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The Citric Acid Cycle 11/25/2008

The Citric Acid Cycle 11/25/2008. The Citric acid cycle.

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The Citric Acid Cycle 11/25/2008

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  1. The Citric Acid Cycle11/25/2008

  2. The Citric acid cycle It is called the Krebs cycle or the tricarboxylic and is the “hub” of the metabolic system. It accounts for the majority of carbohydrate, fatty acid and amino acid oxidation. It also accounts for a majority of the generation of these compounds and others as well. Amphibolic - acts both catabolically and anabolically 3NAD+ + FAD + GDP + Pi + acetyl-CoA 3NADH + FADH + GTP + CoA + 2CO2

  3. Overview

  4. The citric acid cycle enzymes are found in the matrix of the mitochondria Substrates have to flow across the outer and inner parts of the mitochondria

  5. Pyruvate dehydrogenase A multienzyme complexes are groups of non covalently associated enzymes that catalyze two or more sequential steps in a metabolic pathway. Molecular weight of 4,600,000 Da E. coli yeast Pyruvate dehydrogenase -- E1 24 60 dihydrolipoyl transacetylase --E2 24 60 dihydrolipoyl dehydrogenase--E3 12 12

  6. Why such a complex set of enzymes? 1 Enzymatic reactions rates are limited by diffusion, with shorter distance between subunits a enzyme can almost direct the substrate from one subunit (catalytic site) to another. 2. Channeling metabolic intermediates between successive enzymes minimizes side reactions 3. The reactions of a multienzyme complex can be coordinately controlled

  7. Covalent modification of eukaryotic pyruvate dehydrogenase

  8. The five reactions of the pyruvate dehydrogenase multi enzyme complex

  9. Citrate Synthase

  10. Induced fit needs binding of oxaloacetate before Acetyl CoA can bind. Acetyl-CoA Proposed intermediate Acetonly CoA Carboxymethyl-CoA (ground-state analog) (transition state analog)

  11. Aconitase Cis-Aconitate Isocitrate Citrate The double bond is placed on the Pro-R arm

  12. NAD+- Dependent Isocitrate dehydrogenase NAD+ NADH

  13. a-Ketoglutarate dehydrogenase NAD+ CO2 NADH This enzyme is just like pyruvate dehydrogenase, a multi enzyme complex that is specific for longer CoA derivatives

  14. Refresh:The five reactions of the pyruvate dehydrogenase multi enzyme complex

  15. Succinyl-CoA Synthetase or succinate thiokinase ← Note symmetry

  16. Succinate dehydrogenase + 2e- + 2H+ The FAD on the enzyme itself is reduced

  17. Succinate dehydrogenase is the only membrane bound enzyme in the citrate cycle Succdh--FADH2 + Ubiquinone or Coenzyme Q Oxidized form Reduced form

  18. Fumarase

  19. Malate dehydrogenase NADH NAD+

  20. Regulation of the citric acid cycle Standard free energy changes in the citric acid cycle Reaction Enzyme DG'DG' 1 Citrate synthase -31.5 Negative 2 Aconitase ~5 ~0 3 Isocitrate dh -21 Negative 4 a-KG dh -33 Negative 5 Succinyl-CoA synthase -20.1 ~0 6 Succinate dh +6 ~0 7 Fumarase -3.4 ~0 8 Malate dh +29.7 ~0

  21. The points of regulation of the cycle

  22. Citric acid cycle intermediates are always in flux

  23. A single molecule of glucose can potentially yield ~38 molecules of ATP

  24. No Lecture Thursday 11/27/08 ThanksgivingNext LectureTuesday 12/02/08 Pentose phosphate pathway

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