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E1: Pyruvate decarboxylase Coenzyme
Thiamine pyrophosphate (TPP)
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E2: dihydrolipoyl transacetylase Coenzyme is
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E3: dihydrolipoyl dehydrogenase Coenzymes
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Pyruvate
- Endproduct of aerobic glycolysis
- must be transported back to mitochondria before it can enter TCA cycle by a transporter that helps it cross the mito. membrane
- in the matrix; pyruvate turns into Acetyl CoA by pyr. Dehydrogenase complex.
- If elevated, E1 will be 100% active
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Pyruvate Dehydrogenase complex
- not part of TCA proper
- source of acetyl CoA
- 2 carbon substrate
- Has the 3 E's
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E1 (PDH) Pyr-dyhrogen-complex
- kinase phosphorylates and inhibits E1
- Phosphatase dephosphorylates and activates E1
- The Kinase is allosterically activated by ATP,Acetyl CoA, and NADH.
- calcium activates PDH phosphatase which stimulates E1
- pyruvate inhibits kinase; therefore E1 goes up.
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Potent inhibitor of PDH kinase
pyruvate
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skeletal muscle releases
CA2+ during contraction stimulates PDH complex = energy production
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beginning of respiration
- transfer of pyruvate to matrix of mito.
- transfer of coA to pyruvate; makes acetyl CoA
- release of co2
- form nadh
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Each glucose makes 2 pyruvate
1glucose= 2NADH+2acetyl CoA + 2co2
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slide 6: Catabolism
- Nadp+ to nadph
- reduced substrate to oxidized product
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slide 6: Anabolism
- Nadph to Nadp+oxidized precursor to reduced product.
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Pyruvate dehydrogenase
- in the mitochondria
- converts pyruvate to acetyl CoA
- CoA is needed for citrate production ( citrate- 1st substrate in the tca cycle)
- makes 3 enzyme complexes E1,2,3.
- Coenzymes needed for activation
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Pyruvate dehydrogenase deficiency
(4x4 card 19)
- disruption of mitocondria
- neuro degenerative disorders
- sex-linked(effects both M&F) or autosomal dominant defect.
- neonatal death
- weakness, Nervous system defects, lactic acidosis.
- high lactate and pyruvate
- Treatment: PDH enzyme, restriction of carbs and givin TPP may reduce symptoms.
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Arsenic toxicity
- interfere with glycolysis
- inhibits pdh, the complex that needs lipoic acid as cofactor.
- mixes with SH group of lipoic acid making Cofactor unavailable from pdh
- effects CNS(brain), neurological problems
- rash on foot and skin
- treatment: chelating agents(binds to metal making it inactive)
- treatment: anti lewsite, or bal(2,3dimercatopropanol)
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slide 7: TCA (tricarboxylic acid cycle)
Pg113
- also known as citric acid or kerb's cycle
- energy producing pathway
- food turns to the cycle as acetyl CoA and oxidized to CO2 producing coenzymes & GTP
- Starts with 4carbon oxaloacetate, adds 2C from acetyl CoA, loses 2C as CO2, regenerates 4C oxaloacetate.
- Electrons transferred by cycle to NAD & FAD
- Electrons go to O2 by Electron transport chain, and ATP is made by oxidative phosphorylation.
- ATP also made from GTP, by sub-level phospho.
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slide 8: Cristae location
inside the mitochondria (intermembrane space)
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Succinate dehydrogenase (inner membrane)
all ezymes in citric acid cycle are in the matrix or inner membrane which are in all cells except mature RBC's and platelets.
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TCA cycle regulation
- regulated by 3 enzymes
- 1. Citrate synthase
- 2. isocitrate dehydrogenase
- 3. alpha ketoglutarate dehydrogenase
- They are activated/inhibited by different metabolites.
- they control flow of substrates due to need of atp
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Citrate synthase
- inhibited by ATP, NADH, succinyl CoA.
- Stimulated by insulin
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Isocitrate dehydrogenase
- the cycle's "Pacemaker"
- stimulated by ADP
- inhibited by ATP & NADH
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@-Ketoglutarate dehydrogenase
- Inhibited by 2 of it's products ( NADH & succinyl CoA)
- Also inhibited by ATP & GTP
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slide 12: 1st step of TCA
- Acetyl CoA condenses to Citrate
- enzyme: citrate synthase
- Cleavage of thioster bond in Ac-CoA gives energy
- Citrate: the product is an inhibitor of this rxn
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2nd step of TCA
- citrate is isomorized(transformed) to isocitrate
- Aconitate is enzyme intermediate
- enzyme: aconitase
- Equilibrium of rxn favors citrate.
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Slide14: 3rd step - regulative step
- Isocitrate oxidized to alpha-ketoglutarate - in 1st oxidateive decarbox- rxn.
- CO2 produced
- Electrons are passed to NAD to form NadH & H+
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regulatory step-
Enzyme: Isocitrate dehydrogenase
- regulatory enzyme of TCA cycle
- Allosterically activated by ADP
- Inhibited by NADH
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Malfunction of TCA (Fluoroacetate)
- A poison, converts to fluorocitrate and inhibits Aconitase
- blocks the cycle and its energy output
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Deficiency of these vitamins impairs cycle
- Niacin -->NAD
- Riboflavin (vit b2) -->FAD
- Thiamine (vit B1) --> thiamine pyrophosphate. Also in alcoholics - effects CNS
- Vit b12 (cobalamin) --> succ CoA
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What happens to NADH & FADH2
8 nadh & 2fadh2 feed into electron transport chain.
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citric acid cycle and gluconeogenesis
- cit acid cycle accepts metabolites, contributes to intermediates for use in anabolic pathway like gluconeogen.
- Carbons entering as Acet-CoA always turn to Co2, never contribute C to gluconeogen.
- Acet-CoA is not a substrate of gluconeogen.
- C from AA and pyruvate convert to malate, then exported to cytosol, then converted to oxaloacetate to enter gluconeo-pathway.
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Total ATP produced by citric acid cycle
24 ATP/acet-CoA oxidized
2 Acet-CoA per glucose
- 3nadh->3nad = 9ATP
- Fadh2->fad= 2atp
- GDP +p1-> GTP = 1
- Total ATP: 12
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9.1 needed for conversion of pyruvate to acetyl CoA and CO2
lipoic acid
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9.2 condition that decreases (oxidation-combine with 02) of acetyl CoA
low Nad/NadH ratio
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9.3 A+B+FAD+H2O --> C+FADH2+Nadh
what is ABC?
- A. succinate
- B. NAD
- C. oxaloacetate
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9.4
1Mo old, has abnormal CNS, lactic acidosis, low thiamine pyrophosphate (1x10-4mM) tpp normal at 5%, and 80% normal activity on high (.4mM) of TPP.
What do you administer?
admin. thiamine will reduce his serum lactate conc. and improve his symptoms.
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