Oxidative decarboxylation of Pyruvate / Acetyl CoA

1
Oxidative decarboxylation of Pyruvate / Acetyl
CoA ?     Pyruvate Dehydrogenase Complex, Enzymes
and coenzymes ?     Formation of Acetyl CoA,
Regulation of Pyruvate Dehydrogenase
complex ?     Fate of Pyruvate                    
   D4 226-231,    L2  464-465
2
Introduction Most energy-generating metab. Path.
produce acetyl (A) coenzyme A (CoA) fig6.10,  AA
? deamination ? ACoA                 FA ?
oxidation ? ACoA                 Glu ? glycolysis
? ACoA Glu, Lact, AA (ala, ser, cys) ? Pyr ?
PyrDH ? ACoA Pyr (cytosol) ? mitoch memb (pyr is
permeable) ? Pyr (mitosol) ? PyrDH/CoA
(NADH/CO2) ? ACoA
3
(No Transcript)
4
PyrDH (multienzyme complex) Table,     3  Enzs
(PyrDH, DHLTA-lase, DHLDH) fig6.14,  5  CoEnzs
(TPP, Lip, NAD, FAD, CoA) fig6.15,   1) C3O3H3
TPP ? PyrDH ? CO2 C2OH5-TPP                    
(Pyr  loses CO2 Hydroxyethyl is
formed)                 2) C2OH5-TPP Lip-S2
CoA ? PyrDH/DHLTA-lase ? C2OH3-S-Lip-SH
TPP                     (Hydroxyethyl is oxidized
to form Dihydroxylipoamide)                 3)
C2OH3-S-Lip-SH CoA TTP ? DHLTA-lase ?
Lip-S2H2 ACoA                     (Acetyl group
is transferred to CoA Dihydroxylipoamide is
reoxidized)                 4) Lip-S2H2 FAD ?
DHLTA-lase/DHLDH ? FADH2 Lip-S2                 
    (Hydrogen from Lipolic Acid is transffred to
FAD)                 5) FADH2 NAD ? DHLDH ?
FAD NADH H
5
(No Transcript)
6
PyrDH Regulation fig6.16,  PyrDH a "active" ? PK
(Mg2-ATP-dependent) ? PyrDH b "inactive" PyrDH b
"inactive" ? PP-tase (Mg2- Ca2-dependent) ?
PyrDH a "active"   ATP, ACoA, NADH  () PK
inactivates PyrDH   ADP, CoA, NAD, Pyr () PK
activates the PyrDH FA oxidation  () PyrDH
activity in Liver (? in NADH/NAD, ACoA/CoA
ratio) INS    () PyrDH activity in adipose
tissue by () PP-tase Epinephrine / Ca2 ()
PyrDH activity in heart by () PP-tase
7
(No Transcript)
8
Pyruvate (3C) Fate fig6.12,  Pyr
(carboxylation) ? PC-lase (gluconeogenesis) ?
OA Pyr (transamination) ? AT-ase (essential AA) ?
Alanine Pyr (reduction) ? LDH (anaerobic
glycolysis) ? Lactate Pyr (oxidation) ? PyrDH
(aerobic glycolysis) ? ACoA Pyr (fermentation)
? Ethanol (in yeast)
9
Citric Acid Cycle (CAC) CAC is for complete
oxidation of Glu (CO2H2O) production of
further ATP in mitoch. matrix (mitosol) by
high-energy phosphate bond (1 GTP) by reducing
equivalent (3 NADH, 1 FADH2) in the
elect-trans-oxid phosph sequence
(mitosol) fig6.19,   OA (4C) ACoA (2C) ? CS-ase
? C-ate (6C) ? A-tase ? IsoC (6C) ? ICDH ? a-KG
(5C) ? a-KGDH ? SCoA (5C) ? SCoA S-tase ? S-ate
(4C) ? SDH ? F-ate (5C) ? F-ase ? M-ate (4C) ?
MDH ? OA (4C)
10
(No Transcript)
11
fig, Anaplerotic reaction (CAC)
Pyr ? Pyr C-lase (-CO2/ATP) ? OA ? PEP C-lase
(CO2/Pi) ? PEP Pyr ? Malic Enz (NADPH) ? M-ate ?
MDH (NADH) ? OA
12
Clinical Correlations 1.  Pyruvate Dehydrogenase
Deficiency             a)  Deficiency in
different regulatory subunits in
children.             b)  High serum Ala,
Pyruvate, Lactate (lactic acidosis).            
c)  low O2 leads to shock, sever neurological
defect, death.             d)  PyrDH is assayed
in skin fibroblasts culture.             e)  can
be treated with high ketogenic diet low
carbohydrates,             f)  and/or
dichloroacetate (inhibits PyrK)