Biochemistry: A Short Course

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1 Tymoczko Berg Stryer Biochemistry: A Short Course First Edition CHAPTER 19 Harvesting Electrons from the Cycle 2013 W. H. Freeman and Company

3 Chapter 19 Outline

4 The citric acid cycle oxidizes the acetyl fragment of acetyl CoA to CO 2. In the process of oxidation, high energy electrons are captured in the form of NADH and FADH 2. The function of the citric acid cycle is to harvest high energy electrons from carbon fuels.

5 In the first stage of the citric acid cycle, two carbons are introduced into the cycle by condensation of an acetyl group with a four carbon compound, oxaloacetate. The six carbon compound formed (citrate) undergoes two oxidative decarboxylations, generating two molecules of CO 2. In the second stage, oxaloacetate is regenerated. Both stages generate high energy electrons that are used to power the synthesis of ATP in oxidative phosphorylation.

8 The first stage generates two molecules of CO 2 by oxidative decarboxylations.

9 Citrate synthase catalyzes the condensation of acetyl CoA and oxaloacetate to form citrate.

10 Citrate synthase exhibits induced fit. Oxaloacetate binding by citrate synthase induces structural changes that lead to the formation of the acetyl CoA binding site. The formation of the reaction intermediate citryl CoA causes a structural change that completes active site formation. Citryl CoA is cleaved to form citrate and coenzyme A.

12 Aconitase catalyzes the formation of isocitrate from citrate.

13 Aconitase is inhibited by fluoroacetate, a suicide inhibitor, which irreversibly inhibits aconitase after aconitase forms fluorocitrate. Fluoroacetate is found in the genus Gastrolobium, a flowering plant native to Australia.

14 Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate, forming α ketoglutarate and capturing high energy electrons as NADH.

15 α Ketoglutarate dehydrogenase complex catalyzes the synthesis of succinyl CoA from α ketoglutarate, generating NADH. The enzyme and the reactions are structurally and mechanistically similar to the pyruvate dehydrogenase complex.

16 Succinyl CoA synthetase catalyzes the cleavage of a thioester linkage and concomitantly forms ATP.

17 Cleavage of the thioester of succinyl CoA powers the formation of ATP. The formation of ATP by succinyl coenzyme A synthetase is an example of a substrate level phosphorylation because succinyl phosphate, a high phosphoryl transfer potential compound, donates a phosphate to ADP.

19 Succinate dehydrogenase, fumarase, and malate dehydrogenase catalyze successive reactions to regenerate oxaloacetate. FADH 2 and NADH are generated. Oxaloacetate can condense with another acetyl CoA to initiate another cycle.

20 The net reaction of the citric acid cycle is: The electrons from NADH will generate 2.5 ATP when used to reduce oxygen in the electron transport chain. The electrons from FADH 2 will power the synthesis of 1.5 ATP with the reduction of oxygen in the electrontransport chain.

24 The key control points in the citric acid cycle are the reactions catalyzed by isocitrate dehydrogenase and α ketoglutarate dehydrogenase. Recall that pyruvate dehydrogenase controls entry of glucose derived acetyl CoA into the cycle.

26 Many of the components of the citric acid cycle are precursors for biosynthesis of key biomolecules.

28 Because the citric acid cycle provides precursors for biosynthesis, reactions to replenish the cycle components are required if the energy status of the cells changes. These replenishing reactions are called anapleurotic reactions. A prominent anapleurotic reaction is catalyzed by pyruvate carboxylase. Recall that this reaction is also used in gluconeogenesis and is dependent on the presence of acetyl CoA.

31 Defects in succinate dehydrogenase, fumarase or pyruvate dehydrogenase kinase can contribute to the development of cancer. These defects contribute to use of aerobic glycolysis by cancer cells.

32 The glyoxylate cycle is similar to the citric acid cycle but bypasses the two decarboxylation steps, allowing the synthesis of carbohydrates from fats. Succinate can be converted into oxaloacetate and then into glucose. The glyoxylate cycle is prominent in oil rich seeds such as sunflower seeds.

Citric Acid Cycle: Central Role in Catabolism. Entry of Pyruvate into the TCA cycle

Citric Acid Cycle: Central Role in Catabolism Stage II of catabolism involves the conversion of carbohydrates, fats and aminoacids into acetylcoa In aerobic organisms, citric acid cycle makes up the final