Transcript Citric Acid Cycle

Citric Acid Cycle
General Considerations
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What is the importance of citric acid cycle?
final common pathway for oxidation of fuel
molecules
 provides intermediates for biosynthesis
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amino acids
nucleotide bases
porphyrin
General Considerations
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Where in the cell does this cycle occur?
General Considerations
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What basically occurs during this cycle?
Formation of Acetyl
Coenzyme A
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Importance?
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links glycolysis to citric acid cycle
What’s involved?
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oxidative decarboxylation catalyzed by
pyruvate dehydogenase complex
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three enzymes
five cofactors
Formation of Acetyl
Coenzyme A
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Reaction consists of three steps
Formation of Acetyl
Coenzyme A
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Pyruvate dehydrogenase catalyzes the first step
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uses thiamine pyrophosphate (TPP) as coenzyme
Formation of Acetyl
Coenzyme A
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Step 1 - Pyruvate combines with TPP and is
decarboxylated
Formation of Acetyl
Coenzyme A
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Next step also
catalyzed by pyruvate
decarboxylase and
involves lipoamide
Formation of Acetyl
Coenzyme A
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Step 2 – hydroxyethyl group is oxidized and acetyl
group is transferred to lipoic acid
Formation of Acetyl
Coenzyme A
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Step 3 – acetyl group is transferred to coenzyme A
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reaction catalyzed by dihydrolipoyl transacetylase
Formation of Acetyl
Coenzyme A
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Step 4 – lipoamide is regenerated and electrons are
transferred to FAD and NAD+
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catalyzed by dihyrolipoyl dehdrogenase
Formation of Acetyl
Coenzyme A
Formation of Acetyl
Coenzyme A
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Model of pyruvate dehydrogenase complex
Formation of Acetyl
Coenzyme A
Synthesis of Citrate
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How is citrate formed?
What kind of reaction is this?
Synthesis of Citrate
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How does citrate synthase catalyze this
reaction?
binding of oxaloacetate causes structural
rearrangement
 binding site for acetyl CoA forms
 catalysis via proximity of substrates
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Synthesis of Citrate
Synthesis of Citrate
Formation of Isocitrate
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Isomerization of citrate occurs by a dehydration
followed by a hydration
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catalyzed by aconitase
Formation of Isocitrate
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Aconitase is an iron-sulfur protein
Formation of -Ketoglutarate
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Isocitrate is oxidized and decarboxylated to ketoglutarate
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isocitrate dehydrogenase
Formation of Succinyl CoA
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Oxidative decarboxylation of -ketoglutarate uses
same mechanism as conversion of pyruvate to
acetyl CoA
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-ketoglutarate dehdrogenase complex
Formation of Succinate
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Cleavage of thioester bond coupled to formation of GTP
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substrate level phosphorylation
succinyl CoA synthetase
Regeneration of Oxaloacetate
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oxidation of succinate – succinate dehydrogenase
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iron-sulfur protein
hydration of fumarate – fumarase
oxidation of malate – malate dehydrogenase
Summary of Citric Acid Cycle
Regulation of Pyruvate
Dehdrogenase Complex
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end-product inhibition
covalent modification
energy charge
hormones & 1adrenergic agonists via Ca++
Control of Citric Acid Cycle
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allostric enzymes are
at primary control
points
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-ketoglutarate
dehydrogenase
isocitrate
dehydrogenase
pyruvate
dehydrogenase
Intermediates for Biosynthesis
Citric Acid Cycle
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How is oxaloacetate replenished to keep
CAC going?
carboxylation of pyruvate
 energy charge influences use of OAA
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high – converted to glucose
low – converted to citrate
Clinical Applications
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What is beriberi and what causes it?
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nutritional deficiency of thiamine leading to
neurological and cardiovascular problems?
What specifically causes the problems?
 Why does arsenic or mercury poisoning
cause similar symptoms?
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binds lipoamide
Glyoxylate Cycle
What is this cycle
and who uses it?
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metabolic cycle for
utilization of acetate
plants and bacteria