Citric Acid Cycle

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Citric Acid Cycle
What is it? Series of rxns that oxidize acetyl
CoA to 2CO2 in a manner that conserves the
liberated free energy for ATP production Breakdow
n products of glc, fats and amino acids are all
oxidized via the cycle Intermediates also a
source for many biosynthetic pathways -
amphibolic which means serves in both catabolic
and anabolic processes Also called TCA
cycle - tricarboxylic acid cycle or Krebs
cycle
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Citric Acid Cycle
Cellular respiration
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Citric Acid Cycle
Pyruvate dehydrogenase complex 3 mitochondrial
euk enzymes 5 coenzymes
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Citric Acid Cycle
Pyruvate dehydrogenase complex 5 coenzymes -
Coenzyme A (pantothenate) Reactive thiol is an
acyl carrier
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Citric Acid Cycle
Pyruvate dehydrogenase complex 5 coenzymes - NAD
(niacin) Involved in redox, electron carrier
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Citric Acid Cycle
Pyruvate dehydrogenase complex 5 coenzymes - FAD
(riboflavin, vitamin B2) Involved in redox,
electron carrier
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Citric Acid Cycle
Pyruvate dehydrogenase complex 5 coenzymes - TPP
(thiamine, vitamin B1) Helps in cleavage of bonds
next to carbonyl
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Citric Acid Cycle
Pyruvate dehydrogenase complex 5 coenzymes -
lipoate Reversible oxidation at thiols, serves as
electron carrier and acyl carrier
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Citric Acid Cycle
Pyruvate dehydrogenase complex
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Citric Acid Cycle
Pyruvate dehydrogenase complex -
regulation Eukaryotic complex regulated by
phosphorylation
Regulation Pyruvate substrate for complex ADP
indicates low energy charge NADH, acetyl CoA
endproducts of complex Ca2 certain hormones
(insulin) raise Ca2
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Citric Acid Cycle
Every turn of cycle 1. Joining an acetyl group
to oxaloacetate 2. Oxidizing 2 carbons off as
CO2, leaving succinate 3. Converting succinate
back to oxaloacetate 4. Producing 1 GTP and
reduced cofactors
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Citric Acid Cycle
Net reaction AcetylCoA 3NAD FAD GDP Pi
2H2O ? 2CO2 CoA 3NADH FADH2 GTP 2H
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Citric Acid Cycle
Goal capture energy from acetate ? 2CO2 1. One
GTP made equivalent to 1 ATP 2. Lots of reduced
cofactors, reducing power can be converted to ATP
-?G irreversible
-?G irreversible
?G made favorable by fast product removal
?-ketoglutarate dehydrogenase complex -?G
irreversible
Only enzyme bound to inner mitochondrial membrane
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Citric Acid Cycle
Regulation Rate of cycle is determined by 1.
Availability of substrates (acetyl CoA, NAD,
FAD) 2. Inhibition by accumulating products 3.
Allosteric feedback inhibition of enzymes
NAD and FAD are regenerated by oxidative
phosphorylation, which needs O2
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Citric Acid Cycle
Regulation Three nonequilibrium rxns 1. Citrate
synthase 2. Isocitrate dehydrogenase 3.
?-ketoglutarate dehydrogenase
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Citric Acid Cycle
Why so complicated? Hub of intermediary
metabolism Greatest selective advantage
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Citric Acid Cycle
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Citric Acid Cycle
Reaction 1 - Citrate synthase Condensation of
acetylCoA with oxaloacetate to form
citrate Irreversible
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Citric Acid Cycle
Reaction 2 - Aconitase Removal of H2O,
stereospecifically add back H2O Reversible,
pulled to right because isocitrate rapidly
consumed
Prochiral carbon allows for stereospecific rxn
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Citric Acid Cycle
Reaction 3 - isocitrate dehydrogenase Oxidative
decarboxylation of isocitrate Irreversible
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Citric Acid Cycle
Reaction 4 - ?-ketoglutarate dehydrogenase
complex Oxidative decarboxylation of
?-ketoglutarate Identical to pyruvate
dehydrogenase reaction Three homologous enzymes
(E1, E2, E3) Five coenzymes (TPP, lipoate, FAD,
NAD, CoA) Irreversible
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Citric Acid Cycle
Reaction 5 - Succinyl-CoA synthetase Hydrolysis
of thioester bond energizes formation of
GTP Synthetase indicates participation of
nucleoside triphosphate Reversible
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Citric Acid Cycle
Reaction 6 - Succinate dehydrogenase Oxidation of
succinate to fumarate Enzyme bound to inner mito
membrane, only membrane-bound enz Reversible
Malonate (analog of succinate) is a competitive
inhibitor of enz, blocks activity of cycle
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Citric Acid Cycle
Reaction 7 - Fumarase Hydration of fumarate to
L-malate Reversible
Substrate
Product
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Citric Acid Cycle
Reaction 8 - Malate dehydrogenase Oxidation of
malate to oxaloacetate NAD linked to enzyme High
?G, pulled to products by continual removal of
oxaloacetate