1. Oxidative decarboxylation of Pyruvate / Acetyl CoA ط Pyruvate Dehydrogenase Complex, Enzymes and coenzymes ط Formation of Acetyl CoA, Regulation of Pyruvate Dehydrogenase complex ط Fate of Pyruvate D4 226-231, L2 464-465

2. Introduction Most energy-generating metab. Path. produce acetyl (A) coenzyme A (CoA): fig6.10fig6.10, 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/CO 2 )  ACoA

4. PyrDH (multienzyme complex) Table, 3 Enzs (PyrDH, DHLTA-lase, DHLDH) fig6.14, 5 CoEnzs (TPP, Lip, NAD, FAD, CoA) fig6.15fig6.15, 1) C 3 O 3 H 3 – + TPP  PyrDH  CO2 + C 2 OH 5 -TPP (Pyr loses CO 2 & Hydroxyethyl is formed) 2) C 2 OH 5 -TPP + Lip-S 2 + CoA  PyrDH/DHLTA-lase  C 2 OH 3 -S-Lip-SH + TPP (Hydroxyethyl is oxidized to form Dihydroxylipoamide) 3) C 2 OH 3 -S-Lip-SH + CoA + TTP  DHLTA-lase  Lip-S 2 H 2 + ACoA (Acetyl group is transferred to CoA & Dihydroxylipoamide is reoxidized) 4) Lip-S 2 H 2 + FAD +  DHLTA-lase/DHLDH  FADH 2 + Lip-S 2 (Hydrogen from Lipolic Acid is transffred to FAD) 5) FADH 2 + NAD +  DHLDH  FAD + + NADH + H +

6. PyrDH Regulation fig6.16fig6.16, PyrDH a "active"  PK (Mg 2+ -ATP-dependent)  PyrDH b "inactive" PyrDH b "inactive"  PP-tase (Mg 2+ - Ca 2+ -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 / Ca 2+ (+) PyrDH activity in heart by (+) PP-tase

8. Pyruvate (3C) Fate fig6.12fig6.12, 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 (CO 2 +H 2 O) & production of further ATP in mitoch. matrix (mitosol) by high-energy phosphate bond (1 GTP) by reducing equivalent (3 NADH, 1 FADH 2 ) in the elect-trans-oxid phosph sequence (mitosol) fig6.19fig6.19, OA (4C) + ACoA (2C)  CS-ase  C-ate (6C)  A-tase  IsoC (6C)  ICDH  α-KG (5C)  α-KGDH  SCoA (5C)  SCoA S-tase  S-ate (4C)  SDH  F-ate (5C)  F-ase  M-ate (4C)  MDH  OA (4C)

11. figfig, Anaplerotic reaction (CAC): Pyr  Pyr C-lase (-CO 2 /ATP)  OA  PEP C-lase (CO 2 /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 O 2 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)