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Notes on Carbohyrates and it’s Metabolism

Carbohydrates are the most abundant organic molecules in nature. They are primarily composedof the elements carbon, hydrogen and oxygen. Carbohydrates may be defined as polyhydroxyaldehydes or ketones or compounds which produce them on hydrolysis.

FUNCTIONS OF CARBOHYDRATE

1. Carbohydrates are the main sources of energy in the body. Brain cells and RBCs are almost wholly dependent on carbohydrates as the energy source. Energy production from carbohydrates will be 4 kcal/g.

2. Storage form of energy (starch and glycogen).

3. Excess carbohydrate is converted to fat.

4. Glycoproteins and glycolipids are components of cell membranes and receptors.

5. Structural basis of many organisms: Cellulose of plants; exoskeleton of insects, cell wall of microorganisms, mucopolysaccharides as ground substance in higher organisms. The general molecular formula of carbohydrate is Cn(H2O)n. For example, glucose has the molecular formula C6H12O6. Carbohydrates are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis.

METABOLISM 

— The entire spectrum of chemical reactions, occurring in the living system, are referred as metabolism.

— A metabolic pathway constitutes a series of enzymatic reactions to produce specific products.

— Metabolism is divided into two categories
1. Catabolism : The degradative processes concerned with the breakdown of complex molecules to simpler ones , with release of energy.

2. Anabolism : The biosynthetic reactions involving the formation of complex molecules from simple precursors.

CARBOHYDRATE AND IT’S METABOLISM

— Carbohydrates are the major source of energy for the living cells.

— The monosaccharide glucose is the central molecule in carbohydrate metabolism since all the major pathways of carbohydrate metabolism are connected with it.

— Glucose is utilized as a source of energy, it is synthesized from non carbohydrate precursors and stored as glycogen to release as glucose when needed.

— The other monosaccharides important in carbohydrate metabolism are fructose, galactose and mannose.
 

Major pathways of carbohydrate and it’s metabolism:

1. Glycolysis: The oxidation of glucose to pyruvate and lactate.

2. Citric acid cycle: The oxidation of acetyl CoA to CO2.

3. Gluconeogenesis: The synthesis of glucose from non carbohydrate precursors.

4. Glycogenesis: The formation of glycogen from glucose.

5. Glycogenolysis : The breakdown of glycogen to glucose.

6. Hexose monophosphate shunt: An alternative pathway to glycolysis and citric acid cycle for the oxidation of glucose.

7. Uronic acid pathway: Glucose is converted to glucuronic acid, pentoses and ascorbic acid (an alternative oxidative pathway for glucose)

8. Galactose metabolism: conversion of galactose to glucose and the synthesis of lactose.

9. Fructose metabolism: oxidation of fructose to pyruvate

10. Amino sugar and mucopolysaccharide metabolism: The synthesis of amino sugars and other sugars for the formation of mucopolysaccharides and glycoproteins.

GLYCOLYSIS

— Also called as Embden-Meyerhof pathway (E.M pathway)

— Glycolysis is defined as the sequence of reactions converting glucose (or glycogen) to pyruvate or lactate, with the production of ATP.

— Glycolysis takes place in all cells of the body.

— The enzymes of this pathway are present in the cytosomal fraction of the cell.

— Glycolysis can be anaerobic or aerobic.

— Lactate is the end product under anaerobic condition.

— In the aerobic condition, pyruvate is formed, which is then oxidized to CO2 and H2O.

Significance:

— Glycolysis is a major pathway for ATP synthesis in tissues lacking mitochondria.

— Glycolysis is the only source of energy in erythrocytes.

— In strenuous exercise, when muscle tissue lacks enough oxygen , anaerobic glycolysis forms the major form of energy for muscles.

— Glycolysis is very essential for brain. The glucose in brain has to undergo glycolysis before it is oxidized to CO2 and H2O.

— Glycolysis( anaerobic) is summarized by the net reaction
Glucose + 2ADP + 2Pi 2 lactate + 2ATP

— Glycolysis is a central metabolic pathway and the intermediates of glycolysis are useful for the synthesis of amino acids and fat.

— Reversal of glycolysis will result in the synthesis of glucose (gluconeogenesis).

— The glycolytic pathway can be considered as the preliminary step before complete oxidation.

Reactions of Glycolysis:

The pathway is divided into 3 distinct phases:
1. Energy investment phase or priming stage
2. Splitting phase
3. Energy generation phase.

GLYCOLYSIS
          Fig.1:- GLYCOLYSIS

 

Energy investment phase:
— Glucose is phosphorylated to glucose 6-phosphate by hexokinase or glucokinase. This is an irreversible reaction, dependent on ATP and Mg2+.

— Glucose 6 –phosphate undergoes isomerization to give fructose 6- phosphate in the presence of the enzyme phosphohexose isomerase and Mg2+.

— Fructose 6-phosphate is phosphorylated to fructose1 ,6-bisphosphate by phosphofructokinase(PFK) (irreversible and a regulatory step in glycolysis)

Splitting phase:
— The six carbon fructose 1,6-bisphosphate is split to two three-carbon compounds, glyceraldehyde 3-phosphate and di hydroxyacetone phosphate by the enzyme aldolase.

— The enzyme phosphotriose isomerase catalyses the reversible inter conversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate.

— Thus, two molecules of glyceraldehyde 3-phosphate are obtained from one molecule of glucose

Energy generation phase:
— Glyceraldehyde 3-phosphate dehydrogenase converts glyceraldehyde 3- phosphateto 1,3-bisphosphoglycerate.

— NADH + H+ and a high energy compound 1,3-bisphosphoglycerate is formed.

— lodoacetate and arsenate inhibit the enzyme glyceraldehyde 3- phosphate dehydrogenase.

— In aerobic condition, NADH passes through the electron transport chain and 6 ATP (2 x 3 ATP)are synthesized— The enzyme phosphoglycerate kinase acts on 1,3-bisphosphoglycerate resulting in the synthesis of ATP and formation of 3- phosphoglycerate.

— 3-Phosphoglycerate is converted to 2-phosphoglyceratbey phosphoglycerate mutase. This is an isomerization reaction.

— The high energy compound phosphoenol pyruvate is generated from 2-phosphoglycerate by enolase.

— Enolase requires Mg2+ or Mn2+ and is inhibited by fluoride.

— The enzyme pyruvate kinase catalyses the transfer of high energy phosphate from phosphoenol pyruvate to ADP leading to the formation of ATP (Pyruvate kinase requires K+ and either Mg2+ or Mn2+.)

Energetics:

— Under anaerobic conditions, 2 ATP are synthesized.

— Under aerobic conditions, 8 or 6 ATP are synthesized-depending on the shuttle pathway that operates.

Reaction Enzyme responsible ATP
consumed
ATP
formed
Glyceraldehyde 3
phosphate 1,3 bis phosphoglycerate
Glyceraldehyde 3 phosphate
dehydrogenase
0 3*2 = 6
1,3 bis phosphoglycerate
3 phosphoglycerate
Phosphoglycerate kinase 0 2
Phosphoenolpyruvate
pyruvate
Pyruvate kinase 0 2
TOTAL 2 10
NET ATP SYNTHESIS IN GLYCOLYSIS IN AEROBIC CONDITION 10 – 2 = 8
ATPs

CITRIC ACID CYCLE

— Also called Krebs cycle or tricarboxylic acid (TCA)cycle

— It is the most important metabolic pathway for the energy supply to the body.

— About 65-70% of the ATP is synthesized in Krebs cycle.

— It involves the oxidation of acetyl CoA to CO2 & H2O.

— This cycle utilizes about two thirds of total oxygen consumed by the body.

— TCA cycle supplies energy and provides many intermediates required for the synthesis of amino acids, glucose , heme etc.

— Krebs cycle is the most important central pathway connecting almost all the individual metabolic pathways (either directly or indirectly) cycle is the final common oxidative pathway for carbohydrate, fats and amino acids.

— The cycle operates only under aerobic conditions.

— The enzymes of TCA cycle are located in mitochondrial matrix.

— It involves the combination of a two carbon acetyl CoA with a four carbon oxaloacetate to produce a six carbon tricarboxvlic acid, citrate.

— Oxaloacetate is considered to play a catalytic role in citric acid cycle.

Acetyl CoA + 3 NAD+ + FAD + GDP + Pi +2H2O 2CO2 + 3NADH +— Citric acid

3H+ + FADH2 + GTP + CoA

Citric Acid Cycle
                                    Fig.2:- Citric Acid Cycle

 

Reactions of citric acid cycle:

— Oxidative decarboxylation of pyruvate to acetyl CoA by pyruvate dehydrogenase complex.

Formation of citrate :
— Krebs cycle starts with the condensation of acetyl CoA and oxaloacetate, catalysed by the enzyme citrate synthase.
Citrate is isomerized to isocitrate by the enzyme aconitase.

— Dehydration followed by hydration oocurs, through the formation of an intermediate-cis-aconitate.
Formation of α-ketoglutarate :
— The enzyme isocitrate dehydrogenase (lCD) catalyses the conversion (oxidative decarboxylation) of isocitrate to oxalosuccinate and then to α- ketoglutarate.

— The formation o f NADH and the liberation of CO2 occur at this stage.
Conversion of α-ketoglutarate to succinyl CoA occurs through oxidative decarboxylation, catalysed by α-ketoglutarate dehydrogenase complex.

— second NADH is produced and the second CO2 is liberated.

Formation of succinate :
— Succinyl CoA is converted to succinate by succinate thiokinase.

— phosphorylation of GDP to GTP occurs.

— GTP is converted to ATP by the enzyme nucleoside diphosphate kinase. GTP + ADP ATP + GDP

Conversion of succinate to fumarate :
— Succinate is oxidized by succinate dehydrogenase to fumarate.

— This reaction results in the production of FADH2 and not NADH.

Formation of malate :
— The enzyme fumarase catalvses the conversion of fumarate to malate with the addition of H2O.

Conversion of malate to oxaloacetate :
— Malate is then oxidized to oxaloacetate by malate dehydrogenase.

— The third and final synthesis of NADH occurs at this stage.

— The oxaloacetate regenerated can combine with another molecule of acetyl CoA, and continue the cycle.

Energetics of citric acid cycle:

— During the process of oxidation of acetyl CoA via citric acid cycle,4 reducing equivalents(3 as NADH and one as FADH2) are produced.

— Oxidation of 3 NADH by electron transport chain coupled with oxidative phosphorylation results in the synthesis of 9 ATP, whereas FADH2 leads to the formation of 2 ATP.

— Besides, there is one substrate level phosphorylation

— Thus, a total of 12 ATP are produced from one acetyl CoA

— Hence, 2 Acetyl CoA produce total energy = 12* 2= 24 ATPs.

 

Aerobic glycolysis 8 ATP
Pyruvate dehydrogenase reaction(oxidation of 2
pyruvate)
6ATP
Citric acid cycle 24 ATP
Net gain of energy 38 ATP

HMP Shunt

Also called Hexose monophosphate pathway or pentose phosphate pathway or phosphogluconate pathway.

This is an alternative pathway to glycolysis and TCA cycle for the oxidation of glucose.

It is concerned with the biosynthesis of NADPH and pentoses.

The enzymes of HMP shunt are located in the cytosol.

The tissues such as liver, adipose tissue, adrenal gland, erythrocytes, testes and lactating mammary gland, are highly active in HMP shunt.

Most of these tissues are involved in the biosynthesis of fatty acids and steroids which are dependent on the supply of NADPH

REACTIONS OF HMP SHUNT:

— divided into two phases- oxidative and non-oxidative.

Oxidative phase:
— Glucose 6-phosphate dehydrogenase(G6PD) is an NADP-dependent enzyme that converts glucose 6-phosphate to 6- phosphogluconolactone, which is then hydrolysed by the gluconolactone hydrolase to 6-phosphogluconate.

— The next reaction involving the synthesis of NADPH is catalysed by 6-phosphogluconate dehydrogenase to produce 3 keto 6- phosphogluconate which then undergoes decarboxylation to give ribulose-5 -phosphate.

Non-oxidative phase :
— The interconversion of 3, 4, 5 and 7 carbon monosaccharides.

— Epimerase act on Ribulose5 –phosphate to produce xylulose 5- phosphate while ribose-5-phosphate ketoisomerase converts ribulose-5 –phosphate to ribose 5-phosphate— The enzyme transketolase catalyses the transfer of two carbon moiety from xylulose 5-phosphate to ribose 5-phosphate to give a 3-carbon glyceraldehyde 3-phosphate and a 7-carbon sedoheptulose 7-
phosphate.

— Transketolase is dependent on the coenzyme thiamine pyrophosphate (TPP) and Mg2+ ions.

— Transaldolase transfer 3-carbon fragment (dihydroxyacetone) from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to give fructose 6-phosphate and four carbon erythrose 4-phosphate.

— Transketolase acts on xylulose 5-phosphate & transfers a 2-carbon fragment (glyceraldehyde) from it to erythrose 4-phosphate to generate fructose 6-phosphate and glyceraldehyde 3-phosphate.

— The overall reaction may be represented as:

6 G6P + 12 NADP+ + 6H+ 2O 6CO2 + 12 NADPH + 12H+ + 5 G6P

Significance of HMP shunt:

— HMP shunt gives 2 important products-Pentoses and NADPH needed for the biosynthetic reactions and other functions.

Importance of pentoses:
— The pentose or its derivatives are useful for the synthesis of nucleic acids (RNA and DNA) and many nucleotides such as ATP, NAD+, FAD and CoA.

— Ribose 5-phosphate is the pentose of most importance.

Importance of NADPH:
— NADPH is required for the reductive biosynthesis of fatty acids and steroids.

— NADPH is used in the synthesis of certain amino acids involving the enzyme glutamate dehydrogenase.

— Continuous production of H2O2 in the living cells can chemically damage unsaturated lipids, proteins and DNA. This can be prevented to a large extent through antioxidant reactions involving NADPH.

— Microsomal cytochrome P450 system (in liver) brings about the detoxification of drugs and foreign compounds by hydroxylation reactions involving NADPH.

— Phagocytosis (engulfment of foreign particles, including microorganisms) carried out by white blood cells, requires the supply of NADPH

 Special functions of NADPH in RBC :
a. NADPH maintains the concentration of reduced glutathione which is required to preserve the integrity of RBC membrane.

b. NADPH is also necessary to keep the ferrous iron (Fe2+) of hemoglobin in the reduced state so that accumulation of methemoglobin ( Fe3+) is prevented.

Glucose 6 Phosphate dehydrogenase Deficiency

— G6PD deficiency is an inherited sex-linked trait.

— deficiency occurs in all the cells of the affected individuals, but it is more severe in RBC

— Decreased activity of G6PD impairs the synthesis of NADPH in

— RBC, which results in the accumulation of methemoglobin and peroxides in erythrocytes leading to hemolysis.

Clinical manifestations in G6PD deficiency :
— Most patients do not usually exhibit clinical symptoms.

— Some patients develop hemolytic anemia if they are administered oxidant drugs or exposed to a severe infection

— The drugs such as primaquine (antimalarial), acetanilide (antipyretic), sulfamethoxazole (antibiotic) or ingestion of fava beans (favism) produce hemolytic jaundice in these patients.

— Severe infection results in the generation of free radicals which can enter RBC and cause hemolysis.

— G6PD deficiency is associated with resistance to malaria( caused by Plasmodium falciparum).

— This is because the malarial parasites are dependent on HMP shunt and reduced glutathione for their optimum growth in RBC.

Wernicke-Korsakoff syndrome:

— This is a genetic disorder associated with HMP shunt.
— An alteration in transketolase activity that reduces its affinity with thiamine pyrophosphate is the biochemical lesion.
— The symptoms include mental disorder, loss of memory and partial paralysis

GLYCOGENESIS

GLYCOGENESIS
          Fig.3:- GLYCOGEESIS

 

Requirement of primer to initiate glycogenesis:
— A small fragment of preexisting glycogen must act as a ‘primer’ to initiate glycogen synthesis.

Glycogen synthesis by glycogen synthase :
— Glycogen synthase helps in the formation of 1,4-glycosidic linkages.

— Glycogen synthase transfers the glucose from UDP-glucose to the non-reducing end of glycogen to form α-1,4 linkages.

Formation of branches in glycogen

— Glucosyl α-4-6 transferase helps in branching and further elongation.

Glycogenolysis

— The degradation of stored glycogen in liver and muscle.

— Glycogen is degraded by breaking α-1,4 and α-1,6-glycosidic bonds.

— Irreversible pathway.

Action of glycogen phosphorylase:
— α-1,4-glycosidic bonds are cleaved by glycogen phosphorylase to yield glucose 1-phosphate.

— This process (phosphorolysis) continues until 4 glucose residues remain on either side of branching point

(α-1,6-glycosidic link).
— The glycogen so formed is known as limit dextrin which cannot be further degraded by phosphorylase.

Action of debranching enzyme :
— The branches of glycogen are cleaved by debranching enzyme.

— Glycosyl 4 : 4 transferase breaks α-1,4 bonds

— Amylo α-1,6-glucosidase breaks the α- 1,6 bond

Formation of glucose 6-phosphate and glucose :
— glucose 1-phosphate and free glucose are produced in a ratio of 8 : 1 by the action of glycogen phosphorylase and debranching enzyme,.

— Glucose 1- phosphate is converted to glucose 6 -phosphate by the enzyme phosphoglucomutase.

— glucose 6-phosphatase that cleaves G6P to glucose (in liver)

— T his enzyme is absent in muscle and brain

Glycogen Storage Diseases (GSD)

— The metabolic defects concerned with the glycogen synthesis and degradation are called as GSD.

— Occurs due to defects in the enzymes which may be either generalized (affecting all tissues) or tissue-specific.

— The inherited disorders are characterized by deposition of normal or abnormal type of glycogen in one or more tissues.

Von Gierke’s disease (type l):
— The incidence of the disease is 1 per 200,000 persons

— lt is transmitted by autosomal recessive trait.

— This disorder results in various biochemical manifestations

(1)Fasting hypoglycemia :
— Due to the defect in the enzyme glucose 6-phosphatase, enough free glucose is not released from the liver into blood.

(2)Lactic acidemia :
— Glucose is not synthesized from lactate produced in muscle and liver. Lactate level in blood increases and the pH is lowered (acidosis).

(3)Hyperlipidemia :
— There is a blockade in gluconeogenesis. So more fat is mobilized to meet energy requirements of the body.

— This results in increased plasma free fatty acids and ketone bodies.

(4)Hyperuricemia (Elevated plasma levels of uric acid):
— G6P that accumulates is diverted to HMP shunt leading to increased synthesis of ribose phosphates which increase the cellular levels of phosphoribosyl pyrophosphate and enhance the metabolism of purine nucleotides to uric acid.

— Hyperuricemia are often associated with gouty arthritis (painful joints).

Carbohyrates and it's metabolism

GLUCONEOGENESIS

The synthesis of glucose from noncarbohydrate compounds is known as gluconeogenesis.
— The major substrates/precursors for gluconeogenesis are lactate, pyruvate, glucogenic amino acids, propionate and glycerol.

— Gluconeogenesis occurs mainly in the cytosol, although some precursors are produced in the mitochondria.

— Gluconeogenesis mostly takes place in liver and kidney matrix.

— The overall summary of gluconeogenesis for the conversion of pyruvate to glucose:

2 Pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 6H2O Glucose + 2NAD+ + 4ADP + 2GDP + 6Pi + 6H+

Significance:

1. Brain and central nervous system, erythrocytes, testes and kidney medulla are dependent on glucose for continuous supply of energy. Human brain alone requires about 120 g of glucose per day, out of about 160 g needed by the entire body.

2. Glucose is the only source that supplies energy to the skeletal muscle, under anaerobic conditions.

3. In fasting even more than a day, gluconeogenesis must occur to meet the basal requirements of the body for glucose and to maintain the intermediate of citric acid cycle. This is essential for the survival of humans and other animals.

4. Certain metabolites produced in the tissues accumulate in the blood, e.g. lactate, glycerol, propionate etc. Gluconeogenesis clears them from the blood.

Conversion of pyruvate to phosphoenolpyruvate:
— This takes place in two steps.

— Pyruvate carboxylase converts pyruvate to oxalo acetate in presence of ATP and CO2.

— Oxaloacetate is synthesized in the mitochondrial matrix and is converted to malate and then transported to the cytosol (Due to membrane impermeability , oxaloacetate cannot diffuse out of the mitochondria).

— ln the cytosol, phosphoenolpyruvate carboxykinase converts oxaloacetate to phosphoenolpyruvate.

Conversion of fructose 1,6-bisphosphate to fructose 6-phosphate:
— The enzyme fructose 1,6-bisphosphatase (requires Mg 2+ ions) converts fructose 1,6-bisphosphate to fructose 6-phosphate.

Conversion of glucose 6-phosphate to glucose :
— Glucose 6-phosphatase catalyses the conversion of glucose 6-phosphate to glucose

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