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Clinical Presentation Curriculum A Guide to Intermediary Metabolism Jack Blazyk, Ph.D. 2002-2003

Clinical Presentation Curriculum A Guide to Intermediary Metabolism Jack Blazyk, Ph.D. 2002-2003. 2. 3. Thermodynamics. In an actively functioning pathway, the D G for ALL reactions is NEGATIVE. Enzyme Regulation. Covalent Modification (e.g., reversible phosphorylation).

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Clinical Presentation Curriculum A Guide to Intermediary Metabolism Jack Blazyk, Ph.D. 2002-2003

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  1. Clinical Presentation CurriculumA Guide toIntermediary MetabolismJack Blazyk, Ph.D.2002-2003

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  3. 3 Thermodynamics In an actively functioning pathway, the DG for ALL reactions is NEGATIVE Enzyme Regulation Covalent Modification (e.g., reversible phosphorylation) Allosteric Regulation OR Genetic Regulation

  4. 4 High-Energy Phosphates Enol Acyl Example Phosphoenolpyruvate (PEP) Example 1,3-Bisphosphoglycerate Amino Pyro (Phosphoanhydride) Example Adenosine triphosphate (ATP) Example Creatine phosphate Hydrolysis of Phosphates Enol -15 Acyl -10 Amino -10 Pyro -7 Adenosine Pool Hydrolysis of ATP ATP ADP AMP

  5. Nicotinamide Adenine Dinucleotide Nicotinamide Adenine Dinucleotide Phosphate NAD+ + 2e- + H+ NADH Oxidized Reduced NADP+ + 2e- + H+ NADPH Oxidized Reduced Flavin Adenine Dinucleotide FAD + 2e- + 2H+ FADH2 Oxidized Reduced O CoA - S ~ C – CH3 5 Electron Transfer Acyl Group Transfer Coenzyme A ADP + Pantothenic Acid + SH CoA - SH Acetyl-CoA

  6. 6 Citric Acid Cycle or Tricarboxylic acid (TCA) Cycle or Krebs Cycle Located in mitochondrial matrix Citrate - COO- Citric Acid Sneak Preview 1. C2 + C4 C6 2. C6 C5 + CO2 + 2e- Oxidative Decarboxylations 3. C5 C4 + CO2 + ~P + 2e- 4. C4C4 + 4e-

  7. O | | CH3 - C - S - CoA 3 H2O 3 NAD+ 1 FAD GDP + Pi Citrate Synthase Aconitase 7 Isocitrate Dehydrogenase a-KG Dehydrogenase Oxidative Decarboxylations Succinate Thiokinase Succinate Dehydrogenase Fumarase Malate Dehydrogenase Out In CoA - SH 2 CO2 3 NADH + 3 H+ 1 FADH2 GTP + H2O

  8. 8 Tap-Off Points PEP Carboxykinase Malic Enzyme Malate Pyruvate NADP+ NADPH + H+ + CO2 Anaplerotic Pathway Pyruvate Carboxylase Pyruvate Oxaloacetate ATP + CO2 ADP + Pi Biotin (a water-soluble B vitamin) is a coenzyme Allosterically activated by Acetyl-CoA

  9. Complex INADH-Q Reductase • Transfers electrons from NADH to Q • NADH + H+ + Q NAD+ + QH2 • Flavin Mononucleotide (FMN) • Iron-sulfur (Fe-S) proteins • Complex IIICytochrome Reductase • Transfers electrons from QH2 to Cyt c • QH2 + 2Cyt c(Fe+3) Q + 2H++ 2Cyt c(Fe+2) • Cytochrome b (2 types) • Iron-sulfur (Fe-S) proteins • Cytochrome c1 • Complex IVCytochrome Oxidase • Transfers electrons from Cyt c to O2 • 2Cyt c(Fe+2) + ½O2 + 2H+ 2Cyt c(Fe+3) + H2O • Cytochrome a • Cytochrome a3 • Copper (Cu) • Complex IISuccinate-Q Reductase • Transfers electrons from Succinate to Q • Succinate + Q Fumarate + QH2 • Flavin Adenine Dinucleotide (FAD) • Iron-sulfur (Fe-S) proteins Oxidative Phosphorylation 9 Electron Transport Chain = Respiratory Chain • 4 Membrane-Bound Complexes • I – NADH-Q Reductase • II – Succinate-Q Reductase • III – Cytochrome Reductase • IV – Cytochrome Oxidase • 2 Mobile Electron Carriers • Ubiquinone (Coenzyme Q) • Cytochrome c

  10. 10 Chemiosmotic Mechanism • Proposed by Peter Mitchell • Proton Motive Force • PMF = DpH + DY

  11. GTP + ADP GDP + ATP [ATP] + ½ [ADP] [ATP] + [ADP] + [AMP] ATP Production via CAC and Ox Phos 11 3 NADH ~9 ATP 1 FADH2 ~2 ATP 1 GTP 1 ATP ~12 ATP per Acetyl-CoA Regulation of CAC and Ox Phos • Availability of Acetyl-CoA • Availability of O2 • Energy Charge = • Respiratory Control Electron Transport Inhibitors COCN -N3-Rotenone X X

  12. X Atractyloside Oligomycin OH X NO2 NO2 O - + H+ NO2 NO2 H+ H+ H+ X 12 Oxidative Phosphorylation Inhibitors Uncouplers 2,4-Dinitrophenol

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