The Citric Acid Cycle

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Biochemistry & Molecular Bio.
David Gross

Chapter 14: The CitricAcid Cycle • CAC converts 2 C groups (acetyl-CoA) into CO2 & is final stage in oxidation of metabolic fuels • rxns take place in cytosol of prokaryotes & mitochondria of eukaryotes • the starting material can be C’s fromA.A.’s, fatty acids & carbohydrates, pyruvate is used to make it simple 14.1 The Pyruvate dehydrogenase reaction • first CO2 released when pyruvate decarboxylated to acetyl unit • 2 & 3 produced in CAC • the pyruvate dehydrogenase complex (PDC) contains multiple copies of 3 diff. enzymes o this drives the decarboxylation of pyruvate o all located within the mitochondrion in eukaryotes & must be transported in from cytosol o 3 subunits called E1, E2, & E3 o overall rxn: +¿=acetyl−CoA+CO2+NADH ¿  pyruvate+CoA+NA D o size of complex can vary btwn organisms w/ different regulatory proteins to modify activity • Pyruvate dehydrogenase converts pyruvate to acetyl-CoA o step 1: catalyzed by E1, pyruvate is decarboxylated  requires cofactor thiamine pyrophosphate (TPP) to attack  CO2 leaves leaving hydroxyethyl-TPP  o step 2: hydroxyethyl group transferred to E2 of PDC  acceptor is lipoamide prosthetic group  regenerates TPP cofactor, E1 oxidizes hydroxyethyl group to acetyl  o step 3: acetyl group transfers to coenzyme Aproducing acetyl-CoA  this is a thioester (energy currency) o step 4: E3 reoxidizes lipoamide of E2 by transferring e- to Cys-Cys disulfide group within enzyme o step 5: NAD+ reoxidizes reduced Cys sulfhydryl groups  facilitated by FAD prosthetic group • multienzyme complex can carry out multistep rxn efficiently b/c products can quickly become substrate for next rxn w/o diffusing away or reacting w/ other substances • flux through the PDC regulated by product inhibition by both NADH & acetyl-CoA • also regulated by hormones through phosphorylation & dephosphorylation 14.2 The 8 rxns of the CAC • the further oxidation of acetyl-CoAis highly exergonic • energy stored as GTP & reduced cofactors • for each acetyl group that enters the CAC 2 molecules of CO2 are produced representing a 4 e- pair loss • net equation of CAC: o acetyl−CoA+GDP+P+3NAD++Q→2CO2+CoA+GTP+3NADH+QH2 • There are 8 steps to the CAC: 1. citrate synthase adds an acetyl group to oxaloacetate  citrate synthase is a dimer that undergoes large conformational change w/ binding  can synthesize C-C bond w/o metal ion cofactor ∆G =−31.5  highly exergonic rxn 2. Aconitase isomerizes citrate to isocitrate  one carboxymethyl arm of citrate undergoes dehydration and rehydration 3. Isocitrate dehydrogenase releases first CO2  oxidative decarboxylation of isocitrate to alpha-ketoglutarate  substrate first oxidized by NAD+  carboxylate group 2 C away from ketone eliminated as CO2  Mn2+ in active site stabilizes neg charg
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