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Kreb

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Kreb s Cycle Chapter 16 – PowerPoint PPT presentation

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Title: Kreb


1
Krebs Cycle
  • Chapter 16

2
Glycolysis 6C Glu ? 3C
Pyruvate x2
  • Glu 2NAD 2 ADP 2 Pi ?
    2 pyr 2 NADH 2 H
    2 ATP 2 H2O
  • D Go -85 kJ/mole
  • 2 NADH ? e- transport ? ATP synth
  • In cytosol

3
3C Pyruvate Product
  • 2 Cs added to Coenzyme A (CoA)
  • As acetate group
  • Activates CoA (thioester)
  • 1 C as CO2

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Pyruvate Dehydrogenase Complex (PDC)
  • Catalyzes acetylation CoA
  • Oxidative decarboxylation (LEO cleave
    carboxylate)

7
Pyruvate Dehydrogenase Complex
(PDC)
  • In mitochondria
  • Sev copies of 3 associated enzs
  • Pyruvate dehydrogenase (E1)
  • Dihydrolipoyl transacetylase (E2)
  • Dihydrolipoyl dehydrogenase (E3)

8
  • Book mammalian PDC 5X size ribosome
  • Bovine circular arrangement
  • 5 cofactors
  • Thiamine, riboflavin, niacin, pantothenate
  • Two regulatory proteins assocd
  • Kinase, phosphatase

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PDC E1 Pyruvate Dehydrogenase
  • 24 copies in complex (E. coli)
  • Cofactor thiamine pyrophosphate (TPP)
  • From Vitamin B1

(Chpt 14)
12
  • Pyr binds ? ethanolic grp attd to TPP
  • CO2 released
  • Oxn to acetaldehyde attd as hydroxyethyl
  • Acetaldehyde transferred to E2 of PDC

(Chpt 14)
13
PDC E2 Dihydrolipoyl Transacetylase
  • Core of complex
  • 24 copies (E. coli) 60 copies (bovine)
  • Cofactor lipollysyl
  • Molecular arm
  • In oxd form 5 membered ring w/ disulfide

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  • Ethanolic grp to lipollysyl
  • Oxd ? acetaldehyde
  • -S-S- redd to SH HS- w/ oxn to acetaldehyde
  • Forms thioester
  • Site of attack by CoASH
  • Transesterification
  • ? AcetylCoA dithiol lipoyl

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PDC E3 Dihydrolipoyl Dehydrogenase
  • 12 copies attd to E2 (E. coli)
  • Cofactor FAD
  • REMEMBER Flavin nucleotide cofactors bound to
    enzs
  • (Nicotinamide nucleotides cofactors freer to
    dissociate)
  • Used to reoxidize lipollysyl

18
  • FAD redd ? FADH2
  • Lipollysyl oxd back to ring w/ disulfide
  • FADH2 regend by NAD entry
  • FADH2 oxd ? original FAD
  • NAD redd ? NADH
  • Leaves complex
  • Where might it go?

19
PDC Summary
  • 3 Enzs closely assocd
  • Book substrate channeling
  • Acetyl grp physically transferred
  • Regulatory
  • Both allosteric covalently modified regulation
  • E1 has kinase, phosphatase enzs assocd
  • Kinase phosphorylates, inactivates
  • Phosphatase dephosphorylates, activates

20
  • Assocd kinase allosterically controlled
  • ATP stimulates
  • Actd kinase inactivates PDC
  • So ? ATP ? ?? PDC??
  • Modulators
  • Inhibitory ATP, NADH, acetyl CoA, fatty acids
  • Why??
  • Stimulatory ADP/AMP, NAD, pyruvate, CoA
  • Why??

21
Krebs Cycle
  • Citric Acid Cycle Tricarboxylic Acid Cycle
    TCA Cycle
  • 2 Cs from pyr (as acetyl on acetylCoA)
  • 2 Cs leave as CO2 (not same 2 Cs that entered)
  • 4 redox rxns
  • 3 NAD ? 3 NADH 1 FAD ? FADH2
  • Where will these go?

22
  • 1 high energy phosphate bond formed
  • 1 GDP ? 1 GTP (some cells 1 ADP ? 1 ATP)
  • REMEMBER the name of this phosphn?
  • Oxaloacetate regend
  • REMEMBER 2 turns for each glu
  • Up to 38 ATP/glu (gt1160 kJ/mole avail)
  • 1 step uses complex sim to PDC

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Acetyl CoA Oxaloacetate ? Citrate CoASH
25
Citrate Synthetase
  • Condensation rxn
  • CoASH regend
  • Through CH3 of acetyl
  • Transient intermediate citroyl CoA
  • Energy reld from cleavage acetylCoA
  • Why? What grps impt to exergonic rxn

26
  • Oxaloacetate binds first
  • ? Conforml change
  • Now site for acetylCoA

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  • Modulators
  • Availability of substrates
  • Inhibn w/ ? citrate
  • What type of inhibn?
  • ? citrate also inhibits PFK-1
  • Where is PFK-1?
  • What type of inhibn would this be?
  • Inhibn w/ ? ATP
  • Relieved w/ ? ADP
  • Why?
  • Inhibn w/ ? succinyl CoA
  • Feedback inhibn

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Citrate ? Isocitrate
32
Aconitase
  • Isomerization
  • Through reversible addn H2O
  • Cis-aconitate intermediate
  • Iron-sulfur center
  • Prod rapidly consumed in next step

33
Isocitrate ? a Ketoglutarate CO2
34
Isocitrate Dehydrogenase
  • Oxn rxn (oxidative decarboxylation)
  • Mn2 coordinates/stabilizes intermediate
  • NAD or NADP depending on isozyme
  • Regulation
  • Inhibn w/ ? ATP
  • Inhibn w/ ? ratio NADH/NAD
  • Why?

35
a Ketoglutarate ? SuccinylCoA CO2
36
a Ketoglutarate Dehydrogenase Complex
  • Identical rxn to PDC
  • Similar E1, E2, E3 enzymes
  • E1 aas differ, bind a ketoglutarate specifically
  • Same cofactors
  • Regulation
  • Inhibn w/ ? succinyl CoA
  • Inhibn w/ ? ratio NADH/NAD

37
SuccinylCoA ? Succinate CoASH
38
SuccinylCoA Synthetase
  • Addn Pi ? high energy acyl phosphate
    intermediate in enz active site
  • CoASH released

39
  • Phosphate transferred to enz active site His
  • GDP enters active site phosphd ? GTP
  • Substrate level phosphn results
  • Book GTP formed transfers PO4 to ADP later

40
Succinate ? Fumarate
41
Succinate Dehydrogenase
  • Membr-bound
  • Euks inner mitoch membr
  • Proks plasma membr
  • Impt also in e- transport
  • Iron-sulfur centers FAD
  • FAD may be covly bound
  • Malonate is competitive inhibitor

42
Fumarate ? L-Malate
43
Fumarase
  • Hydration trans across db
  • Enz stereo-specific

44
L-Malate ? Oxaloacetate
45
L-Malate Dehydrogenase
  • Substrate limited rxn
  • Large D G
  • Why does the rxn go?

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Cycle
  • Complete w/ regenn oxaloacetate
  • Regulation through
  • substrate, product
  • Coenzymes
  • Nucleotide phosphates
  • Other nutrient pathways

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Catabolism/Anabolism Balanced through Krebs Cycle
  • Amphibolic
  • Impt to both catabolism (breakdown) and anabolism
    (build-up) of cells molecules
  • Catabolism of carbohydrates, FAs, aas through
    pyruvate, acetylCoA? Krebs ? ATP
  • Anabolism by cycle intermediates ? aas, fas,
    lipids, purines/pyrimidines

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  • Balance of amphibolic pathways through
    anapleurotic rxns
  • Replenish cycle intermediates so TCA remains
    constant
  • 4 impt rxns
  • Synth oxaloacetate or malate from pyruvate or
    phosphoenolpyruvate
  • Where did you see these reactants?

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  • If ??? glycolysis (so ??? PEP/pyr products), but
    not enough oxaloacetate to fuel cycle
  • Cell can use excess PEP/pyr to make more
    oxaloacetate
  • Now have sufficient to react w/ excess acetylCoA
    (from excess pyr, from excess PEP)

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