Blazyk Guide to Metabolism

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Clinical Presentation CurriculumA Guide
toIntermediary MetabolismJack Blazyk,
Ph.D.2003-2004
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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
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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
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Electron Transfer
Acyl Group Transfer
Coenzyme A
ADP Pantothenic Acid SH
CoA - SH
Acetyl-CoA
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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. C4 C4 4e-
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Citrate Synthase
Aconitase
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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
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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
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Oxidative Phosphorylation
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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

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Chemiosmotic Mechanism

• Proposed by Peter Mitchell
• Proton Motive Force
• PMF DpH DY

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ATP Production via CAC and Ox Phos
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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
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Oxidative Phosphorylation Inhibitors
Uncouplers
2,4-Dinitrophenol
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R-COOH
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Fatty Acid Oxidation
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Fatty Acid Biosynthesis
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Regulation
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Triglyceride Metabolism
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Lipogenesis
Lipolysis
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Amino Acid Metabolism
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Amino Group Shuttles
Urea Cycle
From Harpers Biochemistry, Murray et al., 25th
ed., 2000, Fig. 31-14
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Glycogenesis
Well-Fed Conditions
Glycolysis
Cholesterol Synthesis
Pentose Shunt
Triglyceride Synthesis
Fatty Acid Synthesis
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Well-Fed Conditions
Glycolysis
Cholesterol Synthesis
Pentose Shunt
Triglyceride Synthesis
Fatty Acid Synthesis
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Glycogenesis
Well-Fed Conditions
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Well-Fed State
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Gluconeogenesis
Glycogenolysis
Fasting Conditions
Ketone Body Synthesis
Fatty Acid Oxidation
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No Uptake
Fasting Conditions
Triglyceride Breakdown
Fatty Acid Oxidation
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No Uptake
Fasting Conditions
Ketone Body Utilization
Fatty Acid Oxidation
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Early Fasting State
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Extended Fasting State