Krebs cycle

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Citric Acid Cycle / Tricarboxylic Acid Cycle / Krebs Cycle / Szent-Györgyi-Krebs cycle  It is a series of enzyme-catalyzed chemical reactions, which is of central importance in all living cells that use oxygen as part of cellular respiration.  In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion.  The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).  The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2.  The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA.

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 The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle.  Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle.  However, because of the role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.  Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+, forming NADH.  For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced.  Electrons are also transferred to the electron acceptor Q, forming QH2.At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

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 Two carbon atoms are oxidized to CO2, the energy from these reactions being transferred to other metabolic processes by GTP or ATP, and as electrons in NADH and QH2.  The NADH generated in the TCA cycle may later donate its electrons in oxidative phosphorylation to drive ATP synthesis.  FADH2 is covalently attached to succinate dehydrogenase, an enzyme functioning both in the TCA cycle and the mitochondrial electron transport chain in oxidative phosphorylation.  FADH2, therefore, facilitates transfer of electrons to coenzyme Q.  This is the final electron acceptor of the reaction catalyzed by the Succinate ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.

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Mitochondria in humans, possess two succinyl-CoA synthetases: 1. produces GTP from GDP, and 2. produces ATP from ADP The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase to form ATP GTP + ADP → GDP + ATP Products of the first turn of the cycle are: one GTP or ATP, three NADH, one QH2, two CO2. Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two QH2, and four CO2.

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Summary of TCA Cycle Acetyl-CoA + 3 NAD+ + Q + GDP + Pi +FAD + 2 H2O ------ CoA-SH + 3 NADH + 3 H+ + QH2 + GTP + FADH2 + 2 CO2 Pyruvate ion + 4 NAD+ + Q + GDP + Pi + 2 H2O --- 4 NADH + 3 H+ + QH2 + GTP + 3 CO2 Glucose + 10 NAD+ + 2Q + 2 ADP + 2 GDP + 4 Pi + 2 H2O -- -10 NADH + 10 H+ + 2 QH2 + 2 ATP + 2 GTP + 6 CO2

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Anaplerotic Reactions ►The reactions concerned to replenish or to fill up the intermediates of Krebs cycle is called as anaplerosis.  Pyruvate + HCO3- + CO2 + ATP ↔ Oxaloacetate + ADP + iP PEP + CO2 + GDP ↔ Oxaloacetate + GTP PEP + HCO3- ↔ Oxaloacetate + iP Pyruvate + HCO3- + NADPH + CO2 + H+ ↔ Malate + NADPH+ + H2O Glutamate + NADP+ + H2O ↔ α-ketoglutarate + NADPH + H+ + NH4+ Glucose + 6CO2 + 38ADP + 38 iP -- 6CO2 + 6H2O+ 38ATP

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Vitamins role in the Citric Acid Cycle Riboflavin – in form of FAD, a cofactor for succinate dehydrogenase Niacin – in form of NAD, the electron acceptor for isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase Thiamin – in form of thiamin phosphate, the coenzyme for decarboxylation in α- ketoglutarate dehydrogenase Pantothenic Acid – as part of coenzyme A , the cofactor attached to Acetyl-CoA and Succinyl-CoA

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Regulation of Citric Acid Cycle Major significance of Krebs cycle is that it acts as common metabolic pathway for oxidation of carbohydrates, lipids and proteins because glucose, fatty acids and amino acids are metabolized to Acetyl-CoA. Reducing equivalents in form of hydrogen electrons are formed by activity of specific dehydrogenases during oxidation of Acetyl-CoA. These reducing equivalents enter respiratory chain and large amount of high energy phosphates are generated. The regulation of the cycle is brought up by three enzymes namely: 1. citrate synthase 2. isocitrate dehydrogenase 3. α- ketoglutarate dehydrogenase

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Citrate synthase : inhibited by ATP, NADH, Acetyl-CoA and Succinyl-CoA Isocitrate dehydrogenase – activated by ADP and inhibited by ATP and NADH. α- ketoglutarate dehydrogenase – inhibited by Succinyl-CoA and NADH. Availability of ATP – Sufficient levels of ADP must be available for oxidation of NADH and FADH2 through ETC stops. Accumulation of NADH and FADH2 will limit the supply of NAD+ and FAD. Krebs cycle is both catabolic and anabolic in nature hence regarded as amphibolic in nature. TCA cycle actively involved in gluconeogenesis, transamination and deamination and also fatty acids.

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Most important synthetic reactions in TCA Cycle Oxaloacetate and α-ketoglutarate serve as precursors for synthesis of aspartate and glutamate which on further synthesize non-essential amino acids , purines and pyrimidines. Succinyl CoA is used for synthesis of Porphyrins and heme. Mitochondrial citrate is transported to cytosol and cleaved to provide Acetyl-CoA for biosynthesis of fatty acids and sterols.

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Bioenergetics ► Energetics of citric acid cycle: Isocitrate --------oxaloacetate = 3 ATP α-ketoglutarate-- Succinyl – CoA = 3 ATP Succinyl-CoA ---- Succinate = 1 ATP Succinate ------ Fumarate = 2 ATP Malate ----- Oxaloacetate = 3 ATP __________________ Total of ATP produced = 12 ATP __________________

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► Total number of ATP in the complete oxidation of one molecule of glucose One molecule of glucose forms 2 molecules of pyruvic acid by glycolysis. Number of ATP formed in Glycolysis = 8 ATP Number of ATP formed in oxidation of Pyruvate to Acetyl – CoA (3*2) = 6 ATP Number of ATP formed in TCA cycle (12*2) = 24 ATP _______________ Total number of ATP produced = 38 ATP _______________

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Number of molecules of CO2 and H2O formed in oxidation of pyruvic acid Pyruvate --- Acetyl-CoA = 1 molecule of CO2 Oxaloacetate-α-ketoglutarate = 1 molecule of CO2 α-ketoglutarate-- Succinyl-CoA = 1 molecule of CO2 ------------------------- Net total = 3 molecule of CO2 ------------------------- 4. Oxidation of reduced NAD & FAD by respiratory chain produces = 5 H2O 5. Utilization in TCA cycle = 3 H2O ---------- Net total = 2 H2O ----------

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