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BI/CH 422/
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OUTLINE:
Glycogenolysis Glycolysis Other sugars Pasteur: Anaerobic vs Aerobic Fermentations
Pyruvate
pyruvate dehydrogenase
Krebs’ Cycle
How did he figure it out? Overview 8 Steps Citrate Synthase Aconitase Isocitrate dehydrogenase Ketoglutarate dehydrogenase Succinyl-CoA synthetase Succinate dehydrogenase Fumarase Malate dehydrogenase Energetics Regulation Summary
Exam-1 material Exam-2 material
The Citric Acid Cycle:
Succinyl-CoA Synthetase
- This step was not appreciated in original cycle until discover of CoA and its role (Fritz Lipmann). Named for the reverse reaction.
- Substrate-level phosphorylation (like GAPDH + 1,3-BPG kinase)
- The energy of thioester allows for incorporation of inorganic phosphate.
- Goes through a phospho-enzyme intermediate
- Produces GTP, which can be converted to ATP
- Slightly thermodynamically favorable/reversible (D G^ ° ’^ = –0.7 kcal/mol).
- product concentration kept low to pull forward (^) (OMSGAP)
Phosphoryl transfer to His; downhill energetically
Phosphorolysis: Thioester to mixed anhydride; uphill energetically
Phospho-His transfer to NDP; slightly downhill energetically
Mechanism
The Citric Acid Cycle:
Succinyl-CoA Synthetase
Phosphoryl transfer to His; downhill energetically
Phospho-His transfer to NDP; slightly downhill energetically
Mechanism
The Citric Acid Cycle:
Succinyl-CoA Synthetase
Phosphorolysis: Thioester to mixed anhydride; uphill energetically
The Citric Acid Cycle: Succinate Dehydrogenase
- Have not seen this cofactor chemistry yet: use in the alkane à alkene oxidation.
- But we have seen these next 3 steps. If it worked once it will work again: Aconitase and ICDH
- Famous competitive inhibitor: malonate (O M SGAP)
- Reduction requires FADH 2 (generally true for alkane to alkene oxidation)
- Reduction potential of carbon-hydrogen bond is too low for production of NADH.
- The 2 hydrogens are removed stereo-specifically.
- FAD is covalently bound at His, unusual
- Series of 3 iron-sulfur clusters to transfer electrons from FADH 2 to electron transport chain
- Bound to mitochondrial inner membrane
- acts as Complex II in the electron-transport chain
- Near equilibrium/reversible (D G °^ ’^ = –0.5 kcal/mol); [fumarate] kept low
The Citric Acid Cycle: Succinate Dehydrogenase
Mechanism
Glu
Arg
Thr
His
Arg
Thr
His
Arg
Thr
His
H
H
H H
trans
H
OO–
OO–
H
H ene-olic intermediate
FADH 2
The Citric Acid Cycle: Succinate Dehydrogenase
Mechanism
Glu
Arg
Thr
His
Arg
Thr
His
Arg
Thr
His
H
H
H H
trans
H
OO–
OO–
H
H ene-olic intermediate
FADH 2
The Citric Acid Cycle
Citrate Synthase
Aconitase
ICDH & a KGDH Suc-CoA Synthetase
“pyruvate” (acetate)
glutarate à succinate à fumarate à malate à oxaloacetate
citrate à^ aconitate à^ isocitrate
a-ketoglutarate
|
Succinate dehydrogenase
Mechanism
The Citric Acid Cycle: Fumarase
C HO – C
H+
COO –
- OOC
H
H
ene-olic intermediate
The Citric Acid Cycle
Citrate Synthase
Aconitase
ICDH&aKGDH Suc-CoA Synthetase SucDH Fumarase
“pyruvate” (acetate)
glutarate à succinate à fumarate à malate à oxaloacetate
citrate à^ aconitate à^ isocitrate
a-ketoglutarate
|
The Citric Acid Cycle:
Malate Dehydrogenase
Oxidation of Alcohol to a Ketone and Regeneration of Oxaloacetate
- Final step of the cycle
- Regenerates oxaloacetate for citrate synthase
• Highly thermodynamically UN favorable (D G °^ ’^ = +7.1 kcal/mol).
- Reversible
- oxaloacetate concentration kept VERY low by citrate synthase
- pulls the reaction forward (–7.7 + 7.1 = –0.6)
The Citric Acid Cycle
Citrate Synthase
Aconitase
ICDH&aKGDH Suc-CoA Synthetase SucDH Fumarase Malate DH
“pyruvate” (acetate)
glutarate à succinate à fumarate à malate à oxaloacetate
citrate à^ aconitate à^ isocitrate
a-ketoglutarate
|
- Net oxidation of two carbons to CO (^2)
- equivalent to two carbons of acetyl- CoA
- but NOT the exact same carbons
- Energy captured by electron transfer to NADH and FADH (^2)
- Generates 1 GTP, which can be converted to ATP
- Cycle acts as a unit; its basically a furnace for burning carbon
Acetyl-CoA + 3NAD +^ + FAD + GDP + P (^) i + 2 H 2 O à 2CO 2 + 3NADH + FADH 2 + GTP + CoA + 3H +
The Citric Acid Cycle
Yield (TCA):
….....except we don’t have the water yet!
Pyruvate + 4NAD +^ + FAD + GDP + P (^) i + 2 H 2 O à 3CO 2 + 4NADH + FADH 2 + GTP + 3H +
Yield (from pyruvate):
Pyruvate CO (^2)
NADH From acetyl-CoA:
The Citric Acid Cycle: Summary
NAD+
NAD+
NAD+ FAD
Mn +
TPP Lipoic acid FAD
FeS
isocitrate
Summary
- a large multi-subunit enzyme, pyruvate dehydrogenase complex, converts pyruvate into acetyl-CoA
- several cofactors are involved in reactions that harness the energy from pyruvate
- the citric acid cycle is an important catabolic process: it makes reduced cofactors (NADH & FADH 2 ), plus GTP, that could yield ATP
- the rules of organic chemistry help to rationalize reactions in the citric acid cycle
- the citric acid cycle is largely regulated by availability of substrates and product inhibition (especially NADH and ATP)
We learned that:
Pyruvate Oxidation & Citric Acid
Cycle
