refers to the ability of living organisms to maintain a constant environment despite changes in surrounding.
*If the blood glucose level increases above 160-180 mg/dl, it is excreted through urine. This this maximum value of glucose
in blood is referred as renal threshold for glucose.
*Glucagon is secreted by α-cells of islets of Langerhans and the condition of hypoglycemia stimulates its production.
*Hypoglycemia is a condition when blood glucose level falls to less than 45mg/dl.
Disease related to abnormal metabolism of carbohydrate:
1. Lactic acidosis: Elevation of lactic acid in circulation (Normal is 4-15mg/dl) due to its increased production or decreased
utilization. Mild form is not life threatening but severe form may lead to death. Its reason is inadequate supply of oxygen
to tissues.
2. Hyperammonemia: Elevated ammonia in circulation may be due severe liver disease or genetic defects of urea synthesis.
Accumulation of ammonia withdraws α-ketoglutarate from Krebs cycle, hence leads to reduction in levels of Krebs cycle
intermediates and decreased ATP generation.
3. Hyperglycemia: Increased production of blood sugar.
4. Glycosuria: It is a condition when kidneys are unable to filter glucose and other sugars properly from urine.
5. Glycogen storage disease (GSD) or glycogenosis: it refers to the metabolic defects concerned with the glycogen synthesis
and degradation like Pompe’s disease, Cori’s disease, Anderson’s disease etc.
6. Galactosemia: a rare diseased condition in infants inherited as autosomal recessive disorder, reason is due to deficiency of
enzyme galactose 1-phosphate uridyltransferase.
7. Fructosuria: Deficiency of enzyme fructokinase.
8. Atherosclerosis: Characterized by thickening of arteries due to accumulation of lipids. Reason is increased glycolysis
which results in lipogenesis and finally leads to elevated triacylglycerol and LDL-cholesterol.
❖ HEXOSE MONOPHOSPHATE SHUNT (HMP SHUNT/PATHWAY): Also known as pentose phosphate pathway or
phospho-gluconate pathway. This is an alternative pathway to glycolysis and citric acid cycle for the oxidation of glucose.
*HMP shunt is more anabolic in nature. The pathway starts with glucose-6-phosphate and no ATP is directly utilized or
produced in this.
*It is a multifunctional pathway which produce several interconvertible substances which proceeds different metabolic
reactions.
*The enzyme for HMP shunt is located in the cytosol. The tissues such as liver, adipose tissue, adrenal gland, erythrocyte,
testes and lactating mammary glands are highly active in HMP shunt.
*The sequence of reactions in HMP shunt is divided in two phases: Oxidative and non-oxidative.
1. Oxidative phase: Glucose 6-phosphate dehydrogenase (G6PD) is an NAPD dependent enzyme that converts glucose-6-
phosphate to 6-phosphogluconolactone.
2. Non-oxidative phase: In this, epimerase converts ribulose-5-phosphate to xylulose-5-phosphate and keto-isomerase
converts ribulose-5-phosphate to ribose-5-phosphate.

Note: HMP shunt is unique in generating two important products—pentoses and NADPH— needed for the biosynthetic
reactions and other functions.