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GLYCOLYSIS In the pathway of glycolysis, glucose (6 carbons molecule) is split into two pyruvate (3-carbon molecule) under aerobic conditions; or lactate under anaerobic conditions, along with production of a small quantity of energy. glucokinase Summary of glycolysis (Embden-Meyerhof pathway) The whole reaction is summarized as Glucose + 2 Pi + 2 ADP --> 2 Lactate + 2 ATP 1 Notes Steps 1, 3 and 9 are key enzymes; these reactions are irreversible. Steps 5, 6 and 9 produce energy. Steps 5 and 10 are coupled for regeneration of NAD+. The steps 1, 2 and 3 are called the preparatory phase, The next steps are together called the energy producing phase. Hexokinase and glucokinase may be considered as iso-enzymes; their properties are compared in Table below. Glucokinase is under the influence of insulin; but hexokinase is not. The phosphorylation of glucose to glucose-6-phosphate traps it within the cells to be metabolized. The enzyme phosphofructokinase (PFK) is an allosteric, inducible, regulatory enzyme. It is an important key enzyme of this pathway. This is an activation process, the energy being derived by hydrolysis of ATP. This irreversible step is the rate limiting reaction in glycolysis. The energy of bisphospho glycerate (1,3-BPG) is trapped to synthesize one ATP molecule with the help of bisphospho glycerate kinase. This is an example of substrate level phosphorylation (where energy is trapped directly from the substrate without the help of the complicated electron transport 2 chain reactions). When energy is trapped by oxidation of reducing equivalents such as NADH, it is called oxidative phosphorylation. In the 5th step, for each molecule of glucose entering in the pathway, two molecules of NAD+ are reduced to NADH. The availability of co-enzymes inside a cell is limited. Therefore, this step becomes a bottleneck in the whole reaction sequence. For smooth operation of the pathway, the NADH is to be reconverted to NAD+ by oxidative phosphorylation which needs oxygen. However, during exercise, there is lack of oxygen so this reconversion is not possible, Therefore, the cell has to couple some other reaction in which NAD+ is regenerated in the cytoplasm itself hence, pyruvate is reduced to lactate; the NAD+ thus generated is reutilized for uninterrupted operation of the pathway. But when oxygen is in plenty, the two NADH molecules, generated in the glyceraldehyde- 3-phosphate dehydrogenase reaction (step 5), can enter the mitochondrial electron transport chain for complete oxidation as each NADH provides 3 ATPs. In RBCs, there are no mitochondria (where oxidative phosphorylation occurs) hence RBCs derive energy only through anaerobic glycolysis, where the end product is lactic acid. Enolase (step 8) requires Mg++, fluoride irreversibly inhibit this enzyme by removing magnesium ions. Thus, fluoride will stop the whole glycolysis. So when taking blood for glucose estimation, fluoride is added to blood. If not, glucose is metabolized by the blood cells and lower blood glucose values are obtained (incorrect result). Factors Regulating Glycolysis A. Glucokinase enzyme is active mainly in liver and has a high Km for glucose and low affinity. Hence, glucokinase can act only when there is adequate glucose supply. Hexokinase with low km and high affinity can phosphorylate glucose even at lower concentrations so that glucose is made available to brain, cardiac and skeletal muscle. Glucokinase can act only when there is plenty of glucose. Thus, when the supply of glucose is limited, glucose is made available to brain and muscles. Insulin increases GK activity whereas glucagon inhibits it. B. Pyruvate Kinase enzyme catalyses an irreversible step and is a regulatory enzyme of glycolysis. When energy is plenty in the cell, 3 glycolysis is inhibited; Pyruvate kinase is inactive in the phosphorylated state. Insulin favors glycolysis by activating the above two key glycolytic enzymes (PK and GK). Glucagon and glucocorticoids inhibit glycolysis and favor gluconeogenesis. C. PF K enzyme as mention above Regulatory enzymes of glycolysis Significance of the Glycolysis Pathway 1. It is the only pathway that is taking place in all the cells (cytoplasm) of the body. 2. Glycolysis is the only source of energy in erythrocytes. 3. In strenuous exercise, when muscle tissue lacks enough oxygen, anaerobic glycolysis forms the major source of energy for muscles. 4. The glycolytic pathway may be considered as the preliminary step before complete oxidation. 5. The glycolytic pathway provides carbon skeletons for synthesis of nonessential amino acids as well as glycerol part of fat (glycerol is required which can be derived from glucose through DHAP also glycerol portion of the neutral fat can enter into glycolytic or gluconeogenic pathways at step 4). 6. Most of the reactions of the glycolytic pathway are reversible, which are also used for gluconeogenesis. Clinical Applications of Glycolytic Enzymes 1. Lactic acidosis may be seen in hypoxia, shock, pulmonary failure, alcohol abuse and diabetes mellitus . 4 2. Deficiency of glycolytic enzymes. These conditions are rare, out of which pyruvate kinase deficiency and hexokinase deficiency are comparatively common. These deficiency states can lead to hemolytic anemia, because energy depleted RBCs are destroyed. Inherited aldolase deficiency also causes hemolysis. In PFK deficiency, muscle weakness is seen. Alternate fates of pyruvate: A. Oxidative decarboxylation of pyruvate Oxidative decarboxylation of pyruvate by pyruvate dehydrogenase complex is an important pathway in tissues with a high oxidative capacity, such as cardiac muscle. Pyruvate dehydrogenase irreversibly converts pyruvate, the end product of glycolysis, into acetyl CoA, a major fuel for the tricarboxylic acid cycle. B. Carboxylation of pyruvate to oxaloacetate Carboxylation of pyruvate to oxaloacetate (OAA) by Pyruvate carboxylase is a biotin-dependent reaction. This reaction is important because it replenishes the citric acid cycle intermediates, and provides substrate for gluconeogenesis. C. Reduction of pyruvate to lactate Reduction of pyruvate to lactate by lactate dehydrogenase under anaerobic condition 5