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Biochemistry Malfunction in Glycolysis

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Biochemistry Malfunction in Glycolysis Paper : 04 Metabolism of carbohydrates Module : 22 Malfunction in Glycolysis Dr. Ramesh Kothari, Professor UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5 Principal Investigator Dr.S.K.Khare, Professor Gujarat-INDIA IIT Delhi Dr. Ramesh Kothari, Professor UGC-CAS Department of Biosciences Paper Coordinator Saurashtra University, Rajkot-5, Gujarat-INDIA Dr. S. P. Singh, Professor Content Reviewer UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5, Gujarat-INDIA Dr. Vikram Raval, Assistant Professor Content Writer UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5, Gujarat-INDIA 1 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Description of Module Subject Name Biochemistry Paper Name 04 Metabolism of carbohydrates Module Name/Title 22: Malfunction in Glycolysis 2 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Malfunction in Glycolysis Objectives 1. To understand the concept of malfunction. 2. To understand the biochemistry during the malfunction of glycolysis 3. To understand diseases associated with the malfunction of glycolysis. 3 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Introduction Malfunction means a failure to function normally Word Glycolysis has been actually derived from two terms from Greek language “glyk” meaning sweet and “lysis” meaning splitting or solubilisation One of the meaning of Glycolysis can essentially be glycol (sugar) + lysis (breakdown) i.e breakdown of sugar. In higher organisms principal sugar present is glucose this it can be called breakdown of glucose molecule It is also one among the most ancient metabolic pathways known to human race Malfunction of glycolysis leads to Inborn Metabolic Disorders. It is also called Inborn Errors of Metabolism In born errors of metabolism are a set of genetic diseases occurs due to malfunctioning of a specific metabolic pathway Metabolic pathways consist of a number of processes. It involves sequence of chemical reactions. This reaction occurs in human body on products of dietary or endogenous origin with the aim of make it available or avoids their accumulation. Consequences of the Malfunction/block of the metabolic pathway: Accumulation of precursors found before the biochemical fault which leads to toxic effects; Deficiency of the final products /metabolite of the metabolic pathway , It lead to a fault in energy production; 4 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Activation of alternative pathways (if present/available) with creation of potentially toxic metabolites usually not found in organism. Coexistence of above described mechanism is possible. Generally a metabolic disease involves more organs. It also shows systematic symptoms. Glycolysis is a process that is constituted by sequential biochemical reactions through which a single molecule of glucose [6C] can be metabolized completely giving 2 molecules of Pyruvate [3C] (pyruvic acid) and an overall yield of energy equivalent to 2 ATP 2 Pyruvate Glucose 2 ATP Primarily cytosol or a more common term cytoplasm is the place within the cell where chiefly all the reactions of glycolysis occur Glycolysis is a pathway that is common to both aerobic as well as anaerobic organisms by which they acquire preliminary energy as a mode of respiratory mechanism Glycolysis, is a process which as a whole does not require a single oxygen molecule in glucose metabolism and hence technically a process which is anaerobic in nature. But similar reactions do occur in aerobic organisms though oxygen is present in cellular environment but is not involved in glucose breakdown and does not affect it 5 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis The end product of glycolysis is a three carbon intermediate Pyruvate [3C] which can further be metabolised in two ways 1. Anaerobic 2.Aerobic Towards the end of nineteenth century an absolute map of glycolysis was expounded. Gustav G. Embden a German chemist, Otto F. Meyerhof, a German physician and biochemist and Jakub K. Pernas, a Russian biochemist, were the pioneers of this work. Embden studied the metabolism in liver and basics behind diabetes. Embden studied thoroughly carbohydrate metabolism, muscle contraction and later of conversion of glucose to lactic acid. He also linked the key step involved in this metabolism Meyerhof correlated his work on muscle contraction and muscle metabolism with the former studies While Jakub Parnas mainly focused on carbohydrate metabolism in muscle tissues. The entire theoretical analysis of glycolysis had been proposed by Parnas giving a perfect shape to metabolic process and breakdown of glycose Hence the pathway is collectively referred to as the Embden-Meyerhof- Pernas pathway owing to their contributions and efforts made towards better understanding of the mechanism Carl A. Neuberg, a German biochemist made a noteworthy contribution by studying alcoholic fermentations of glucose in yeast and other anaerobes Otto H. Warburg, a German physiologist and biochemist did a keynote discovery of various enzymes involved in fermentative processes 6 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Gerty T. Cori and her husband Carl F. Cori both were Czech biochemists and did a notable contribution in studying glycogen breakdown in muscle tissues and formation of lactic acid and vice-versa the reverse mechanism of formation of glycogen popularly called The Cori cycle M.Doudoroff born Russian but migrated to America, a microbiologist by profession and his student Nathan Entner worked on alternative pathways by which reactions similar to glycolysis are performed in different prokaryotes specially archaea. To commemorate their contributions the alternative pathway is popularly called Entner- Doudoroff pathway Metabolic disorders arise because of malfunctioning of specific enzymes (structural deformities of protein or its cofactor) or defect in cellular transportation For your information (FYI): Entner-Doudoroff pathway considerably varies from a classic glycolytic pathway. Here two different enzymes viz. 6-phosphogluconate dehydratase and 2-keto-3- deoxyphosphogluconate aldolase are engaged for the catabolism of pyruvate. As a matter of fact the energy efficiency of ED pathway is only 50% to that of EMP pathway. In ED pathway there is formation of a singly ATP molecule while for each glucose molecule 2ATP are formed in EMP pathway 7 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis Overview of Glycolysis cycle Glycolytic pathway comprise of 10 different reactions that lead to two moles of pyruvic acid from one mole of glucose as an end product. All of the reactions are catalysed by specific enzymes and enlisted below Glucose to Glucose-6-phosphate is a phosphorylation reaction that draws energy from ATP and is an irreversible reaction catalysed by hexokinase (glucokinase) For your information (FYI): Hexokinase is the enzyme that initiates glycolysis in muscles, brain and other vital tissues while glucokinase is the enzyme that does similar reactions in liver and pancreas. Glucose-6-phosphate to Fructose-6-phosphate a reversible isomerisation reaction catalysed by glucose-6-phosphate isomerase enzyme (also called phosphoglucomutase) Fructose-6-phosphate to Fructose-1-6-bisphosphate is another irreversible reaction of this pathway and is catalysed by phosphofructokinase enzyme utilizing energy from ATP Fructose-1-6-bisphosphate to 2 molecules of glycerladehyde-3- phosphate. Fructose-1,6-bisphosphate actually splits into 2 3-carbon moieties, an aldehyde and a ketone: glyceraldehyde 3-phosphate (GAP) and di-hyroxy-acetone-phosphate (DHAP). The reaction is catalysed by fructose-bis-phosphate aldolase enzyme For your information (FYI): In glycolytic pathway dihydroxy-acetone-phosphate (DHAP) and Glyceraldehyde-3- phoshpate (GAP) [also called Phosphoglyceraldehyde (PGAL]) are isomers and are easily interconvertible. A reaction catalysed by triose-phosphate isomerase. Glyceraldehyde-3- phoshpate acts as a substrate for glycolytic reactions and hence the entire keto-product DHAP is converted to PGAL (GAP). Hence we now have 2 molecules of GAP from each molecule of glucose 8 Metabolism of Carbohydrates Biochemistry Malfunction in Glycolysis 2 molecules of glycerladehyde-3-phosphate to 1-3-bisphosphoglycerate a dehydrogenation reaction catalysed by glyceraldehydes-3-phosphate dehydrogenase. Here in this reaction, NAD+ is reduced to NADH + H+ from NAD. Additionally above oxidation reaction is coupled with a phosphorylation reaction that yields 1-3-bisphosphoglycerate 1-3-bisphosphoglycerate to 3-phosphoglycerate is an exergonic reaction catalysed by phosphoglycerate kinase high energy bond in 1-3- bisphosphoglycerate is hydrolyzed to a carboxylic acid and the energy liberated in that is used conveniently for the formation of energy rich phosphate bond of ATP from ADP 3-phosphoglycerate to 2-phosphoglycerate reaction where phosphate group shifts from 3rd position to the 2nd position. The reaction is an isomerisation reactions and is catalysed by phosphoglycerate mutase 2-phosphoglycerate to phospho-enol-pyruvate a dehydration reaction catalysed by an enolase (phosphor-puryvate hydratase) Phospho-enol-pyruvate to pyruvate, an irreversible reaction is catalysed by transferase activity followed by dephosphorylation. The enzyme involved is Pyruvate kinase. The enolphosphate intermediate has a high energy phosphate bond which when hydrolyzed
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