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Citric Acid Cycle
Gylcolysis
Electron Transport and
Oxidative phosphorylation
TCA Cycle
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 in
electron transport and oxidative
phosphorylation
Entry into the TCA Cycle
• Pyruvate is translocated from the cytosol to the
mitochondria
• Pyruvate is oxidatively decarboxylated to form
acetyl-CoA
• Pyruvate dehydrogenase uses TPP, CoASH, lipoic
acid, FAD and NAD+
• Acetyl-CoA then enters TCA cycle thru citrate
synthase
Pyruvate Dehydrogenase
Complex
Composed of three enzymes:
• pyruvate dehydrogenase (E1) (cofactor =
TPP)
• Dihydrolipoamide acetyltransferase (E2)
(cofactor = Lipoamide, CoA)
• Dihydrolipoamide dehydrogenase (E3)
(cofactor = FAD, NAD+)
Pyruvate Dehydrogenase
Citrate Synthase
• Only step in TCA cycle that involves the
formation of a C-C bond
Aconitase
• Isomerization of Citrate to Isocitrate
• Citrate is a poor substrate for oxidation
• So aconitase isomerizes citrate to yield
isocitrate which has a secondary -OH, which
can be oxidized
• Aconitase uses an iron-sulfur cluster to position
citrate (binds –OH and carboxyl of central
carbon)
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 makes
NADH
• Rxn is metabolically irreversible
 -Ketoglutarate Dehydrogenase
• A second oxidative decarboxylation
• This enzyme is nearly identical to pyruvate
dehydrogenase - structurally and
mechanistically
• Five coenzymes used - TPP, CoASH, Lipoic acid,
NAD+, FAD
Succinyl-CoA Synthetase
• A substrate-level phosphorylation
• A nucleoside triphosphate is made (ATP
in plants/bacteria and GTP in animals)
• Its synthesis is driven by hydrolysis of a
CoA ester
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 mitochondrial
membrane
• The electrons transferred from succinate to
FAD (to form FADH2) are passed directly to
ubiquinone (UQ) in the electron transport
pathway
• Enzyme inhibited by malonate
Fumarase
• Hydration across the double bond
• trans-addition of the elements of
water across the double bond
• Stereospecific reaction
Malate Dehydrogenase
• An NAD+-dependent oxidation
• The carbon that gets oxidized is the one
that received the -OH in the previous
reaction
• This reaction is energetically expensive
• Go' = +30 kJ/mol
Reduced Coenzymes Fuel ATP
Production
• Acetyl-CoA + 3 NAD+ + Q + GDP + Pi +2 H20 
HS-CoA + 3NADH + QH2 + GTP + 2 CO2 + 2 H+
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Isocitrate Dehydrogenase
-ketoglutarate dehydrogenase
Succinyl-CoA synthetase
Sunccinate dehydrogenase
Malate Dehydrogenase
1 NADH=2.5 ATP
1 NADH=2.5 ATP
1 GTP=1 ATP
1 QH2=1.5 ATP
1 NADH=2.5 ATP
• Total of 10 ATPs gained from oxidation of 1 AcetylCoA
Regulation
of TCA
Cycle
TCA Cycle provides
intermediates for
many biosynthetic
processes
The Anaplerotic Reactions
The "filling up" reactions
• PEP carboxylase - converts PEP to oxaloacetate
• Pyruvate carboxylase - converts pyruvate to
oxaloacetate
• Malic enzyme converts pyruvate into malate