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TCA CYCLE Dr Mohammad Muzaffar Mir Professor of Biochemistry Al- jouf University Biochem-224 Pharma

Introduction Let us review fates of Pyruvate:

Introduction Let us review fates of Pyruvate Depending on the oxidation state of the cell: Aerobic – converted to acetyl- CoA and metabolized via TCA cycle Anaerobic – converted to lactate (lactate dehydrogenase reaction) Pyruvate also is c onverted to : Alanine oxaloacetate Glucose [ Gluco-neogenesis ] to alcohol (yeasts)

Importance of conversion of pyruvate into acetyl-CoA:

Importance of conversion of pyruvate into acetyl- CoA Pyruvate formed in Cytosol is transferred to mitochondrion by a transport protein to be converted to acetyl- CoA by oxidative decarboxylation. Catalyzed by a multienzyme complex called as pyruvate dehydrogenase enzyme complex [PDH). This conversion is of Central Importance in Metabolism---- Why?????

TCA or Tricarboxylic Acid Cycle [also known Kreb’s or Citric Acid cycle] :

TCA or Tricarboxylic Acid Cycle [also known Kreb’s or Citric Acid cycle] Definition: TCA cycle is defined as the metabolic pathway in which Acetyl-coA A is oxidized to carbon dioxide and water and leads to formation of ATP, NADH and FADH 2 . TCA cycle is a common pathway for oxidation of all nutrients (carbohydrate, lipids and proteins). Location : The cycle operates in mitochondrial matrix in close proximity to electron transport chain which is present in the inner mitochondrial membrane.

Sources and fates of Acetyl Co-A:

Sources and fates of Acetyl Co-A 5

TCA Cycle Reactions:

TCA Cycle Reactions

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At each turn of TCA cycle , 3 NADH , 1 FADH2 , 1 GTP (or ATP ), and 2CO 2 are released . (2 carbons) Products of one turn of the citric acid cycle

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Oxidative decarboxylation of the two pyruvates gives 2 NADH + that gives  6 ATP. Oxidation of isocitrate by isocitrate dehydrogenase gives 2 NADH + that gives  6 ATP. Oxidative decarboxylation of  - ketoglutarate to succinyl-CoA gives--- 2 NADH + that gives  6 ATP. Substrate level phosphorylation from succinyl-CoA gives  2 ATP . Oxidation of succinate to fumarate gives 2 FADH 2 , that gives  4 ATP. Oxidation of malate to oxaloacetate gives 2 NADH + that gives ,  6 ATP Thus, for each mole of glucose oxidized by oxidative decarboxylation followed by Krebs' cycle, 30 ATP are produced. Complete oxidation of one glucose molecule under aerobic conditions gives 8 ATP at aerobic glycolysis + 30 ATP at Krebs' cycle ---------giving a total of 38 ATP Bioenergetics of Kreb’s cycle:

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Generation of ATP in Catabolism of Glucose

Amphibolic nature of TCA cycle :

Amphibolic nature of TCA cycle TCA cycle is both anabolic and catabolic in nature hence regarded as Amphibolic.

Amphibolic nature of TCA cycle :

Amphibolic nature of TCA cycle Involved in gluconeogenesis , Transamination and Deamination. Oxaloacetae and α - ketpglutarate ---precursors for Asp and Glu which in turn are precursors for other amino acids, purines and pyrimidines. Succinyl Co-A –used for synthesis of porphyrins and heme . Mitochondrial Citrate is transported to cytosol where it is cleaved to provide acetyl Co-A for synthesis of fatty acids , sterols etc,

Importance of Krebs' cycle :

I mportance of Krebs' cycle Energy production: Oxidation acetyl- CoA into CO 2 + H 2 O with generation of energy. (30ATP from one glucose molecule in TCA). It is a major source of succinyl-CoA which is used for: Synthesis of hemoglobin and other porphyrins Ketolysis : For activation of ketone bodies Detoxication by conjugation . It provides intermediates for synthesis of non-essential amino acids e.g.  - Ketoglutarate can give rise to glutamic acid by transamination. Oxaloacetate can give rise to asparatic acid by transamination.

Control of citric acid cycle:

13 Control of citric acid cycle Regulation of PDH Complex TCA Cycle regulated primarily by three rate controlling enzymes . Citrate Synthase Isocitrate dehydrogenase  - ketoglutarate dehydrogenase Regulation of activity by: Substrate availability Product inhibition Allosteric inhibition or activation by other intermediates

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Allah Bless [email protected] Recommended books : Textbook of Biochemistry with Clinical Correlations By Thomas M. Devlin . L ehninger Principles of Biochemistry