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Citric Acid Cycle
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Gylcolysis
TCA Cycle
Electron Transport andOxidative phosphorylation
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The TCA Cycle(aka Citric Acid Cycle, Krebs Cycle)
Pyruvate (actually acetate) from
glycolysis is degraded to CO2 Some ATP is produced
More NADH is made
NADH goes on to make more ATP inelectron transport and oxidativephosphorylation
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Entry into the TCA Cycle Pyruvate is translocated from the cytosol to the
mitochondria
Pyruvate is oxidatively decarboxylated to formacetyl-CoA
Pyruvate dehydrogenase uses TPP, CoASH, lipoicacid, FAD and NAD+
Acetyl-CoA then enters TCA cycle thru citratesynthase
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Pyruvate Dehydrogenase
ComplexComposed of three enzymes:
pyruvate dehydrogenase (E1) (cofactor =
TPP) Dihydrolipoamide acetyltransferase (E2)
(cofactor = Lipoamide, CoA)
Dihydrolipoamide dehydrogenase (E3)(cofactor = FAD, NAD+)
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Pyruvate Dehydrogenase
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Citrate Synthase Only step in TCA cycle that involves the
formation of a C-C bond
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Aconitase Isomerization of Citrate to Isocitrate
Citrate is a poor substrate for oxidation
So aconitase isomerizes citrate to yieldisocitrate which has a secondary-OH, whichcan be oxidized
Aconitase uses an iron-sulfur cluster to positioncitrate (binds OH and carboxyl of centralcarbon)
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Isocitrate Dehydrogenase Oxidative decarboxylation of isocitrate to yield
-ketoglutarate Classic NAD+ chemistry (hydride removal)
followed by a decarboxylation
Isocitrate dehydrogenase is a link to the
electron transport pathway because it makesNADH
Rxn is metabolically irreversible
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-Ketoglutarate Dehydrogenase A second oxidative decarboxylation
This enzyme is nearly identical to pyruvatedehydrogenase - structurally andmechanistically
Five coenzymes used - TPP, CoASH, Lipoic acid,NAD+, FAD
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Succinyl-CoA Synthetase
A substrate-level phosphorylation
A nucleoside triphosphate is made (ATPin plants/bacteria and GTP in animals)
Its synthesis is driven by hydrolysis of aCoA ester
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Succinate Dehydrogenase
An oxidation involving FAD Mechanism involves hydride removal by FAD and
a deprotonation
This enzyme is actually part of the electron
transport pathway in the inner mitochondrialmembrane
The electrons transferred from succinate toFAD (to form FADH2) are passed directly to
ubiquinone (UQ) in the electron transportpathway
Enzyme inhibited by malonate
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Fumarase
Hydration across the double bond
trans-addition of the elements of
water across the double bond Stereospecific reaction
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Malate Dehydrogenase An NAD+-dependent oxidation The carbon that gets oxidized is the one
that received the -OH in the previousreaction
This reaction is energetically expensive
Go' = +30 kJ/mol
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Reduced Coenzymes Fuel ATP
Production Acetyl-CoA + 3 NAD+ + Q + GDP + Pi +2 H20
HS-CoA + 3NADH + QH2 + GTP + 2 CO2 + 2 H+
Isocitrate Dehydrogenase 1 NADH=2.5 ATP -ketoglutarate dehydrogenase 1 NADH=2.5 ATP Succinyl-CoA synthetase 1 GTP=1 ATP Sunccinate dehydrogenase 1 QH2=1.5 ATP
Malate Dehydrogenase 1 NADH=2.5 ATP
Total of 10 ATPs gained from oxidation of 1 Acetyl-CoA
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Regulationof TCACycle
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TCA Cycle providesintermediates formany biosyntheticprocesses
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The Anaplerotic ReactionsThe "filling up" reactions
PEP carboxylase - converts PEP to oxaloacetate
Pyruvate carboxylase - converts pyruvate tooxaloacetate
Malic enzyme converts pyruvate into malate