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Lecture 4 - Citric Acid Cycle

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Lecture 4 - Citric Acid Cycle Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire 1 Introduction The Citric Acid Cycle is a metabolic round- about It is the final common pathway for oxidation of fuel molecules 2 2 Introduction Most material enters the Citric Acid Cycle as Acetyl-CoA The acetyl group 3 3 Introduction For eukaryotes, Citric Acid Cycle located in the mitochondrial matrix 4 4 Introduction Citric acid cycle is also an important source of precursors Two of the intermediates are only one step away from an amino acid One of the intermediates is used in the synthesis of porphorins Another is used in the synthesis of fatty acids and sterols. 5 5 Introduction 6 6 Introduction Citric acid cycle contains a series of oxidation-reduction reactions Carbon entering the cycle, leaves fully oxidized as CO2. “High energy” electrons leave the cycle with high energy electron carriers as NADH and FADH2. Very little ATP is made directly in the cycle. No oxygen is used in the cycle. 7 7 Introduction 8 8 Introduction The “high energy” electrons are used elsewhere to make ATP from ADP and Pi 9 9 1. Oxidation of Two-Carbon Units The citric acid cycle oxidizes two carbon units. These enter the cycle as Acetyl-CoA Acetyl-CoA is synthesized from pyruvate or from fats 10 10 1.1. Formation of Acetyl-CoA Acetyl-CoA is formed from pyruvate by an oxidative decarboxylation. O O + Pyruvate CH3 C C O + CoA-SH + NAD Dehydrogenase Pyruvate O CH3 C S CoA + O C O + NADH Acetyl-CoA 11 11 1.2. Pyruvate Dehydrogenase Complex Pyruvate Dehydrogenase is a large multi-subunit complex 12 12 1.2. Pyruvate Dehydrogenase Complex 13 13 1.2. Pyruvate Dehydrogenase Complex Cofactors used include Thiamine pyrophosphate (TPP) Lipoic Acid 14 14 1.2. Pyruvate Dehydrogenase Complex The pyruvate dehydrogenase reaction involves three steps: 15 15 1.2. Pyruvate Dehydrogenase Complex (E1) - Pyruvated dehydrogenate component 16 16 1.2. Pyruvate Dehydrogenase Complex (E1) - Pyruvated dehydrogenate component 17 17 1.2. Pyruvate Dehydrogenase Complex (E2)-Dihydrolipoyl transacetylase component 18 18 1.2. Pyruvate Dehydrogenase Complex (E2)-Dihydrolipoyl transacetylase component 19 19 1.2. Pyruvate Dehydrogenase Complex (E2)-Dihydrolipoyl transacetylase component 20 20 1.2. Pyruvate Dehydrogenase Complex (E3)-Dihydrolipoyl dehydrogenase component 21 21 1.2. Pyruvate Dehydrogenase Complex 22 22 1.2. Pyruvate Dehydrogenase Complex 23 23 1.3. Citrate Synthase First reaction of the citric acid cycle 24 24 1.3. Citrate Synthase The enzyme brings the two reactants into juxtaposition 25 25 1.4 Aconitase Isomerizes citrate to isocitrate 26 26 1.4 Aconitase Aconitase contains a 4Fe-4S iron-sulfur center 27 27 1.5. Isocitrate Dehydrogenase 28 28 1.6. α-Ketoglutarate Dehydrogenase 29 29 1.6. α-Ketoglutarate Dehydrogenase 30 30 1.7. Succinyl-CoA Synthetase 31 31 1.7. Succinyl-CoA Synthetase The mechanism involves a series of transfer reactions 32 32 1.8. Regeneration of Oxaloacetate 33 33 1.9. Stoichiometry of Citric Acid Cycle O + FAD H3C C S CoA + 3 NAD + GDP + Pi + 2 H2O 2 CO + + + + + + CoA-SH 34 2 3 NADH 3 H FADH2 GTP 34 1.9. Stoichiometry of Citric Acid Cycle 35 35 1.9. Stoichiometry of Citric Acid Cycle 36 36 Problem What is the fate of the radioactive label when each of the following compounds is added to a cell extract containing the enzymes and cofactors of the glycolytic pathway, the citric acid cycle, and the pyruvate dehydrogenase complex? O O O O C C C C H3C COO H3C COO H3C COO H3C S CoA 37 37 The Citric Acid Cycle 38 38 Problem In experiments carried out in 1941 to investigate the citric acid cycle, oxaloacetate labeled with 14C in the carboxyl carbon atom furthest from the keto group was introduced to an active preparation of mitochondria Analysis of the α-ketoglutarate formed showed that none of the radioactive label had been lost. Decarboxylation of the α-ketoglutarate then yielded succinate devoid of radioactivity. All the label was in the released CO2. Why were the early investigators of the citric acid cycle surprised that all the label emerged in the CO2? 39 39 Regulation of Citric Acid Cycle The citric acid cycle Final common pathway for oxidation of food Also is a source of building blocks 40 40 2.1. Regulation of Pyruvate Dehydrogenase The pyruvate dehydrogenase step is irreversible in animals 41 41 2.1. Regulation of Pyruvate Dehydrogenase Pyruvate Dehydrogenase is regulated both allosterically and by reversible phosphorylation 42 42 2.2. Control Points in the Citric Acid Cycle Citric acid cycle is controlled at two points 43 43 3. Source or Biosynthetic Precursors Citric acid cycle is also an important source of precursors for biosynthetic reactions 44 44 3.1. Replenishing the Intermediates Pyruvate carboxylase reaction is used to synthesize oxaloacetate from pyruvate O O O O C C + O C + CO2 + ATP + H2O O C + ATP + Pi + 2 H CH3 CH2 C O O Pyruvate Oxaloacetate 45 45 3.2. Disruption of Pyruvate Metabolism Thiamine difficiency causes beriberi 3- Arsenite (AsO3 ) and mercury bind to dithiols, such as dihydrolipoamide. 46 46 The Glyoxylate Cycle Some plants and bacteria can live off of acetate as a fuel source. These organisms possess two enzymes that allow them to carry out the glyoxylate cycle: 47 47 Problem It is possible, with the use of the reactions and enzymes discussed in this chapter, to convert pyruvate into α-ketoglutarate without depleting any of the citric acid cycle components. Write a balanced reaction scheme for this conversion, showing cofactors and identifying the required enzymes 48 48.
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