Download - The Krebs Tricarboxylic Acid Cycle
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The Krebs Tricarboxylic Acid Cycle
The Final Common Pathway of Oxidative Metabolism
9/24/07
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⑤
⑥
Liver
①
④
②
Gluconeogenesis; 1 Liver, Kidney
e-
Ox phos ③
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Citric Acid Cycle (CAC)“Kreb Cycle”
Tricarboxylic Acid Cycle
2/3 of O2 consumption needed foroxidation of Acetyl CoA CO2
• Occurs exclusively in the mitochondrion (matrix)• OAA acts as carrier or acceptor of acetyl CoA units – is regenerated
• “Burns” acetyl CoA to CO2 – during this oxidation eˉs from acetyl CoA are trapped in the form of:
NADHFADH
Pyruvate
Pyruvate DehydrogenaseComplex “links”glycolysis to CAC
+ 2eˉ
+ 2eˉ
GTP ATP (substrate levelphosphorylation)
+ 2eˉ
+ 2eˉ
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The Three Stages of Metabolism
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The Krebs CycleCitric Acid Cycle; The TCA Cycle
• Pyruvate (actually the acetyl group) from glycolysis is degraded to CO2 – The acetyl group is formed in stage II of metabolism from
carbohydrate and amino acid metabolism• 1GTP (ATP in bacteria) and 1 FADH2 is produced
during one turn of the cycle• 3 NADH are produced during one turn of the cycle • NADH and FADH2 energize electron transport and
oxidative phosphorylation• Eight reactions make up the Krebs cycle
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The Chemical Logic of the Krebs Cycle
• After condensing acetate with oxaloacetate to form citrate – oxidation yields CO2, oxaloacetate is regenerated, and the energy is captured as NADH, FADH2, and GTP (ATP)– Acetyl-CoA is called the stoichiometric substrate; it is
consumed in large amounts– Oxaloacetate is called the regenerating substrate; it is
continuously regenerated (it is not consumed)• The cycle is catalytic; oxaloacetate is consumed and
then regenerated.
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Overview of the Krebs Cycle: A Mitochondrial Process
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Anatomy of the Mitochondrion
• Which membrane is impermeable to protons and other ions?
• Which membrane will allow for the transport of molecules up to a molecular weight of about 1000?
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Pyruvate Dehydrogenase Complex
Multimolecular aggregate3 Enzymes5 Coenzymes
5 Reactions
CoA contains thevitamin Pantothenic acid
Product Inhibition
CoenzymesThiamine Pyrophosphate (TTP) B1NAD+
FAD+
CoA
Lipoic acid
Mitochondrial matrix
Cytoplasm Pyruvate
* Pyruvate transporter
* Pyruvate mito matrix
Irreversible
Links glycolysis to CAC
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PDH Deficiency – results in Congenital Lactic AcidosisPyruvate cannot enter the CAC and results in ↑ Lactic AcidPrimarily affects the brain – neonatal death3 Forms – psychomotor retardation√ Possible treatment is ketogenic diet:
Low in CHOHigh in fats
Produces ketone bodies as an alternate form of energy for the brain
CAC
Arsenic Poisoning – Pyruvate Dehydrogenase – -Ketoglutarate Dehydrogenase
Both require lipoic acid as a cofactor
Arsenite – Trivalent form of arsenic I° – Forms a stable complex with the thiol (-SH) group of Lipoic Acid II° – Glyceraldehyde 3-PO4 step forms complex with inorganic Pi thus prevents ATP formation in glycolysis
Affects the brain – Death, neurologic problems
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√ Allosteric Regulation
√ AllostericRegulation
cAMP independent
Skeletal muscleContraction
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Fluorocitrate OAA
( ¯ )
FluoroacetateFluroacetyl CoA
Rat poison
ADP (+)
One of the rate limiting Rxsof the CAC
ATP
Carrier
Aldo condensation
The entrance of acetyl CoA doesnot ↑ or ↓ intermediates in the CAC
Oxidative decarboxylatione¯Irreversible (1)
Isomerization
NADH ( - )
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Oxidative decarboxylationVery similar to the Pyruvate Dehydrogenase complex
Irreversible (2)ATP. GTPSuccinyl CoANADH
( ¯ )
e¯
From oxidation ofodd number FAs
ADP GDPATP
Nucleoside BiphosphateKinase
“Substrate LevelPhosphorylation”
e¯ Oxidation reaction
Hydration reaction
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e¯( 4 )
Reversible oxidation reaction
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Main Points of the Krebs Cycle• Occurs in mitochondrion• All enzymes are hydrophilic and occur in the matrix
except for succinate dehydrogenase, which occurs in the inner mitochondrial membrane
• Citrate synthase, Isocitrate dehydrogenase and -ketoglutarate dehydrogenase are the three irreversible reactions
• ICD is the main regulatory enzyme, and it is activated by ADP
• Succinate dehydrogenase is inhibited by malonate and oxaloacetate
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Summary
Regulation of the CACDependent on the energy state ofthe cell which is reflected by[ADP] [Pi]
[ATP]ratio
This ratio determines the rate ofoxidative phosphorylation
Named “Respiratory Control”of energy production because oxidationand phosphorylation of ADP must occur simultaneously
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Electrochemical gradientOxidized Reduced
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1
2 3
4
6
75
8
2 Shuttle systems to bring cytosolic NADH intomitochondria for oxidative phosphorylation
1) Glycerophosphate shuttle = 36 ATP
2) Malate-aspartate shuttle = 38 ATP
Count ATPs: Anerobic glycolysis = 2 Glycolysis + CAC + oxidative phosphorylation = 38NADH FADH2 ATP
1 Glycolysis 2
2 Glycolysis (G-3-P 1,3,BisP) 2 6
3 Pyruvate Acetyl CoA 2 6
4, 5, 6 CAC 6 18
7 CAC-FADH2 2 4
8 CAC – substrate level ATP 2
Total 38
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