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 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 21 Pyruvate Oxidation The five coenzymes include • Nicotinamde Adenine Dinucleotide (NAD+), which serves as a cosubstrate to reoxidize the enzyme- bound FAD
Chem 352, Lecture 10, Part II - Citric Acid Cycle 22 Pyruvate Oxidation The five coenzymes include • Nicotinamde Adenine Dinucleotide (NAD+), which serves as a cosubstrate to reoxidize the enzyme- bound FAD
Chem 352, Lecture 10, Part II - Citric Acid Cycle 22 Pyruvate Oxidation The five coenzymes include • Nicotinamde Adenine Dinucleotide (NAD+), which serves as a cosubstrate to reoxidize the enzyme- bound FAD
Chem 352, Lecture 10, Part II - Citric Acid Cycle 22 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 Pyruvate Oxidation Pyruvate Dehydrogenase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 23 13.3 The Citric Acid Cycle The Citric Acid Cycle Catabolic Mode
S CoA
- + - C O + 2 H2O + OH 2 CO2 + HS-CoA + 7 H + 8 e
CH3 acetyl CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 25 The Citric Acid Cycle Catabolic Mode
S CoA
- + - C O + 2 H2O + OH 2 CO2 + HS-CoA + 7 H + 8 e
CH3 acetyl CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 25 The Citric Acid Cycle Catabolic Mode
S CoA
- + - C O + 2 H2O + OH 2 CO2 + HS-CoA + 7 H + 8 e
CH3 acetyl CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 25 The Citric Acid Cycle Catabolic Mode
S CoA
- + - C O + 2 H2O + OH 2 CO2 + HS-CoA + 7 H + 8 e
CH3 acetyl CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 25 The Citric Acid Cycle Catabolic Mode
S CoA
- + - C O + 2 H2O + OH 2 CO2 + HS-CoA + 7 H + 8 e
CH3 acetyl CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 25 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 26 The Citric Acid Cycle 1. Introduction of Two Carbons as Acetyl-CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 26 The Citric Acid Cycle 1. Introduction of Two Carbons as Acetyl-CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 26 The Citric Acid Cycle 1. Introduction of Two Carbons as Acetyl-CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 26 The Citric Acid Cycle 1. Introduction of Two Carbons as Acetyl-CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 26 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle 2. Isomerization of Citrate to Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle 2. Isomerization of Citrate to Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle 2. Isomerization of Citrate to Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle 2. Isomerization of Citrate to Isocitrate
citrate is prochiral
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle 2. Isomerization of Citrate to Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 27 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle 3. Oxidative Decarboxylation of Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle 3. Oxidative Decarboxylation of Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle 3. Oxidative Decarboxylation of Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle 3. Oxidative Decarboxylation of Isocitrate
The oxidation of the 2- hydroxyl group to a ketone produces a β-keto acid, which then spontaneously undergoes decarboxylation.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle 3. Oxidative Decarboxylation of Isocitrate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 28 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 29 The Citric Acid Cycle 4. Second Oxidative Decarboxylation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 29 The Citric Acid Cycle 4. Second Oxidative Decarboxylation
Like pyruvate dehydrogenase, this is the oxidative decarboxylation of an α-keto acid.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 29 The Citric Acid Cycle 4. Second Oxidative Decarboxylation
Like pyruvate dehydrogenase, this is the oxidative decarboxylation of an α-keto acid.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 29 The Citric Acid Cycle 4. Second Oxidative Decarboxylation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 29 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 30 The Citric Acid Cycle 5. Substrate-Level Phosphorylation of GDP (ADP)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 30 The Citric Acid Cycle 5. Substrate-Level Phosphorylation of GDP (ADP)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 30 The Citric Acid Cycle 5. Substrate-Level Phosphorylation of GDP (ADP)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 30 The Citric Acid Cycle 5. Substrate-Level Phosphorylation of GDP (ADP)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 30 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle 6. Flavin-Dependent Dehydrogenation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 31 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 32 The Citric Acid Cycle 7. Hydration of Carbon-Carbon Double Bond
Chem 352, Lecture 10, Part II - Citric Acid Cycle 32 The Citric Acid Cycle 7. Hydration of Carbon-Carbon Double Bond
Chem 352, Lecture 10, Part II - Citric Acid Cycle 32 The Citric Acid Cycle 7. Hydration of Carbon-Carbon Double Bond
Chem 352, Lecture 10, Part II - Citric Acid Cycle 32 The Citric Acid Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 33 The Citric Acid Cycle 8. Oxidation and Regeneration of Oxaloacetate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 33 The Citric Acid Cycle 8. Oxidation and Regeneration of Oxaloacetate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 33 The Citric Acid Cycle 8. Oxidation and Regeneration of Oxaloacetate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 33 The Citric Acid Cycle 8. Oxidation and Regeneration of Oxaloacetate
Chem 352, Lecture 10, Part II - Citric Acid Cycle 33 13.4 Stoichiometry and Energetics of the Citric Acid Cycle Stoichiometry and Energetics
Chem 352, Lecture 10, Part II - Citric Acid Cycle 35 Stoichiometry and Energetics
Chem 352, Lecture 10, Part II - Citric Acid Cycle 35 Stoichiometry and Energetics
• Per Acetyl-CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 35 Stoichiometry and Energetics
• Per Acetyl-CoA
• Per Glucose (glycolysis+PDH+citric acid cycle)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 35 13.5 Regulation of Pyruvate Dehydrogenase and the Citric Acid Cycle Regulation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include • The reactions involved in entry of fuel into the cycle - The Pyruvate Dehydrogenase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include • The reactions involved in entry of fuel into the cycle - The Pyruvate Dehydrogenase reaction - The Citrate Synthase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include • The reactions involved in entry of fuel into the cycle - The Pyruvate Dehydrogenase reaction - The Citrate Synthase reaction • And the two reactions with large, negative ΔG’ values. - The Isocitrate Dehydrogenase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include • The reactions involved in entry of fuel into the cycle - The Pyruvate Dehydrogenase reaction - The Citrate Synthase reaction • And the two reactions with large, negative ΔG’ values. - The Isocitrate Dehydrogenase reaction - The α-Ketoglutarate Dehydrogenase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation The Citric acid cycle plays both a catabolic and an anabolic which makes regulation a bit more complicated. The major control points include • The reactions involved in entry of fuel into the cycle - The Pyruvate Dehydrogenase reaction - The Citrate Synthase reaction • And the two reactions with large, negative ΔG’ values. - The Isocitrate Dehydrogenase reaction - The α-Ketoglutarate Dehydrogenase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 37 Regulation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 38 Regulation The Pyruvate Dehydrogenase Reaction is controlled both by • Feedback inhibition
- Competitive product inhibition of E2 by acetyl-CoA - Competitive product inhibition of E3 by NADH
Chem 352, Lecture 10, Part II - Citric Acid Cycle 38 Regulation The Pyruvate Dehydrogenase Reaction is controlled both by
Chem 352, Lecture 10, Part II - Citric Acid Cycle 39 Regulation The Pyruvate Dehydrogenase Reaction is controlled both by • Covalent Modification
- Involving phosphorylation and dephosphorylation of E1 - Ca+2 is signal molecule for muscle contraction. - Insulin signals high blood glucose levels.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 39 Regulation
Chem 352, Lecture 10, Part II - Citric Acid Cycle 40 Regulation The flux within the citric acid cycle is controlled by: • The energy state of the cell through allosteric activation of isocitrate dehydrogenase by ADP.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 40 Regulation The flux within the citric acid cycle is controlled by: • The energy state of the cell through allosteric activation of isocitrate dehydrogenase by ADP. • The redox state of the cell, through flux rate limitation caused when the intramitochondrial [NAD+]/ [NADH] ratio decreases
Chem 352, Lecture 10, Part II - Citric Acid Cycle 40 Regulation The flux within the citric acid cycle is controlled by: • The energy state of the cell through allosteric activation of isocitrate dehydrogenase by ADP. • The redox state of the cell, through flux rate limitation caused when the intramitochondrial [NAD+]/ [NADH] ratio decreases • The availability of energy-rich compounds, through inhibition of relevant enzymes by acetyl-CoA or succinyl- CoA
Chem 352, Lecture 10, Part II - Citric Acid Cycle 40 13.8 Anaplerotic Sequences: The Need to Replace Cycle Intermediates Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 42 Replacing Intermediates The citric acid cycle is amphibolic, meaning it serves both a catabolic and anabolic role. • While the catabolic mode does not affect the levels of the citric acid intermediates, in the anabolic mode, the intermediates become starting material for pathways that lead out of the citric acid cycle.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 42 Replacing Intermediates The citric acid cycle is amphibolic, meaning it serves both a catabolic and anabolic role. • While the catabolic mode does not affect the levels of the citric acid intermediates, in the anabolic mode, the intermediates become starting material for pathways that lead out of the citric acid cycle.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 42 Replacing Intermediates The citric acid cycle is amphibolic, meaning it serves both a catabolic and anabolic role. • While the catabolic mode does not affect the levels of the citric acid intermediates, in the anabolic mode, the intermediates become starting material for pathways that lead out of the citric acid cycle.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 42 Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 43 Replacing Intermediates To replenish the citric acid cycle intermediate there are alternative pathways leading into the cycle that can increase the concentrations of the the intermediates • These are collective referred to as anaplerotic (“filling up”) pathways.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 43 Replacing Intermediates To replenish the citric acid cycle intermediate there are alternative pathways leading into the cycle that can increase the concentrations of the the intermediates • These are collective referred to as anaplerotic (“filling up”) pathways.
anaplerotic pathways
Chem 352, Lecture 10, Part II - Citric Acid Cycle 43 Replacing Intermediates To replenish the citric acid cycle intermediate there are alternative pathways leading into the cycle that can increase the concentrations of the the intermediates • These are collective referred to as anaplerotic (“filling up”) pathways.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 43 Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 44 Replacing Intermediates Pyruvate Carboxylase Reaction
• We have already seen this reaction in gluconeogenesis.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 44 Replacing Intermediates Pyruvate Carboxylase Reaction
• We have already seen this reaction in gluconeogenesis. • It is allosterically activated by acetyl-CoA - An example of feed-forward activation.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 44 Replacing Intermediates Pyruvate Carboxylase Reaction
• We have already seen this reaction in gluconeogenesis. • It is allosterically activated by acetyl-CoA - An example of feed-forward activation.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 44 Replacing Intermediates Pyruvate Carboxylase Reaction
• We have already seen this reaction in gluconeogenesis. • It is allosterically activated by acetyl-CoA - An example of feed-forward activation.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 44 Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 45 Replacing Intermediates PEP Carboxylase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 45 Replacing Intermediates PEP Carboxylase Reaction
• In plants and bacteria, this reaction is an alternative for producing oxaloacetate from glycolytic intermediates. • It has the advantage of not requiring ATP hydrolysis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 45 Replacing Intermediates PEP Carboxylase Reaction
• In plants and bacteria, this reaction is an alternative for producing oxaloacetate from glycolytic intermediates. • It has the advantage of not requiring ATP hydrolysis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 45 Replacing Intermediates PEP Carboxylase Reaction
• In plants and bacteria, this reaction is an alternative for producing oxaloacetate from glycolytic intermediates. • It has the advantage of not requiring ATP hydrolysis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 45 Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 46 Replacing Intermediates Malic Enzyme (Malate Dehydrogenase)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 46 Replacing Intermediates Malic Enzyme (Malate Dehydrogenase)
• This reaction is also used in the reverse direction to produce reducing equivalents as NADPH/H+ for fatty acid synthesis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 46 Replacing Intermediates Malic Enzyme (Malate Dehydrogenase)
• This reaction is also used in the reverse direction to produce reducing equivalents as NADPH/H+ for fatty acid synthesis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 46 Replacing Intermediates Malic Enzyme (Malate Dehydrogenase)
• This reaction is also used in the reverse direction to produce reducing equivalents as NADPH/H+ for fatty acid synthesis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 46 Replacing Intermediates
Chem 352, Lecture 10, Part II - Citric Acid Cycle 47 Replacing Intermediates Transamination Reactions
• The transamination reactions are used to interchange α-amino acids with α-keto acids.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 47 Replacing Intermediates Transamination Reactions
• The transamination reactions are used to interchange α-amino acids with α-keto acids. • Two of the α-keto acids in the citric acid cycle can be produced by transamination of the amino acids glutamate (α-ketoglutarate) and aspartate (oxaloacetate)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 47 Replacing Intermediates Transamination Reactions
• The transamination reactions are used to interchange α-amino acids with α-keto acids. • Two of the α-keto acids in the citric acid cycle can be produced by transamination of the amino acids glutamate (α-ketoglutarate) and aspartate (oxaloacetate)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 47 Replacing Intermediates Transamination Reactions
• The transamination reactions are used to interchange α-amino acids with α-keto acids. • Two of the α-keto acids in the citric acid cycle can be produced by transamination of the amino acids glutamate (α-ketoglutarate) and aspartate (oxaloacetate)
Chem 352, Lecture 10, Part II - Citric Acid Cycle 47 13.9 The Glyoxylate Cycle: An Anabolic Variant of the Citric Acid Cycle The Glyoxylate Cycle Plants and some bacteria are able to convert fat to carbohydrate. • Humans and other animals, unfortunately, are unable to do this. • This is allows seeds, when they germinate, to quickly mobilize energy that is stored as fat into carbohydrates that then provide both energy and raw materials to sustain the rapidly growing seedling.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 49 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 50 The Glyoxylate Cycle The reasons animals cannot convert fats to carbohydrate include • When fats are degraded they produce glycerol and acetyl-CoA - While the little bit of glycerol produced can be converted carbohydrates by gluconeogenesis, the bulk of the carbon is present as acetyl-CoA cannot.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 50 The Glyoxylate Cycle The reasons animals cannot convert fats to carbohydrate include • When fats are degraded they produce glycerol and acetyl-CoA - While the little bit of glycerol produced can be converted carbohydrates by gluconeogenesis, the bulk of the carbon is present as acetyl-CoA cannot. • This is because - The pyruvate dehydrogenase reaction is irreversible. - The equivalent of the two carbons that enter the citric acid cycle as acetyl-CoA, leave as CO2 before getting to oxaloacetate, which can enter gluconeogenesis.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 50 The Glyoxylate Cycle The reasons animals cannot convert fats to carbohydrate include • When fats are degraded they produce glycerol and acetyl-CoA - While the little bit of glycerol produced can be converted carbohydrates by gluconeogenesis, the bulk of the carbon is present as acetyl-CoA cannot. • This is because - The pyruvate dehydrogenase reaction is irreversible. - The equivalent of the two carbons that enter the citric acid cycle as acetyl-CoA, leave as CO2 before getting to oxaloacetate, which can enter gluconeogenesis.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 50 The Glyoxylate Cycle The reasons animals cannot convert fats to carbohydrate include • When fats are degraded they produce glycerol and acetyl-CoA - While the little bit of glycerol produced can be converted carbohydrates by gluconeogenesis, the bulk of the carbon is present as acetyl-CoA cannot. • This is because - The pyruvate dehydrogenase reaction is irreversible. - The equivalent of the two carbons that enter the citric acid cycle as acetyl-CoA, leave as CO2 before getting to oxaloacetate, which can enter gluconeogenesis.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 50 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 51 The Glyoxylate Cycle The solution that plants have devised is to bypass the the two reactions in the citric acid cycle that release CO2.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 51 The Glyoxylate Cycle The solution that plants have devised is to bypass the the two reactions in the citric acid cycle that release CO2.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 51 The Glyoxylate Cycle The solution that plants have devised is to bypass the the two reactions in the citric acid cycle that release CO2.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 51 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 52 The Glyoxylate Cycle The alternative pathway is called the glycoxylate cycle.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 52 The Glyoxylate Cycle The alternative pathway is called the glycoxylate cycle.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 52 The Glyoxylate Cycle The alternative pathway is called the glycoxylate cycle. • Along with fatty acid degradation, this cycle occurs in a cellular organelle called a glyoxysome.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 52 The Glyoxylate Cycle The alternative pathway is called the glycoxylate cycle. • Along with fatty acid degradation, this cycle occurs in a cellular organelle called a glyoxysome. • In the glyoxysomes, reactions 3 through 5 in the citric acid cycle are replaced with - The isocitrate lyase reaction - The malate synthase reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 52 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 53 The Glyoxylate Cycle The Isocitrate Lyase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 53 The Glyoxylate Cycle The Isocitrate Lyase Reaction
• The reaction is a reversible aldol- cleavage, similar to the aldolase reaction in glycolysis/gluconeogenesis
Chem 352, Lecture 10, Part II - Citric Acid Cycle 53 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 54 The Glyoxylate Cycle The Malate Synthase Reaction
Chem 352, Lecture 10, Part II - Citric Acid Cycle 54 The Glyoxylate Cycle The Malate Synthase Reaction
• This reaction is mechanistically similar to the citrate synthase reaction, which couples a condensation reaction with the hydrolysis of a thioester bond.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 54 The Glyoxylate Cycle The Malate Synthase Reaction
• This reaction is mechanistically similar to the citrate synthase reaction, which couples a condensation reaction with the hydrolysis of a thioester bond.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 54 The Glyoxylate Cycle The Malate Synthase Reaction
• This reaction is mechanistically similar to the citrate synthase reaction, which couples a condensation reaction with the hydrolysis of a thioester bond.
Chem 352, Lecture 10, Part II - Citric Acid Cycle 54 The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 55 The Glyoxylate Cycle The Glyoxylate Cycle
Chem 352, Lecture 10, Part II - Citric Acid Cycle 55