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Pyruvate DehydrogenaseComplex
andTricarboxylic Acid-cycle
May 12, 2014Hagop Atamian
• Glycolysis is the first step of aerobic cellularrespiration.
• The end product of glycolysis is .
• Glycolysis takes place in the of cellswhere all the enzymes are present.
• Pyruvate enters the mitochondrion to be metabolizedfurther.
Recall from Glycolysis
pyruvate
cytosol
Mitochondrial Compartments
• Pyruvate dehydrogenase is a large complex containingmany copies of each of three enzymes:– Pyruvate Dehydrogenase (PDH)– Dihydrolipoyl Transacetylase (DALT)– Dihydrolipoyl Dehydrogenase (DLD)
• Has five cofactors:– TPP– Lipoic acid– FAD– NAD+– CoA-SH
Pyruvate Dehydrogenase Complex
Catalytic
Oxidative Decarboxylation of Pyruvate
CH3 C
O
O
C O- CH3 C
O
S CoA
Pyruvate Acetyl CoA
Pyruvatedehydrogenasecomplex
CO2
CH3 C
O
-‐
Decarboxylation
CH3 C
O
+Oxidation
2e-‐
CoA-SH
NAD+ NADH H++
Oxidative Decarboxylation of Pyruvate
• Pyruvate dehydrogenase is a large complex containingmany copies of each of three enzymes:– Pyruvate Dehydrogenase (PDH)– Dihydrolipoyl Transacetylase (DALT)– Dihydrolipoyl Dehydrogenase (DLD)
• Has five cofactors:– TPP– Lipoic acid– FAD– NAD+– CoA-SH
Pyruvate Dehydrogenase Complex
Catalytic
Pyruvate + + ——> + + +
What is the Net Result of PDHc Reactions?
H+CoA NAD+ CO2 acetyl-CoA NADH
• Acetyl-CoA is an important molecule in metabolism.
• In chemical structure, acetyl-CoA is the thioesterbetween coenzyme A (a thiol) and acetic acid (an acylgroup carrier).
• Several metabolic pathways converge to Acetyl-CoAincluding:1. Fatty acid metabolism2. Amino acid metabolism3.
Acetyl CoA: A Common Meeting Point
CH3 C
O
S CoA
Carbohydrate metabolism
Acetyl CoA: A Common Meeting Point
synthesis of theneurotransmitteracetylcholine
• Also known as citric acid cycle and Krebs cycle.
Tricarboxylic Acid Cycle (TCA-cycle)
Nobel Prize in Medicine (1953), which heshared with Fritz Lipmann.
Hans Adolf Krebs(1900-‐1981)
h$p://en.wikipedia.org/wiki/Hans_Adolf_Krebs
• Harvests chemical energy from biological fuel in theform of electrons in NADH and FADH2.
• Consists of a series of eight reactions.
• Converts acetyl-CoA to two CO2 while conserving thefree energy for ATP production.– The energy is stored as: three NADHs, one
FADH2, and one GTP.
• Intermediates from the TCA-cycle can be used tosynthesize molecules such as amino acids and fattyacids.
TCA-cycle
• The final product of glycolysis is . It is locatedin the .
• In order to enter the TCA-cycle pyruvate has to beoxidized to Acetyl-CoA, releasing C02.
• This is achieved by pyruvate dehydrogenase complex(PDHc), which consists of three enzymes and is locatedin the mitochondrial matrix.
• use inner mitochondrial membrane is impermeable.
Summary
pyruvatecytosol
converted acetyl-CoA
pyruvate dehydrogenase complex (PDHc) three
mitochondrial matrix
• The primary function of the TCA-cycle is oxidation ofacetyl CoA to two CO2.
• The energy from these oxidation reactions iscaptured as:1. NADH2. FADH2
• e.
Summary
acetyl CoA
NADHFADH2
TCA-cycle in Detail
Total of eightreactions
Reaction 1: Condensation Reaction
CH3 C
O
S CoA
Acetyl CoA
C
O
O- C
O
CH2 C
O
O-
Oxaloacetate
+
C
O
O- C
O
CH2 C
O
O-CH2
C
O-
Citrate
CoA-SH
CitrateSynthase
*
*
OH
H2O
1 2 3 4
1
3 4∆G°’ = -‐32.2 kJ/mol
Reaction 2: Rearrangement Reaction
Citrate
Isocitrate
Aconitase
C
O
O- CO
CH2 C
O
O-CH2
C
O-
*
OH
1
3 4
C
O
O- CH
O
CH C
O
O-CH2
C
O-
*
OH1
3 4
∆G°’ = 13.3 kJ/mol
Isocitrate
Reaction 3: First Oxidative decarboxylation
α-ketaglutarate
Isocitratedehydrogenase
CO2
NAD+ NADH
C
O
O- CH
O
CH C
O
O-CH2
C
O-
OH1
3 4
C
O
O- CH2 C C
O
O-CH23 4
O
∆G°’ = -‐20.9 kJ/mol
2
2
H++
The only irreversiblereaction.
Reaction 4: Second Oxidative Decarboxylation
α-ketaglutarate
S CoA Succinyl CoA
α-ketaglutaratedehydrogenase
CO2
NAD+ NADH
C
O
O- CH2 C C
O
O-CH23 4
O
C
O
O- CH2 CCH23
O
∆G°’ = -‐33.5 kJ/mol
2
2
H++Back to fourcarbon molecule
Reaction 5: Oxidation Reaction
Succinyl CoA
Succinate
CoA-SH
GDP GTP
Succinyl CoAsynthetase
S CoAC
O
O- CH2 CCH23
O
C
O
O- CH2 CCH23
O
O-
∆G°’ = -‐2.9 kJ/mol
2
2
• In terms of carbons:
• In terms of energy captured:
Summary
A two carbon acetyl group has been linked tooxaloacetate and two CO2 molecules have beenliberated.
Two NAD+ have been reduced to NADH + H+.One ATP produced.
Leaving us with a molecule of succinate
Reaction 6: Oxidation Reaction
Succinate
Fumarate
SuccinateDehydrogenase(membrane bound)
FAD FADH2
C
O
O- CH2 CCH23
O
O-
C
O
O- CH CCH3
O
O-
∆G°’ = 0 kJ/mol
2
2
Alkane
Alkene
Reaction 7: Hydration Reaction
Fumarate
Fumarase
Malate
H2O
C
O
O- CH CCH3
O
O-
C
O
O- CH CCH3
O
O-
OH H
∆G°’ = -‐3.8 kJ/mol
2
2
Reaction 8: Final Oxidation Reaction Regeneration of Oxaloacetate
Malate
Oxaloacetate
NAD+ NADH
Malatedehydrogenase
C
O
O- CH CCH3
O
O-
OH H
C
O
O- CH CC3
O
O-
HO
∆G°’ = 29.7 kJ/mol
2
2
H++
OxaloacetateC
O
O- CH CC3
O
O-
HO
2
C
O
O- C
O
CH2 C
O
O-
1 2 3 4Oxaloacetate
Regenerated VS Starting Oxaloacetate
Review of the TCA-cycle
h$p://tru-‐wealth.blogspot.com/2013/05/your-‐bodys-‐chemistry-‐pyruvate-‐for.html
Acetyl CoA
OAA CitrateCitrate Synthase
Isocitrate
Aconitase
α-Ketaglutarate
Isocitratedehydrogenase
SuccinylCoA
α-Ketaglutarate dehydrogenase
Succinate
Fumarate
Succinatedehydrogenase
Malate
Fumarase
Malatedehydrogenase
NADH & CO2
NADH & CO2
GTP
FADH2
NADH
Succinyl CoAsyhthetase
TCA-cycle: In Terms of Carbon # of theDifferent Steps
h$p://www.uic.edu/classes/bios/bios100/summer2002/lect10.htm
• We saw how the acetyl-CoA made from glucose, fat,or protein burnt and energy captured as NADH andFADH2.
• Next lecture we will see how this captured energy isused to make ATP via oxidative phosphorylation.
What’s Next
