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 FADH 2 Ubiquinone (Q)Reduced Ubiquinone (QH 2 )

Transport of Pyruvate from the cytosol into the Mitochondria Pyruvate translocase transports pyruvate into the mitochondria in symport with H + Pyruvate dehydrogenase complex

Conversion of Pyruvate to Acetyl CoA Pyruvate dehydrogenase complex is a multienzyme complex containing: 3 enzymes + 5 coenzymes + other proteins E 1 = pyruvate dehydrogenase E 2 = dihydrolipoamide acetyltransferase E 3 = dihydrolipoamide dehydrogenase

Prentice Hall c2002Chapter 124 Components of the PDH Complex in mammals and E. coli

Fig 13.1 Reactions of the PDH complex

Acetylated lipoamide

Fig 13.1 Reactions of the PDH complex TCA cycle Reduced lipoamide

Fig 13.1 Reactions of the PDH complex Oxidized lipoamide

Fig 13.1 Reactions of the PDH complex Oxidized lipoamide

Fig 13.1 Reactions of the PDH complex Acetylated lipoamide

Fig 13.1 Reactions of the PDH complex TCA cycle Reduced lipoamide

Fig 13.1 Reactions of the PDH complex Oxidized lipoamide

The Citric Acid Cycle Oxidizes AcetylCoA Table 13.1

Prentice Hall c2002Chapter 1215 Summary of the citric acid cycle For each acetyl CoA which enters the cycle: (1) Two molecules of CO 2 are released (2) Coenzymes NAD + and Q are reduced to NADH and QH 2 (3) One GDP (or ADP) is phosphorylated (4) The initial acceptor molecule (oxaloacetate) is reformed

Fig 13.5 Citric acid cycle

Fig 13.5

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 FADH 2, then to ubiquinone (Q), a lipid-soluble mobile carrier of electrons Reduced ubiquinone (QH 2 ) is released as a mobile product

Fig 12.4

Fates of carbon atoms in the cycle 6C  5C  4C

Energy conservation by the cycle Energy is conserved in the reduced coenzymes NADH, QH 2 and one GTP NADH, QH 2 can be oxidized to produce ATP by oxidative phosphorylation

Glucose degradation via glycolysis, citric acid cycle, and oxidative phosphorylation

Prentice Hall c2002Chapter 1224 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

Fig Regulation of the pyruvate dehydrogenase complex Increased levels of acetyl CoA and NADH inhibit E 2, E 3 Increased levels of CoA and NAD + activate E 2, E 3

Fig Regulation of mammalian PDH complex by covalent modification Phosphorylation/dephosphorylation of E 1

Prentice Hall c2002Chapter 1227 Regulation of isocitrate dehydrogenase Mammalian ICDH Activated by calcium (Ca 2+ ) and ADP Inhibited by NADH NAD + NADH ++ (-)

Prentice Hall c2002Chapter 1228 Regulation of the citric acid cycle

Prentice Hall c2002Chapter 1229 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

Fig 13.20

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 CO 2 ) 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

Fig 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).