Chem 336 - Spring 1999 - Organic Chemistry III
Portland State University - Dr. Carl C. Wamser

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Chapter 26 - Metabolism

Metabolic Processes

• catabolism - breakdown of larger molecules to smaller ones
• anabolism - buildup of larger molecules from smaller ones

Digestion

• a specific example of catabolism, in which food is broken down to extract raw materials (for anabolism) and energy
• initial digestion steps are simple hydrolyses:
  • fats -> glycerol and fatty acids
  • carbohydrates -> glucose and other simple sugars
  • proteins -> amino acids
• further digestion steps convert these molecules into acetyl CoA, which enters the citric acid cycle and gets oxidized to 2 CO₂
  • the steps are oxidations and generate reduced cofactors
  • the steps are exothermic and generate ATP for energy storage
• the net result of digestion is food -> CO₂ plus reduced cofactors and ATP

ADP / ATP

• ATP is used as stored energy, useful for coupling to other reactions
• ATP hydrolysis to ADP plus phosphate releases 8 kcal/mole
• for example, glycerol -> glycerol phosphate is endothermic
  but glycerol + ATP -> glycerol phosphate + ADP is exothermic
• ATP is coupled to many other reactions (not necessarily involving phosphate) to make them more favorable

NAD⁺ / NADH

• NAD⁺ is used as a general oxidant
• reduction of NAD⁺ (by adding 2 e^- and H⁺) generates NADH
• NADH is used as a general reductant
• NAD⁺ and NADH are cofactors used with enzymes that carry out oxidation or reduction reactions

FAD / FADH2 is another common reducing agent

Digestion of Fatty Acids - the Beta-Oxidation Pathway

• fatty acids are broken down 2 carbons at a time
• each stage releases one acetyl CoA and uses one FAD and one NAD+ as oxidants

1. oxidation creates a conjugated double bond (uses FAD)
2. hydration of the double bond makes an alcohol
3. oxidation of the alcohol makes a beta-keto ester (uses NAD+)
4. a reverse Claisen condensation gives acetyl CoA plus a shorter CoA ester
5. repeat steps 1 - 4 until the chain is broken down to only two carbons (acetyl CoA)

Digestion of Glucose - Glycolysis

• breakdown of glucose in 10 steps to 3-carbon fragments, eventually pyruvate
• uses 2 ATP to set up the breakdown, then gets back 2 ATP from high-energy phosphates
• also uses 1 NAD+ as an oxidant

1. glucose to glucose-6-phosphate (uses ATP)
2. glucose-6-phosphate to fructose-6-phosphate
3. fructose-6-phosphate to fructose-1,6-diphosphate (uses ATP)
4. reverse aldol reaction: fructose-1,6-diphosphate to dihydroxyacetonephosphate + glyceraldehyde-3-phosphate
5. dihydroxyacetonephosphate isomerized to glyceraldehyde-3-phosphate
6. glyceraldehyde-3-phosphate to glycerate-1,3-diphosphate (uses NAD+)
7. glycerate-1,3-diphosphate to 3-phosphoglycerate (generates an ATP)
8. 3-phosphoglycerate to 2-phosphoglycerate
9. 2-phosphoglycerate to phosphoenolpyruvate
10. phosphoenolpyruvate to pyruvate (generates an ATP)

Fates of Pyruvate

• anaerobic (regenerate NAD+, i.e., no net oxidation overall)
  • reduction by NADH to lactate (generates an NAD+)
  • decarboxylation to acetaldehyde, reduction to ethanol (generates an NAD+)
• aerobic (use up more NAD+, i.e., overall oxidation)
  • decarboxylation and coupling to CoA (uses NAD+)
  • generates acetyl-S-CoA, which enters the Krebs cycle and is oxidized to CO2
  • the Krebs cycle generates additional ATP and NADH