Chapter 19 The two-carbon unit needed at the start of the citric acid

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Chapter 19

The Citric Acid Cycle

SUMMARY

Section 19.1

 The citric acid cycle is amphibolic. It plays a role in both catabolism and

anabolism. It is the central metabolic pathway.

Section 19.2

 The citric acid cycle takes place in the mitochondrial matrix, with exception that

Section 19.3

 The two-carbon unit needed at the start of the citric acid cycle is obtained by

converting pyruvate to acetyl-CoA.

Section 19.4

Section 19.5

 The citric acid cycle is exergonic in terms of overall free-energy changes. In

addition, it produces four NADH and one FADH2 for each pyruvate that enters

Section 19.6

 In plants and bacteria, the glyoxylate cycle is a pathway that bypasses the two

2 Chapter 19

Section 19.7

 All metabolic pathways are related, and all operate simultaneously.

Section 19.8

 The citric acid cycle plays a central role in anabolic pathways as well as in

 catabolism.

Section 19.9

 The citric acid cycle is considered part of aerobic metabolism because of the link

LECTURE NOTES

The citric acid cycle plays a central role in both central energy metabolism and

biosynthesis. As such, at least two lectures should be devoted to this chapter. The

LECTURE OUTLINE

I. Central role of the citric acid cycle

A. Central energy metabolism – ETC and OxPhos

B. Amphibolic nature – catabolism and anabolism

II. Overall Pathway

A. Mitochondrial structure review

III. Pyruvate conversion to acetyl-CoA

A. Pyruvate dehydrogenase complex

B. Coenzyme A

C. Pyruvate dehydrogenase

The Citric Acid Cycle 3

E. Dihydrolipoyl dehydrogenase

1. Reoxidation to disulfide form

IV. The reactions of the citric acid cycle

A. Citrate formation

1. Condensation reaction

B. Isomerization

1. Aconitase

2. Stereospecificity of product

3. Requirement of Fe(II)

C. First oxidation

1. Isocitrate dehydrogenase

E. Succinate formation

1. Production of GTP

2. Succinyl-CoA synthetase

3. Transfer of phosphate between GTP and ATP

F. Fumarate formation

1. Succinate dehydrogenase

2. Integral membrane protein – inner mitochondrial membrane

3. Use of FAD

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I. Overall reactions

1. Pyruvate dehydrogenase complex

V. Energetics and control

A. General thermodynamic considerations

B. Control of pyruvate dehydrogenase

1. Inhibition by ATP and NADH

2. Activation by ADP

VI. Glyoxylate cycle

A. Use of acetyl-CoA for carbohydrate synthesis in non-animals

B. Isocitrate lyase and malate synthase

VII. CAC and catabolism

A. Stages of catabolism

B. CAC as central point for catabolic pathways

ANSWERS TO PROBLEMS

19.1 The Central Role of the Citric Acid Cycle in Metabolism

1. Anaerobic glycolysis is the principal pathway for the anaerobic metabolism of

2. Anaerobically, two ATPs can be produced from one glucose molecule.

Aerobically, this figure is 30 to 32, depending on in which tissue it is occurring.

and the TCA cycle.

The Citric Acid Cycle 5

4. Amphibolic means that the pathway is involved in both catabolism and

anabolism.

19.2 The Overall Pathway of the Citric Acid Cycle

5. The citric acid cycle takes place in the mitochondrial matrix. Glycolysis takes

place in the cytosol.

19.3 How Pyruvate Is Converted to Acetyl-CoA

9. Five enzymes are involved in the pyruvate dehydrogenase complex of mammals.

Pyruvate dehydrogenase transfers a two-carbon unit to TPP and releases CO2.

10. Lipoic acid plays a role both in redox and in acetyl-transfer reactions.

11. Five enzymes are all in close proximity for efficient shuttling of the acetyl unit

between molecules and efficient control of the complex by phosphorylation.

12. Thiamine pyrophosphate comes from the B vitamin thiamine. Lipoic acid is a

riboflavin.

13.

14. See Figure 19.4.

19.4 The Individual Reactions of the Citric Acid Cycle

15. A condensation reaction is one in which a new carbon–carbon bond is formed.

The reaction of acetyl-CoA and oxaloacetate to produce citrate involves

17. Fluoroacetate is a poison that is produced naturally in some plants and is also

used as a poison against undesirable pests. It is poisonous because it is used by

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19. Conversion of pyruvate to acetyl-CoA, conversion of isocitrate to -ketoglutarate,

21. These enzymes catalyze oxidative decarboxylations.

22. The reactions proceed by the same mechanism and use the same cofactors. The

difference is the initial substrate, which is pyruvate or -ketoglutarate. During the

course of the reaction, pyruvate dehydrogenase shuttles an acetyl unit through

the reaction while -ketoglutarate dehydrogenase shuttles a succinyl unit.

23. A synthetase is an enzyme that synthesizes a molecule and uses a high-energy

chain generates energy to allow the conversion of ADP to ATP.

25. We have previously encountered substrate-level phosphorylation in glycolysis.

An example is the transfer of a phosphate from 1,3-bisphosphoglycerate to ADP

to afford 3-phosphoglycerate and ATP

26. GTP is equivalent to ATP because an enzyme, nucleoside diphosphate kinase, is

able to interconvert GTP and ATP.

27. The enzymes that reduce NAD+ are all soluble, matrix enzymes, while succinate

reaction.

30.

The Citric Acid Cycle 7

31.

19.5 Energetics and Control of the Citric Acid Cycle

32. The reactions are catalyzed by pyruvate dehydrogenase, citrate synthase,

isocitrate dehydrogenase, and -ketoglutarate dehydrogenase.

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35. If the amount of ADP in a cell increases relative to the amount of ATP, the cell

needs energy (ATP). This situation not only favors the reactions of the citric acid

cycle, which release energy, activating isocitrate dehydrogenase, but also

37. The citric acid cycle is less active when a cell has a high ATP/ADP ratio and a

high NADH/NAD+ ratio. Both ratios indicate a high “energy charge” in the cell,

indicating less of a need for the energy-releasing reactions of the citric acid cycle.

38. Thioesters are “high–energy” compounds that play a role in group-transfer

reactions; consequently, their G°′ of hydrolysis is large and negative to provide

energy for the reaction.

42. Lactose is a disaccharide of glucose and galactose. There is no energy cost in

the hydrolysis of the bond between the two monosaccharides, so essentially

there are two hexoses to consider. Because the processing of any of the

hexoses yields the same amount of energy, the aerobic processing of lactose

would lead to 60 to 64 ATPs, depending on the tissue and on the shuttle system

used.

19.6 The Glyoxylate Cycle: A Related Pathway

43. Isocitrate dehydrogenase, -ketoglutarate dehydrogenase, and succinyl-CoA

synthetase.

44. The conversion of isocitrate to succinate and glyoxylate catalyzed by isocitrate

The Citric Acid Cycle 9

19.7 The Citric Acid Cycle in Catabolism

46. The citric acid cycle is the central metabolic pathway and indirect producer of

energy. It receives fuels from the other pathways at many points and generates

reduced electron carriers that go into the electron transport chain. It is also

involved in anabolism, as many of its intermediates can be drawn off to

synthesize other compounds.

19.8 The Citric Acid Cycle in Anabolism

50. The following series of reactions exchanges NADH for NADPH.

Oxaloacetate + NADH + H+  Malate + NAD+

19.9 The Link to Oxygen

53. The NADH and FADH2 produced by the citric acid cycle are the electron donors

in the electron transport chain linked to oxygen. Because of this connection, the

citric acid cycle is considered part of aerobic metabolism.