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Chem 352 - Lecture 10, Part II Citric Acid Cycle Chem 352 - Lecture 10, Part II Citric Acid Cycle Question for the Day: One of the observations that led Hans Krebs to discover the citric acid cycle, was that dicarboxylic acids, such as fumarate and succinate, had a catalytic effect on the oxidation of glucose to CO2 and H2O by muscle tissue. Explain his observation. Introduction Chem 352, Lecture 10, Part II - Citric Acid Cycle 2 Introduction 13.1 Overview of Pyruvate Oxidation and the Citric Acid Cycle 13.2 Pyruvate Oxidation: A Major Entry Route for Carbon in the Citric Acid Cycle 13.3 The Citric Acid Cycle 13.4 Stoichiometry and Energetics of the Citric Acid Cycle 13.5 Regulation of Pyruvate Dehydrogenase and the Citric Acid Cycle 13.8 Anapleoritic Sequences: The Need to Replace Cycle Intermediates. 13.9 The Glyoxylate Cycle: An Anabolic Variant of the Citric Acid Cycle Chem 352, Lecture 10, Part II - Citric Acid Cycle 2 Introduction Chem 352, Lecture 10, Part II - Citric Acid Cycle 3 Introduction Chem 352, Lecture 10, Part II - Citric Acid Cycle 3 13.1 Overview of Pyruvate Oxidation and the Citric Acid Cycle Overview Chem 352, Lecture 10, Part II - Citric Acid Cycle 5 Overview The citric acid cycle has both catabolic and anabolic functions. • Catabolic - Oxidizes the 2-carbon acetyl group to CO2 and produces reduced nucleotides (NADH + H+ and FADH2) Chem 352, Lecture 10, Part II - Citric Acid Cycle 5 Overview The citric acid cycle has both catabolic and anabolic functions. • Catabolic - Oxidizes the 2-carbon acetyl group to CO2 and produces reduced nucleotides (NADH + H+ and FADH2) • Anabolic - The citric acid cycle intermediates serve as starting material for the biosynthesis of amino acids, heme groups, glucose, et al. Chem 352, Lecture 10, Part II - Citric Acid Cycle 5 Overview Chem 352, Lecture 10, Part II - Citric Acid Cycle 6 Overview The metabolic oxidation of organic substrates can be broken down into three stages. • Oxidation occurs in dehydrogenation reaction with the removal of hydride ions (�:−). Chem 352, Lecture 10, Part II - Citric Acid Cycle 6 Overview The metabolic oxidation of organic substrates can be broken down into three stages. • Oxidation occurs in dehydrogenation reaction with the removal of hydride ions (�:−). Chem 352, Lecture 10, Part II - Citric Acid Cycle 6 Overview The metabolic oxidation of organic substrates can be broken down into three stages. • Oxidation occurs in dehydrogenation reaction with the removal of hydride ions (�:−). Chem 352, Lecture 10, Part II - Citric Acid Cycle 6 Overview Chem 352, Lecture 10, Part II - Citric Acid Cycle 7 Overview In eukaryotes, these reactions occur in the mitochondrial matrix and the inner mitochondrial membrane. Chem 352, Lecture 10, Part II - Citric Acid Cycle 7 Overview Chem 352, Lecture 10, Part II - Citric Acid Cycle 8 Overview • Two carbon atoms enter the citric acid cycle as an acetyl group derived from pyruvate. • Two carbons then leave the citric acid cycle as CO2. - The strategy used dehydrogenase reactions to create α-keto and β-keto acids, which easily undergo decarboxylation. Chem 352, Lecture 10, Part II - Citric Acid Cycle 8 Overview • Two carbon atoms enter the citric acid cycle as an acetyl group derived from pyruvate. • Two carbons then leave the citric acid cycle as CO2. - The strategy used dehydrogenase reactions to create α-keto and β-keto acids, which easily undergo decarboxylation. Chem 352, Lecture 10, Part II - Citric Acid Cycle 8 Overview • Two carbon atoms enter the citric acid cycle as an acetyl group derived from pyruvate. • Two carbons then leave the citric acid cycle as CO2. - The strategy used dehydrogenase reactions to create α-keto and β-keto acids, which easily undergo decarboxylation. Chem 352, Lecture 10, Part II - Citric Acid Cycle 8 Overview The citric acid cycle was discovered by Hans Kreb’s and colleagues in 1937. ✦ Citric acid cycle is also called the Kreb’s Cycle and the TCA (tricarboxylic acid) Cycle. ✦ Krebs recognized why some dicarboxylic acid, when added in small amounts, would catalytically increase the rate of O2 consumption by respiring muscle tissue. Hans Krebs (1900-1981) Nobel Prize in Physiology and Medicine, 1953 Chem 352, Lecture 10, Part II - Citric Acid Cycle 9 Overview The citric acid cycle was discovered by Hans Kreb’s and colleagues in 1937. ✦ Citric acid cycle is also called the Kreb’s Cycle and the TCA (tricarboxylic acid) Cycle. ✦ Krebs recognized why some dicarboxylic acid, when added in small amounts, would catalytically increase the rate of O2 consumption by respiring muscle tissue. Hans Krebs (1900-1981) Nobel Prize in Physiology and Medicine, 1953 Chem 352, Lecture 10, Part II - Citric Acid Cycle 9 Overview The citric acid cycle was discovered by Hans Kreb’s and colleagues in 1937. ✦ Citric acid cycle is also called the Kreb’s Cycle and the TCA (tricarboxylic acid) Cycle. ✦ Krebs recognized why some dicarboxylic acid, when added in small amounts, would catalytically increase the rate of O2 consumption by respiring muscle tissue. Hans Krebs (1900-1981) Nobel Prize in Physiology and Medicine, 1953 Chem 352, Lecture 10, Part II - Citric Acid Cycle 9 13.2 Pyruvate Oxidation: A Major Entry Route for Carbon in the Citric Acid Cycle Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation The entry point of carbon into the citric acid cycle is acetyl CoA O CH3 C S CoA Chem 352, Lecture 10, Part II - Citric Acid Cycle 11 Pyruvate Oxidation Chem 352, Lecture 10, Part II - Citric Acid Cycle 12 Pyruvate Oxidation Acetyl CoA is produced from the oxidative decarboxylation of pyruvate Chem 352, Lecture 10, Part II - Citric Acid Cycle 12 Pyruvate Oxidation Acetyl CoA is produced from the oxidative decarboxylation of pyruvate • It is also produce in the degradation of fatty acids. Chem 352, Lecture 10, Part II - Citric Acid Cycle 12 Pyruvate Oxidation Chem 352, Lecture 10, Part II - Citric Acid Cycle 13 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • Comprising multiple copies of three enzymes - pyruvate dehydrogenase (E1) - dihydrolipoamide transacetylase (E2) - dihydrolipoamide dehydrogenase (E3) Chem 352, Lecture 10, Part II - Citric Acid Cycle 13 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • Comprising multiple copies of three enzymes - pyruvate dehydrogenase (E1) - dihydrolipoamide transacetylase (E2) - dihydrolipoamide dehydrogenase (E3) • And five coenzymes Chem 352, Lecture 10, Part II - Citric Acid Cycle 13 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • 60 copies of E2 form a core structure with icosahedral symmetry. Chem 352, Lecture 10, Part II - Citric Acid Cycle 14 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • 12 copies of E3 take up positions at each of the 12 vertices of the iscosahedron. Chem 352, Lecture 10, Part II - Citric Acid Cycle 15 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • 12 copies of E3 take up positions at each of the 12 vertices of the iscosahedron. Chem 352, Lecture 10, Part II - Citric Acid Cycle 15 Pyruvate Oxidation Pyruvate dehydrogenase is actually a large enzyme complex. • The E2-E3 subcomplex is then surround by ~30 tetramers of E1. Chem 352, Lecture 10, Part II - Citric Acid Cycle 16 Pyruvate Oxidation The five coenzymes include • Thiamine pyrophosphate, which is used in the decarboxylation of α-keto acids • Unlike β-keto, α-keto acids cannot stabilize the carbanion intermediate that forms during decarboxylation. Chem 352, Lecture 10, Part II - Citric Acid Cycle 17 Pyruvate Oxidation The five coenzymes include • Thiamine pyrophosphate, which is used in the decarboxylation of α-keto acids • Unlike β-keto, α-keto acids cannot stabilize the carbanion intermediate that forms during decarboxylation. Chem 352, Lecture 10, Part II - Citric Acid Cycle 18 Pyruvate Oxidation The five coenzymes include • Lipoic acid, which is used in the decarboxylation of α-keto acids - It is attached to a lysine side chain on the E2 subunits. - It accepts the 2-carbon aldehyde fragment from TPP and oxidizes it to an acetyl group. - And then it to Coenzyme A. Chem 352, Lecture 10, Part II - Citric Acid Cycle 19 Pyruvate Oxidation The five coenzymes include • Coenzyme A, which is an activated acyl carrier and serves as a cosubstrate in this reaction. Chem 352, Lecture 10, Part II - Citric Acid Cycle 20 Pyruvate Oxidation The five coenzymes include • Flavin Adenine Dinucleotide (FAD), which is an enzyme- bound redox coenzyme that reoxidizes the dihydrolipoamide back to lipoamide Chem 352, Lecture 10, Part II - Citric Acid Cycle 21 Pyruvate Oxidation The five coenzymes include • Flavin Adenine Dinucleotide (FAD), which is an enzyme- bound redox coenzyme that reoxidizes the dihydrolipoamide back to lipoamide Chem 352, Lecture 10, Part II - Citric Acid Cycle
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