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Citric Acid Cycle What is it? Series of rxns that oxidize acetyl CoA to 2CO2 in a manner that conserves the liberated free energy for ATP production Breakdown products of glc, fats and amino acids are all oxidized via the cycle Intermediates also a source for many biosynthetic pathways “amphibolic” which means serves in both catabolic and anabolic processes Also called “TCA cycle” - tricarboxylic acid cycle or “Krebs cycle” Citric Acid Cycle Cellular respiration Citric Acid Cycle Pyruvate dehydrogenase complex 3 mitochondrial euk enzymes 5 coenzymes Citric Acid Cycle Pyruvate dehydrogenase complex 5 coenzymes - Coenzyme A (pantothenate) Reactive thiol is an acyl carrier Citric Acid Cycle Pyruvate dehydrogenase complex 5 coenzymes - NAD+ (niacin) Involved in redox, electron carrier Citric Acid Cycle Pyruvate dehydrogenase complex 5 coenzymes - FAD (riboflavin, vitamin B2) Involved in redox, electron carrier Citric Acid Cycle Pyruvate dehydrogenase complex 5 coenzymes - TPP (thiamine, vitamin B1) Helps in cleavage of bonds next to carbonyl Citric Acid Cycle Pyruvate dehydrogenase complex 5 coenzymes - lipoate Reversible oxidation at thiols, serves as electron carrier and acyl carrier Citric Acid Cycle Pyruvate dehydrogenase complex Citric Acid Cycle Pyruvate dehydrogenase complex - regulation Eukaryotic complex regulated by phosphorylation Regulation Pyruvate: substrate for complex ADP: indicates low energy charge NADH, acetyl CoA: endproducts of complex Ca2+: certain hormones (insulin) raise [Ca2+] Citric Acid Cycle Every turn of cycle: 1. Joining an acetyl group to oxaloacetate 2. Oxidizing 2 carbons off as CO2, leaving succinate 3. Converting succinate back to oxaloacetate 4. Producing 1 GTP and reduced cofactors Citric Acid Cycle Net reaction: AcetylCoA + 3NAD+ + FAD + GDP + Pi + 2H2O 2CO2 + CoA + 3NADH + FADH2 + GTP + 2H+ Citric Acid Cycle Goal: capture energy from acetate 2CO2 1. One GTP made: equivalent to 1 ATP 2. Lots of reduced cofactors, reducing power can be converted to ATP -G irreversible -G irreversible +G made favorable by fast product removal -ketoglutarate dehydrogenase complex -G irreversible Only enzyme bound to inner mitochondrial membrane Citric Acid Cycle Regulation Rate of cycle is determined by: 1. Availability of substrates (acetyl CoA, NAD+, FAD) 2. Inhibition by accumulating products 3. Allosteric feedback inhibition of enzymes NAD+ and FAD are regenerated by oxidative phosphorylation, which needs O2 Citric Acid Cycle Regulation Three nonequilibrium rxns: 1. Citrate synthase 2. Isocitrate dehydrogenase 3. -ketoglutarate dehydrogenase Citric Acid Cycle Why so complicated? Hub of intermediary metabolism Greatest selective advantage Citric Acid Cycle Citric Acid Cycle Reaction 1 - Citrate synthase Condensation of acetylCoA with oxaloacetate to form citrate Irreversible Citric Acid Cycle Reaction 2 - Aconitase Removal of H2O, stereospecifically add back H2O Reversible, pulled to right because isocitrate rapidly consumed Prochiral carbon allows for stereospecific rxn Citric Acid Cycle Reaction 3 - isocitrate dehydrogenase Oxidative decarboxylation of isocitrate Irreversible Citric Acid Cycle Reaction 4 - -ketoglutarate dehydrogenase complex Oxidative decarboxylation of -ketoglutarate Identical to pyruvate dehydrogenase reaction Three homologous enzymes (E1, E2, E3) Five coenzymes (TPP, lipoate, FAD, NAD+, CoA) Irreversible Citric Acid Cycle Reaction 5 - Succinyl-CoA synthetase Hydrolysis of thioester bond energizes formation of GTP Synthetase indicates participation of nucleoside triphosphate Reversible Citric Acid Cycle Reaction 6 - Succinate dehydrogenase Oxidation of succinate to fumarate Enzyme bound to inner mito membrane, only membrane-bound enz Reversible Malonate (analog of succinate) is a competitive inhibitor of enz, blocks activity of cycle Citric Acid Cycle Reaction 7 - Fumarase Hydration of fumarate to L-malate Reversible Substrate Product Citric Acid Cycle Reaction 8 - Malate dehydrogenase Oxidation of malate to oxaloacetate NAD+ linked to enzyme High +G˚, pulled to products by continual removal of oxaloacetate
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