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Aerobic Metabolism of carbohydrate

Aerobic Metabolism of carbohydrate. The three stages of respiration. Stage I All the fuel molecules are oxidized to acetyl-CoA. Stage II The acetyl-CoA is completely oxidized into CO 2 , electrons were collected by NAD and FAD via the citric acid cycle.

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Aerobic Metabolism of carbohydrate

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  1. Aerobic Metabolism of carbohydrate

  2. The three stagesofrespiration Stage I All the fuel molecules are oxidized to acetyl-CoA. Stage II The acetyl-CoA is completely oxidized into CO2, electrons were collected by NAD and FAD via the citric acid cycle. Stage III Passage of electrons through the electron transport system to yield ATP from oxidative phosphorylation.

  3. Pyruvate Oxidation Pyruvate + CoA + NAD+  acetylCoA + CO2 + NADH + H+

  4. Pyruvate Dehydrogenaseis a large complex: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), dihydrolipoyl dehydrogenase (E3) Requires 5 coenzymes: TPP, Lipoic Acid, Coenzyme A, FAD, NAD+

  5. Reactions of the PDH complex

  6. Regulation of Pyruvate Dehydrogenase 1). Product inhibition byNADH & acetyl CoA 2). Covalent modification

  7. Citric Acid Cycle Hans Krebs proposed the “citric acid cycle” for the complete oxidation of pyruvate in animal tissues in 1937 (1953 Nobel Prize laureate). The tricaboxylic acid (TCA) Cycle, Krebs Cycle

  8. Citric Acid Cycle The common pathway leading to complete oxidation of carbohydrates, fatty acids, and amino acids to CO2. Some ATP is produced, More NADH is made ,NADH goes on to make more ATP in electron transport and oxidative phosphorylation A pathway providing many precursors for biosynthesis

  9. citric acid cycle overview

  10. Individual reaction

  11. Reaction 1: Citrate Synthase A thioester: so a high energy compound Hydrolysis helps drive this reaction forward Allosteric, -ATP,NADH, succinyl-CoA

  12. Fluoroacetate blocks the cycle Fluoroacetate is poisonous because it can convert to fluorocitrate which is an inhibitors of TCA cycle.

  13. Reaction 2: Aconitase Dehydration followed by hydration

  14. Reaction 3: Isocitrate Dehydrogenase FirstOxidative decarboxylation Allosteric enzyme -ATP,NADH

  15. Reaction 4: -Ketoglutarate Dehydrogenase SecondOxidative decarboxylation

  16. Ketoglutarate dehydrogenase complex is very similar to the pyruvate degydrogenase complex. • allosteric inhibitor: NADH,succinylCoA,ATP • Five coenzymes used – • TPP, CoASH, Lipoic acid,NAD+, FAD

  17. (also called succinyl CoA synthetase) Reaction 5: Succinate thiokinase Hydrolysis Substrate Level Phosphorylation A thioester: so a high energy cpd

  18. Reaction 6: Succinate Dehydrogenase Oxidation 2 e- carrier is FAD

  19. Succinate Dehydrogenase Part of electron transport chain in the inner membrane of mitochondria. Removal of H across a C-C bond is not sufficiently exergonic to reduce NAD+,but it does yield enough energy to reduce FAD. Malonate is a competitive inhibitor

  20. Reaction 7: Fumarase Hydration trans-addition of the elements of water across the double bond, forms L-malate

  21. Reaction 8: Malate Dehydrogenase Oxidation This and the previous two reactions form a reaction triad +

  22. TCA Cycle Summary 1 acetate through the cycle produces 2 CO2, 1 GTP, 3NADH, 1FADH2

  23. Aerobic Nature of the Cycle NADH and FADH2 must be reoxidized by the electron transport chain. Succinate Dehydrogenase is part of electron transport chain in the inner membrane of mitochondria.

  24. Energetics • Energy is conserved in the reduced coenzymes NADH, FADH2 and one GTP • NADH, FADH2 can be oxidized to produce ATP by oxidative phosphorylation 1.5 1.5 7.5 ETS 1.5 7.5 7.5

  25. ATP generated by the cycle 3 NADH 3 NAD+ ETS 3*2.5=7.5 ATP FADH2 FAD 10 ATP Equivalents Total ETS 1.5 ATP Substrate level phosphorylation 1 GTP

  26. ATP generated by complete oxidation of glucose 5-7ATP Glucose glycolysis 2ATP(Substrate-level phosphorylation)2 2NADH ( oxphos) 3-5 2Pyruvate oxidative decarboxylation 2 NADH ( oxphos) 5 2 Acetyl CoA TCA cycle 20 6 NADH 2 FADH2 2 GTP total 30-32ATP 25ATP CO2

  27. The Fate of Carbon in TCA

  28. Reaction 2: Aconitase Always the 2 carbons from acetyl CoA Stereospecific A symmetrical compound is converted to a chiral compound

  29. How much radioactivity has been lost after one turn? * * * * * * * * * * Stereospecific * * Zero * * Not stereospecific * * * * Not stereospecific * * * * * *

  30. How much radioactivity has been lost after 2 turns? * * * * * * * * * * * * * * 50% * * * * Cycle 2 * * * * * * * * * * * * * * *

  31. Carboxyl C of acetate turns to CO2 only in the second turn of the cycle Methyl C of acetate survives two cycles completely, but half of what's left exits the cycle on each turn after that.

  32. Regulation of the TCA Cycle Again, 3 irreversible reactions are the key sites Citrate synthase - regulated by availability of substrates - acetyl-CoA and oxaloacetate, citrate is a competitive inhibitor; Allosteric: - NADH , ATP,succinyl-CoA Isocitrate dehydrogenase – NADH,ATP inhibit, ADP and NAD+ Ca++ activate  -Ketoglutarate dehydrogenase - NADH and succinyl-CoA inhibit, AMP Ca++activate

  33. Major regulatory sites are irreversible reactions

  34. Anaplerotic reactions Anaplerotic (filling up) reactions replenish citric acid cycle intermediates Amphibolic Nature of TCA Cycle means it both Anabolic and Catabolic. TCA cycle provides several of Intermediates for Biosynthesis

  35. Anaplerotic reactions PEP carboxylase - converts PEP to oxaloacetate , Anaplerotic reaction in plants and bacteria Pyruvate carboxylase - converts pyruvate to oxaloacetate, a major anaplerotic reaction in mammaliantissues Malic enzyme converts pyruvate into malate

  36. The Glyoxylate Cycle An Anabolic Variant of the Citric Acid Cycle for plants and bacteria Acetate-based growth - net synthesis of carbohydrates and other intermediates from acetate - is not possible with TCA Glyoxylate cycle offers a solution for plants and some bacteria and algae The CO2-evolving steps are bypassed and an extra acetate is utilized Isocitrate lyase and malate synthase are the short-circuiting enzymes

  37. Acetyl-CoA Citrate Oxaloacetate Isocitrate Isocitrate lyase Malate sythase Malate Glyoxalate Acetyl-CoA Succinate

  38. 在肌肉糜中加入柠檬酸可刺激氧的消耗，而加入丙二酸后呼吸被抑制，并造成琥珀酸的积累，请解释这现象，有什么办法可以去除丙二酸的抑制。

  39. 糖酵解可以在有氧和无氧的情况下发生，而TCA循环却只能在有氧情况下发生。解释为什么糖酵解可以在无氧情况下进行而TCA循环却不能。TCA循环中最直接受到无氧影响的是哪些步？糖酵解可以在有氧和无氧的情况下发生，而TCA循环却只能在有氧情况下发生。解释为什么糖酵解可以在无氧情况下进行而TCA循环却不能。TCA循环中最直接受到无氧影响的是哪些步？

  40. Home work Starting with pyruvate labelled with 13C on the keto-carbon, where will this isotopic label end up in oxaloacetate after one round of the citric acid cycle?

  41. Briefly describe The reaction catalyzed by the pyruvate dehydrogenase complex in carbohydrate metabolism: One advantage of a multienzyme complex explain how pyruvate dehydrogenase is regulated. (Graphs of enzyme activity would be cool)! What effect would increasing expression of the PDH kinase gene have on carbohydrate metabolism?

  42. If you add pyruvate labeled in the carboxylate group to actively metabolizing eukaryotic cells under aerobic conditions, under what conditions will that labeled carbon enter the citric acid cycle?

  43. What is the primary regulatory site in glycolysis? Explain the role of energy charge in controlling the enzyme. Name other sites for regulation in glycolysis.

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