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Ch 16. Citric Acid Cycle. Pyruvate is converted to acetyl-CoA and CO 2 by pyruvate dehydrogenase complex (E1,E2, E3) One NADH is generated, (NADH => 3 ATP in ox-phos) Acetyl-CoA + oxaloacetate –> citrate In 7 reactions 2 carbons are converted to CO 2 and oxaloacetate is regenerated

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ch 16 citric acid cycle
Ch 16. Citric Acid Cycle
  • Pyruvate is converted to acetyl-CoA and CO2 by pyruvate dehydrogenase complex (E1,E2, E3)

One NADH is generated, (NADH => 3 ATP in ox-phos)

  • Acetyl-CoA + oxaloacetate –> citrate
  • In 7 reactions 2 carbons are converted to CO2 and oxaloacetate is regenerated

Products: 3 NADH (x 3) + FADH2 (x 2) + GTP = 12 ATP

  • Intermediates are substrates for biosynthesis
  • Reactions take place in mitochondria
generation of acetyl coa
Generation of Acetyl-CoA
  • Coenzyme A receives 2 carbons from pyruvate
  • Thioester linkage
    • ∆G°’=-31kJ mol-1
  • Multi-enzyme process
    • Pyruvate + CoA + NAD+ –> acetyl CoA + CO2 + NADH
pyruvate dehydrogenase multienzyme complex
Pyruvate dehydrogenase multienzyme complex
  • Pyruvate dehydrogenase - E1
    • Pyruvate + TPP –> Hydroxyethyl TPP + CO2
  • Dihydrolipoyl transacetyase - E2
    • HOEt-TPP + lipoamide–> Acetyl-dihydrolipoamide + TPP
    • Acetyl-dihydrolipoamide + CoA-SH –> acetyl CoA + dihydrolipoamide
  • Dihydrolipoyl dehydrogenase - E3
    • NAD+ + dihydrolipoamide –> NADH + H+ + lipoamide
pyruvate dehydrogenase
Pyruvate dehydrogenase
  • Thiamine Pyrophosphate (TPP)
  • Attacks carbonyl, releases CO2
  • Hydroxyethyl TPP remains bound
lipoamide flexible redox arm
Lipoamide flexible redox arm
  • Covalent E2 cofactor
  • S-S can be reduced to SH, SH
  • Lipoamide is a target for arsenic toxicity
dihydrolipoyl transacetyase
Dihydrolipoyl transacetyase
  • Lipolysyl side chain extends to E1
  • Transfers hydroxyethyl from TPP to Dihydrolipoamide
  • Transfers Acetyl group to CoA
dihydrolipoyl dehydrogenase
Dihydrolipoyl dehydrogenase
  • Exchange of enzyme disulfide for lipoamide
    • E3 S-S + dihydrolipoamide –> E3–SH, SH + lipoamide
  • Bound FAD cofactor oxidizes E3 to disulfide
    • E3– SH, SH + FAD –> E3 S-S +
  • NAD+ oxidizes FADH2 to regenerate FAD
    • E3FADH2 + NAD+ –> E3FAD + NADH+ + H+
control of pyruvate dehydrogenase
Control of pyruvate dehydrogenase
  • Product Inhibition by NADH and acetyl-CoA
    • Competitive inhibition of substrate binding
    • E2 and E3 are reversible
  • Phosphorylation inactivates mammalian E1
    • Pyruvate dehydrogenase kinase
      • Stimulated by NADH and acetyl-CoA
    • Pyruvate dehydrogenase phosphatase - activates E1
      • Activated by Ca2+ as part of Insulin response
      • Provides Acetyl CoA for fatty acid synthesis
citric acid cycle intermediates

Acetyl-CoA

Citric Acid Cycle intermediates

Pyruvate

Oxaloacetate

Citrate

Malate

Isocitrate

Fumarate

a-ketoglutarate

Succinate

Succinyl-CoA

citric acid cycle enzymes i
Citric Acid Cycle Enzymes - I

1. Citrate synthase

Oxaloacetate + Acetyl-CoA + H2O –>

Citrate + CoASH

2. Aconitase

Citrate –> Cis Aconitate –> Isocitrate

3. Isocitrate dehydrogenase

Isocitrate + NAD+ <–>

 ketoglutarate + CO2 + NADH + H+

4. -Ketoglutarate Dehydrogenase

 ketoglutarate + CoA-SH + NAD+ <–> Succinyl-CoA + CO2 + NADH + H+

citric acid cycle enzymes ii
Citric Acid Cycle Enzymes - II

5. Succinyl-CoA Synthetase

Succinyl-CoA + GDP + Pi –> Succinate + GTP + CoA-SH

6. Succinate succinate Dehydrogenase

Succinate + FAD –> FADH2 + Fumarate

7. Fumarase

Fumarate + H2O –> Malate

8. Malate Dehydrogenase

Malate + NAD –> Oxaloacetate + NADH + H+

citrate synthase

COO-

CH2

HO-C–COO-

CH2

COO-

Citrate synthase

CoA

S

C=O

H3C

H2O

COO-

C=O

CH2

COO-

  • Oxaloacetate binds - cleft closure
  • Acetyl-CoA binds to closed form only
  • Acid base catalysis forms Enolate of Acetyl-CoA
  • Nucleophilic attack on OAA C=O forms Citryl CoA
  • Citrate and CoA-SH are released

CoASH

aconitase

COO-

CH2

HO-C–COO-

CH2

COO-

COO-

CH2

C–COO-

HO-CH

COO-

Aconitase

COO-

CH2

C–COO-

CH2

COO-

H2O

  • Transfers C3-OH of citrate to C2-OH of isocitrate
  • Cis Aconitate (C2-C3 double bond) intermediate
  • Iron sulfur cluster [4Fe - 4S]
  • Fluoroacetate is converted to Fluorocitrate inhibits aconitase

H2O

isocitrate dehydrogenase

COO-

CH2

C–COO-

HO-CH

COO-

COO-

CH2

C–COO-

C=O

COO-

COO-

CH2

CH2

C=O

COO-

Isocitrate dehydrogenase
  • Isocitrate + NAD+ <–>  ketoglutarate + CO2 + NADH + H+
  • Initial oxidation of isocitrate to oxalosuccinate intermediate?
  • Decarboxylation to Give CO2 and  ketoglutarate

CO2

ketoglutarate dehydrogenase

COO-

CH2

CH2

C=O

COO-

COO-

CH2

CH2

C=O

S–CoA

-Ketoglutarate Dehydrogenase

CO2

NADH

H+

CoASH

NAD

  • Similar to Pyruvate Dehydrogenase
    • Product is Succinyl CoA instead of Acetyl CoA
  • Multienzyme complex
    • E1- dehydrogenase, E2- dihydrolipoyl transsuccinylase, E3 identical to PD-E3
succinyl coa synthetase

COO-

CH2

CH2

C=O

S–CoA

Succinyl-CoA Synthetase

COO-

CH2

CH2

COO-

GTP

CoASH

GDP

Pi

  • Products Succinate, GTP and CoASH
    • ATP instead of GTP in plants and bacteria
  • Thioester free energy almost entirely conserved in phospho anhydride
  • Phosphoryl enzyme intermediate
succinate dehydrogenase
Succinate Dehydrogenase

H COO-

C

C

-OOC H

COO-

CH2

CH2

COO-

  • Electrons accepted by covalently bound FAD
  • Embedded in mitochondrial membrane
    • FADH2 reoxidized by electron transport chain

E-FADH2

E-FAD

fumarase
Fumarase

H COO-

C

C

-OOC H

COO-

HO–CH

CH2

COO-

  • H2O added across fumarate double bond to give Malate

H2O

malate dehydrogenase
Malate Dehydrogenase

COO-

HO–CH

CH2

COO-

COO-

C=O

CH2

COO-

  • Hydride transfer from malate to NAD regenerates oxaloacetate for another cycle
  • Reaction pulled by citrate synthase consumption of OAA

NADH

H+

NAD+

citric acid cycle regulation
Citric Acid Cycle Regulation
  • Rate limiting steps (negative DG°’)
    • Citrate Synthase
      • Inhibited by citrate, NADH and Succinyl CoA
    • Isocitrate Dehydrogenase
      • Inhibited by ATP, NADH
      • Activated by Ca2+ and ADP
    • a-Ketoglutarate Dehydrogenase
      • Inhibited by NADH and Succinyl CoA
      • Activated by Ca2+
anabolic uses of cycle intermediates
Anabolic uses of cycle intermediates
  • Gluconeogenesis (Ch 14)
    • Malate –> OAA –> –> Glucose
  • Lipid Biosynthesis (Ch 21)
    • Citrate –> OAA + Acetyl CoA –> –> lipids
  • Amino Acid Biosynthesis (Ch 22)
    • OAA and a-ketoglutarate
  • Porphyrin Biosynthesis (Ch 22)
    • Succinyl CoA
catabolic sources of cycle intermediates
Catabolic sources of cycle intermediates
  • Fatty acid oxidation
    • Succinyl CoA
  • Amino Acid degradation
    • Succinyl CoA
  • Transamination of Amino Acid s
    • OAA and a-ketoglutarate
the glyoxylate pathway
The Glyoxylate Pathway
  • Converts acetyl-CoA to Glucose in plant glyoxosomes
  • Isocitrate Lyase bypasses decarboxylations in CAC
    • Isocitrate –> succinate + glyoxylate
  • Malate Synthase
    • Glyoxylate + Acetyl CoA –> Malate