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Carbohydrate Metabolism Glucose Metabolism ● Glucose is the preferred source of energy for most tissues . ● Erythrocytes are fully reliant on glucose for energy . ● Brain , in normal conditions , uses only glucose as ATP source and metabolize it at a constant rate ; it depends on glucose in blood ; at basal metabolic rate 60% of glucose oxidized is by brain . ● Glucose metabolism include the following metabolic pathways : 1. Glycolysis & Citric acid cycle 2. Glycogenesis & Glycogenolysis 3. Gluconeogenesis 4. Pentose Phosphate Pathway 5. Minor Pathways ( ex : Polyol Pathway ) ● Glucose is oxidized to generate energy ( ATP ) by the pathways of Glycolysis & Citric Acid Cycle . ● When the blood glucose level is high (after meals ) the excess is converted to glycogen and stored (Glycogenesis ) .The body has limited capacity for storing glycogen and the remaining excess glucose is converted to fat and stored ( Lipogenesis ) . ● During fasting , when glucose level in blood decreases , the supply of glucose for the brain is maintained by Glycogenolysis ( glycogen breakdown ) and Gluconeogenesis ( synthesis of glucose from non-carbohydrate sources ) . Oxidation of Glucose A – Aerobic Oxidation of Glucose ● Under aerobic conditions ( oxygen in plenty ) and in the tissues containing mitochondria , glucose is oxidized in two stage (Glycolysis & Citric acid cycle) to generate energy ( ATP ) . Glycolysis ( first stage ) A series of reactions by which each molecule of glucose ( 6-carbon compound ) is converted to two molecules of pyruvate ( 3-carbon compound ) as end product . It is cytosolic pathway taking place in all the cells of the body . Pyruvate is then transported into mitochondria where it is completely oxidized through Citric Acid cycle ( second stage) to CO2 and H2O . Reactions of glycolysis : Step 1 : phosphorylation of glucose by ATP and glucose-6-phosphate is formed . The reaction is irreversible and catalyzed by Hexokinase (present in all tissues ) & Glucokinase ( present only in liver and pancreas ) . Step 2 : isomerization of glucose-6-p to fructose-6-phosphate . Step 3 : phosphorylation of fructose-6-p to give F-1,6-bisphosphate by the enzyme phosphofructokinase (PFK-1) . Reaction is irreversible . PFK-1 is the ratelimiting enzyme . Step 4 : cleavage of F-1,6-bisphosphate into two 3-carbon compounds : glyceraldehydes-3-p & dihydroxy acetone-p . These are inter-converted to each other by an isomerase enzyme . Step 5 : phosphorylation and simultaneous oxidation of glyceraldehydes-3-p to 1,3-bisphosphoglycerate . One molecule of NADH is produced . Step 6 : transfer of high energy phosphate group (~P) from 1,3-bisphosphoglycerate to ADP forming ATP ( substrate level phosphorylation) and the product 3-phosphoglycerate . Step 7 : isomerization of 3-phosphoglycerate to give 2-phosphoglycerate . Step 8 : dehydration of 2-phosphoglycerate to form phosphoenol pyruvate (PEP) . Step 9 : transfer of ~P from PEP to ADP producing ATP and pyruvate .The enzyme is pyruvate kinase (PK) and the reaction is irreversible Note : ● NADH formed in both stages of aerobic oxidation of glucose oxidation ( glycolysis & citric acid cycle ) is oxidized back to NAD+ through the electron transport chain and significant number of ATP molecules are generated . A – Anaerobic Glycolysis : Under anaerobic conditions ( hypoxia ; oxygen in short supply) or in the absence of mitochondria , Pyruvate is reduced to lactate by the enzyme lactate dehydrogenase (LDH) to regenerate NAD+ .This is called anaerobic glycolysis in which the end product of glycolysis is lactate . ■ Skeletal muscle tissue is highly anaerobic tissue because : 1. actively contracting skeletal muscle during intensive exercise develops hypoxic conditions because the need for ATP formation exceeds the rate of oxygen consumption . 2. muscle LDH (M4) has a low km ( higher affinity ) for pyruvate . 3. Fast–twitch white skeletal muscles lack myoglobin and contain very few mitochondria . ********************* ■ Anaerobic glycolysis is the only source of energy in erythrocytes as they lack mitochondria . ■ Cancer cells grow more rapidly than normal cells leading to relative degree of hypoxia . Cancer cells metabolize glucose by anaerobic pathway and at a higher rate and so lactate accumulates causing acidic environment in the tumor . ■ Cardiac muscle tissue is aerobic tissue ; LDH in heart muscles ( H4 ) has low affinity for pyruvate and high affinity for lactate . Heart muscles metabolize glucose aerobically and have low anaerobic glycolytic activity and poor survival under hypoxic (ischemic ) conditions . Pyruvate Dehydrogenase ( PDH ) Reaction : ● In the matrix of mitochondria , pyruvate undergo oxidative decarboxylation and converted into 2-carbon high energy compound Acetyl-CoA . This reaction is catalyzed by a multi-enzyme complex system called pyruvate dehydrogenase complex (PDH system) which require five coenzymes ( derived from five vitamins ) and also require Mg2+ as cofactors : ■ ■ ■ ■ ■ Thiamine pyrophosphate (TPP) Lipoamide Coenzyme A ( CoA-SH ) FAD , and NAD+ ● In this reaction , One molecule of NADH is formed and one molecule of CO2 is liberated . ● Acetyl-CoA is then enters the citric acid cycle and completely oxidized to CO2 and H2O and generate significant ATP . ● Pyruvate dehydrogenase (Oxidative decarboxylation of pyruvate to acetyl-CoA ) is the link between glycolysis and citric acid cycle . ● This reaction is completely irreversible process and there is no alternate reaction in the body that forms pyruvate from acetyl-CoA . ************************************* Energy Yield ( ATP ) from Glycolysis * Number of ATP molecules generated by glycolysis per molecule of glucose under aerobic conditions ( oxygen in plenty ) : Step Enzyme Source Number of ATP gained or used ─────────────────────────────────────────────────── 1Hexokinase ATP Minus one ( used ) 3- Phosphofructokinase-1(PFK-1) ATP Minus one (used) 5- Glyceraldehyde-3-p dehydrogenase NADH 3 x 2 = 6 ( gained ) 6- Phosphoglycerate Kinase ATP 1 x 2 = 2 ( gained ) 9- Pyruvate Kinase ATP 1 x 2 = 2 ( gained ) ─────────────── Total = 10 − 2 = 8 ATP * Number of ATP molecules generated by glycolysis per molecule of glucose under anaerobic conditions ( hypoxia ) or in the lack of mitochondria : Step Enzyme Source Number of ATP gained or used 1- Hexokinase ATP Minus one ( used ) 3- Phosphofructokinase-1 (PFK-1) ATP Minus one ( used ) 6- Phosphoglycerate Kinase ATP 1 x 2 = 2 ( gained ) 9- Pyruvate Kinase ATP 1 x 2 = 2 ( gained ) ─────────────── Total = 4 − 2 = 2 ATP **************************** Regulation of Glycolysis Phosphofructokinase-1 ( PFK-1 ) is the key rate-limiting enzyme in glycolysis . The activity of this enzyme is controlled as follows : A - PFK-1 is inhibited by : 1 - allosterically inhibited by high ATP level . 2 - feed-back inhibition by the product Citrate ( allosteric inhibition ) . 3 - low pH ( high H+ concentration ) due to increased Lactate . II - PFK-1 activated by : 1. AMP ( high levels ) . Advantage of having both the enzymes Hexokinase & Glucokinase in liver : 1. Hexokinase has high affinity for glucose ( Km ≈ 0.04 mM ) . Since the resting level for blood glucose is about 5mM , therefore hexokinase would be expected to be fully active for all body cells at the resting level and the liver would not be competing with other cells for glucose . On the other hand , Glucokinase has lower affinity for glucose ( Km ≈ 6 mM ) ; have significant activity when blood glucose levels exceed 10 mM ( such as after a carbohydrate–rich diet ) , and at that concentration liver competes with other tissue for glucose and the excess glucose preferentially taken into liver where it can be stored as glycogen . 2. Hexokinase is inhibited allosterically by high levels of its product glucose-6-p . But glucokinase is not inhibited by the product glucose-6-p . Therefore , liver can metabolize glucose preferentially over the other tissues . Clinical aspects : *Hexokinase deficiency inherited deficiency of the enzyme hexokinase cause hemolytic anemia ; less ATP is generated in erythrocytes and are easily destroyed . *Pyruvate Kinase deficiency in erythrocytes There is decreased production of ATP from glycolysis . Red blood cells have insufficient ATP for their sodium pump . The cells become dehydrated and are phagocytosed by cells in the spleen and a hemolytic anemia result . Intermediates of glycolysis including 2,3-Bisphosphoglycerate accumulate . Elevated levels of 2,3-BPG decreases the affinity of hemoglobin for oxygen and the oxygen-carrying capacity of RBCS decreased . *Taruis disease ● Rare inherited deficiency in the muscle and erythrocyte PFK isoenzyme ; there is anemia , muscle weakness and work capacity is low specially on high carbohydrate diet which is improved on fasting and starvation because the muscle start metabolizing fatty acids . ■ Glucose feeding to these individuals increases insulin levels and inhibits lipolysis in adipose tissue so they have less fatty acids in the blood to serve as fuel . *Dietary deficiency of thiamine cause pyruvate to accumulate . Nutritionally deprived alcoholics are thiamine-deficient and may develop potentially fatal pyruvate and lactic acidosis . ******************************************