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TCA Cycle

TCA Presentation
by

Sean Buck

on 12 December 2012

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Transcript of TCA Cycle

Wade Banta and Sean Buck The Citric Acid Cycle Citrate is isomerized into isocitrate Hydroxyl group is not properly located for the oxidative decarboxylation that follows
Isomerized with Aconitase
Accomplished with a dehydration step followed by a hydration step Succinyl CoA is formed by the oxidative decarboylation of α-Ketoglutarate Catalyzed by the α-Ketoglutarate dehydrogenase complex
Organized assembly of three kinds of enzymes
Homologous to pyruvate dehydrogenase complex The Citric Acid Cycle Overview: The Citric Acid Cycle Step 1: Citrate Synthesis Also called the tribcarboxylic acid (TCA) cycle or Krebs cycle
Final common pathway for the oxidation of fuel molecules
Most fuel molecules enter the cycle as acetyl coenzyme A
Takes place in the mitochondria
Harvests high energy electrons
Doesn't generate a large amount of ATP nor uses oxygen as a reactant
Provides the "vast preponderance" of energy in aerobic cells (in conjunction with oxidative phosphorylation)
First stage in cellular respiration Pyruvate + CoA + NAD+ acetyl CoA +CO2+ NADH + H+ Pyvruvate Dehydrogenase Links Glycolysis to the Citric Acid Cycle The Setting Acetyl CoA + oxaloacetate + water citrate + CoA + H+ Enzyme: citrate synthase
Condensation reaction (aldol condensation)
Hydrolysis of the thioester powers the synthesis of citrate On the Hot Seat with... Aconitase An iron-sulfur protein (aka nonheme-iron protein)
The four iron atoms are complexed to four inorganic sulfurs and three cysteine sulfur atoms
Leaving one iron atom available to bind citrate through one of its COO- groups
Fe-S cluster participates in dehydrating and rehydrating the bound substrate Isocitrate is oxidized and Decarboxylated to α-Ketoglutarate First of four redox reactions in the TCA cycle Catalyzed by ioscitrate dehydrogenase
Creates oxalosuccinate, an unstable β-ketoacid
Rate of this step is important in determining the overall rate of the cycle
First generation of of high-transfer-potential electron carrier, NADH A compound with high phosphoryl-transfer potential is generated from Succinyl CoA Succinyl CoA is a energy-rich thioester compound
Cleavage of thrioester bond of succinyl CoA is coupled to the phosphorylation of a purine nucleoside diphosphate
Usually GDP
Synthesized by succinyl CoA synthase (succinate thiokinase)
Only step that directly yields a compound with HPTP Mechanism: Succinyl CoA Synthase transforms types of biochemical energy On the hot seat with...Succinyl CoA Synthase An α(2)β(2) heterodimer
The functional unit is one αβ pair
Each subunit has two domains
Used to capture energy associated with succinyl CoA cleavage A Short Film on the Citric Acid Cycle Pyruvate Dehydrogenase Complex is regulated Allosterically by Reversible Phosphorylation The Citric Acid Cycle is Controlled at Several Points (post pyruvate dehydrogenase) The TCA Cycle is a Source of Biosynthetic Precursors Summary Glyoxylate Cycle Mechanism: The synthesis of Acetyl CoA from Pyruvate Flexible linkages allow lipoamide to move between different active sites Reactions of the pyruvate dehydrogenase complex Coenzymes thiamine pyrophosphate (PTP), lipolic acid, and FAD serve as catalytic cofactors
NAD+ and CoA serve as stoichiometric cofactors
Three steps:
Decarboxylation
Oxidation
Transfer of resultant acetyl group to CoA Decarboxylation Pyruvate combines with TTP and is then decarboylated Formation of Acetyl CoA Catalyzed by dihydropolipoyl transacetrylase (E2) Oxidation Hydroxyethyl group attached to TTP is oxidized to form an acetyl group Catalyzed by the pyruvate dehydrogenase complex (E1) of the multienzyme complex Transfer results in an energy-rich thioester bond In a fourth step the oxidized form of lipoamide is regenerated by dilipoyl dehydrogenase (E3). Two electrons are transferred to an FAD prosthetic group and then to NAD+. Core is formed by the transacetylase component E2
Consists of 8 catalytic trimers that form a hollow cube
1. Pyruvate is decarboxylated at the active site of E1
2. E2 inserts the lipoamide arm of the lipoamide domain into the deep channel in E1 leading to the active site
3. E1 catalyzes the transfer of the acetyl group
4. The acetyl moiety is transferred to CoA
5. Lipoamide is oxidized by coenzyme FAD at E3 active site
6. Final product, NADH, is produced with the reoxidation of FAD2 to FAD Structural integration of three kinds of enzymes and the long flexible lipoamide arm makes the coordinated catalysis possible Oxaloacetate is regenerated by the oxidation of succinate 3 reactions catalyze the conversion of succinate to oxaloacetate.
Succinate dehydrogenase catalyzes double bond formation between C2 and C3.
FAD accepts hydrogen (not protons)
Electrons go directly into CoQ from succinate dehydrogenase and participate in the electron transport chain.
Succinate fumarase is embedded in inner mitochondrial membrane. Succinate is oxidized to fumarate Fumarate is hydrated to malate Fumarase catalyzes stereospecific addition of H+ and OH-.
Only L-Malate is made. Malate is oxidized to oxaloacetate Malate dehydrogenase catalyzes the abstraction of the hydroxyl proton of L-malate by NAD+
ΔG°'=+29.7kJ/mol
Driven by reaction of NADH and oxaloacetate Formation of acetyl CoA from pyruvate is an irreversible step, so all acetyl CoA forms either CO2 or is used in lipid biosynthesis.
Pyruvate dehydrogenase complex is regulated by negative feedback mechanisms.
Acetyl CoA competetively inhibits transacetylase.
NADH inhibits dihydrolipoyl dehydrogenase.
High energy environment inhibits irreversible oxidation of glycolysis products.
Pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphorylase (PDP) inactivate and activate pyruvate dehydrogenase complex.
ATP, Acetyl CoA and NADH inactivate pyruvate dehydrogenase.
ADP, pyruvate, and Ca2+ (muscle contraction) activate dehydrogenase. 1) Isocitrate dehydrogenase is allosterically activated by ADP and inhibited by ATP. NADH is a competetive inhibitor that displaces NAD+.
Citrate builds up and enters cytoplasm, inhibiting phosphofructokinase.
Used in FA synthesis.
2) α-ketoglutarate dehydrogenase has negative feedback regulation from its products, succinyl CoA and NADH. It is also regulated by ATP.
α-ketoglutarate that builds up is used in amino acid and purine base synthesis. Citrate: Fatty Acids, Sterols
α-ketoglutarate: Glutamate, other AA's, Purines
Succinyl CoA: Porphyrins (heme, chlorophyll)
Oxaloacetate: Glucose, Aspartate, other AA's, nucleotide bases Glyoxylate cycle converts Acetyl CoA into Glucose. 2 acetyl CoA+NAD++H2O---> Succinate+2 CoASH+NADH+2H+ In plants, this reaction occurs in organelles called glyoxosomes.
Succinate is converted into carbohydrates by TCA and gluconeogenesis.
Oil rich seeds use this reaction to provide carbohydrate energy to seedlings. The citric acid cycle produces high-transfer-potential electrons, ATP, and CO2 1) Two carbons enter the cycle as an acetyl unit, and two leave as two molecules of CO2.
2) Four hydrogens atoms leave in oxidation reactions.
3) Three NAD+ molecules are reduced in oxidative decarboxylations of isocitrate, pyruvate, and α-ketoglutarate, one is reduced in malate oxidation. (4 counting pyruvate oxidation).
4) One FAD is reduced in succinate oxidation.
5) One ATP is formed.
6) Two H2O consumed. Control over enzymatic activity in TCA cycle is highly regulated according to the energy state of the cell.
ATP, NADH, Acetyl CoA inactivate, while ADP and Pyruvate activate.
TCA cycle intermediates are used in diverse biosynthetic reactions.
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