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Chapter 13 - The Citric Acid Cycle • The citric acid cycle is involved in the aerobic catabolism of carbohydrates, lipids and amino acids • Intermediates of the cycle are starting points for many biosynthetic reactions • Enzymes of the cycle are in the mitochondria of eukaryotes • Energy of the oxidation reactions is largely conserved as reducing power (stored electrons) • Coenzymes reduced: NAD+ NADH FAD FADH2 Ubiquinone (Q) Prentice Hall c2002 Reduced Ubiquinone (QH2) Chapter 12 1 Transport of Pyruvate from the cytosol into the Mitochondria • Pyruvate translocase transports pyruvate into the mitochondria in symport with H+ Prentice Hall c2002 Pyruvate dehydrogenase complex Chapter 12 2 Conversion of Pyruvate to Acetyl CoA • Pyruvate dehydrogenase complex is a multienzyme complex containing: 3 enzymes + 5 coenzymes + other proteins E1 = pyruvate dehydrogenase E2 = dihydrolipoamide acetyltransferase E3 = dihydrolipoamide dehydrogenase Prentice Hall c2002 Chapter 12 3 Components of the PDH Complex in mammals and E. coli Prentice Hall c2002 Chapter 12 4 Fig 13.1 Reactions of the PDH complex Prentice Hall c2002 Chapter 12 5 Fig 13.1 Reactions of the PDH complex Prentice Hall c2002 Chapter 12 6 Fig 13.1 Reactions of the PDH complex Acetylated lipoamide Prentice Hall c2002 Chapter 12 7 Fig 13.1 Reactions of the PDH complex TCA cycle Reduced lipoamide Prentice Hall c2002 Chapter 12 8 Fig 13.1 Reactions of the PDH complex Prentice Hall c2002 Oxidized lipoamide Chapter 12 9 Fig 13.1 Reactions of the PDH complex Prentice Hall c2002 Oxidized lipoamide Chapter 12 10 Fig 13.1 Reactions of the PDH complex Acetylated lipoamide Prentice Hall c2002 Chapter 12 11 Fig 13.1 Reactions of the PDH complex TCA cycle Reduced lipoamide Prentice Hall c2002 Chapter 12 12 Fig 13.1 Reactions of the PDH complex Prentice Hall c2002 Oxidized lipoamide Chapter 12 13 The Citric Acid Cycle Oxidizes AcetylCoA • Table 13.1 Prentice Hall c2002 Chapter 12 14 Summary of the citric acid cycle • For each acetyl CoA which enters the cycle: (1) Two molecules of CO2 are released (2) Coenzymes NAD+ and Q are reduced to NADH and QH2 (3) One GDP (or ADP) is phosphorylated (4) The initial acceptor molecule (oxaloacetate) is reformed Prentice Hall c2002 Chapter 12 15 Fig 13.3 • Citric acid cycle Prentice Hall c2002 Chapter 12 16 Fig 13.3 Prentice Hall c2002 Chapter 12 17 Fig 13.3 Prentice Hall c2002 Chapter 12 18 6. The Succinate Dehydrogenase (SDH) Complex • Located on the inner mitochondrial membrane, in contrast to other enzymes of the TCA cycle which are dissolved in the mitochondrial matrix • Complex of polypeptides, FAD and iron-sulfur clusters • Electrons are transferred from succinate to FAD, forming FADH2, then to ubiquinone (Q), a lipid-soluble mobile carrier of electrons • Reduced ubiquinone (QH2) is released as a mobile product Prentice Hall c2002 Chapter 12 19 Fig 12.4 Prentice Hall c2002 Chapter 12 20 • Fates of carbon atoms in the cycle • 6C5C4C Prentice Hall c2002 Chapter 12 21 Energy conservation by the cycle • Energy is conserved in the reduced coenzymes NADH, QH2 and one GTP • NADH, QH2 can be oxidized to produce ATP by oxidative phosphorylation Prentice Hall c2002 Chapter 12 22 Reduced Coenzymes Fuel the Production of ATP • Each acetyl CoA entering the cycle nets: (1) 3 NADH (2) 1 QH2 (3) 1 GTP (or 1 ATP) • Oxidation of each NADH yields 2.5 ATP • Oxidation of each QH2 yields 1.5 ATP • Complete oxidation of 1 acetyl CoA = 10 ATP Prentice Hall c2002 Chapter 12 23 Fig 13.10 Glucose degradation via glycolysis, citric acid cycle, and oxidative phosphorylation Prentice Hall c2002 Chapter 12 24 Regulation of the Citric Acid Cycle • The citric acid cycle is controlled by: (1) Allosteric modulators (2) Covalent modification of cycle enzymes (3) Supply of acetyl CoA (4) Regulation of pyruvate dehydrogenase complex controls acetyl CoA supply Prentice Hall c2002 Chapter 12 25 Fig 13.11 Regulation of the pyruvate dehydrogenase complex • Increased levels of acetyl CoA and NADH inhibit E2, E3 • Increased levels of CoA and NAD+ activate E2, E3 Prentice Hall c2002 Chapter 12 26 Fig 13.12 Regulation of mammalian PDH complex by covalent modification • Phosphorylation/dephosphorylation of E1 Prentice Hall c2002 Chapter 12 27 Regulation of isocitrate dehydrogenase Mammalian ICDH • Activated by calcium (Ca2+) and ADP • Inhibited by NADH (-) NAD+ + Prentice Hall c2002 + Chapter 12 28 NADH Regulation of the citric acid cycle Prentice Hall c2002 Chapter 12 29 Entry and Exit of Metabolites • Intermediates of the citric acid cycle are precursors for carbohydrates, lipids, amino acids, nucleotides and porphyrins • Reactions feeding into the cycle replenish the pool of cycle intermediates Prentice Hall c2002 Chapter 12 30 Fig 13.13 Prentice Hall c2002 Chapter 12 31 1. Citrate Synthase • Citrate formed from acetyl CoA and oxaloacetate • Only cycle reaction with C-C bond formation Prentice Hall c2002 Chapter 12 32 2. Aconitase • Elimination of H2O from citrate to form C=C bond of cis-aconitate • Stereospecific addition of H2O to cis-aconitate to form 2R,3S-Isocitrate Prentice Hall c2002 Chapter 12 33 3. Isocitrate Dehydrogenase • Oxidative decarboxylation of isocitrate to a-ketoglutarate (a metabolically irreversible reaction) • One of four oxidation-reduction reactions of the cycle • Hydride ion from the C-2 of isocitrate is transferred to NAD+ to form NADH Prentice Hall c2002 Chapter 12 34 4. The a-Ketoglutarate Dehydrogenase Complex • Similar to pyruvate dehydrogenase complex E1 - a-ketoglutarate dehydrogenase (with TPP) E2 - succinyltransferase (with flexible lipoamide prosthetic group) E3 - dihydrolipoamide dehydrogenase (with FAD) Prentice Hall c2002 Chapter 12 35 5. Succinyl-CoA Synthetase • Free energy in thioester bond of succinyl CoA is conserved as GTP (or ATP in plants and some bacteria) Prentice Hall c2002 Chapter 12 36 6. The Succinate Dehydrogenase (SDH) Complex • Located on the inner mitochondrial membrane, in contrast to other enzymes of the TCA cycle which are dissolved in the mitochondrial matrix • Complex of polypeptides, FAD and iron-sulfur clusters • Electrons are transferred from succinate to FADH2, then to ubiquinone (Q), a lipid-soluble mobile carrier of electrons • Reduced ubiquinone (QH2) is released as a mobile product Prentice Hall c2002 Chapter 12 37 7. Fumarase • Addition of water to the double bond of fumarate to form malate Prentice Hall c2002 Chapter 12 38 8. Malate Dehydrogenase • Oxidation of malate to oxaloacetate, with transfer of electrons to NAD+ to form NADH Prentice Hall c2002 Chapter 12 39 The Glyoxylate Cycle • Pathway for the formation of glucose from noncarbohydrate precursors in plants, bacteria and yeast (not animals) • Glyoxylate cycle leads from 2-carbon compounds to glucose • In animals, acetyl CoA is not a carbon source for the net formation of glucose (2 carbons of acetyl CoA enter cycle, 2 are released as 2 CO2) • Allows for the formation of glucose from acetyl CoA • Ethanol or acetate can be metabolized to acetyl CoA and then to glucose via the glyoxylate cycle • Stored seed oils in plants are converted to carbohydrates during germination Prentice Hall c2002 Chapter 12 40 Fig 13.14 The Glyoxylate Cycle bypasses the two decarboxylation steps of the citric acid cycle, conserving the carbon atoms as glyoxylate for synthesis of glucose. Germinating seeds use this pathway to synthesize sugar (glucose) from oil (triacylglycerols). Prentice Hall c2002 Chapter 12 41 Glyoxylate cycle in germinating castor beans • Conversion of acetyl CoA to glucose requires the transfer of metabolites among three metabolic compartments (1) The glyoxysome (2) The cytosol (3) The mitochondria Prentice Hall c2002 Chapter 12 42 Fig 13.14 Isocitrate lyase: first bypass enzyme of glyoxylate cycle Prentice Hall c2002 Chapter 12 43 Malate synthase: second bypass enzyme of glyoxylate cycle Prentice Hall c2002 Chapter 12 44 Bypass reactions of glyoxylate cycle Citric Acid Cycle Prentice Hall c2002 Chapter 12 45