Carbohydrate Metabolism

Energy Investment Phase

• Glucose → Glucose-6-phosphate (Hexokinase, 1 ATP used)
• Glucose-6-P → Fructose-6-P (Phosphoglucose isomerase)
• Fructose-6-P → Fructose-1,6-bisphosphate (Phosphofructokinase, 1 ATP used)
• Fructose-1,6-BP → DHAP + G3P (Aldolase)
• DHAP → G3P (Triose phosphate isomerase)

Energy Payoff Phase

• 2 G3P → 2 1,3-Bisphosphoglycerate (G3P dehydrogenase, 2 NADH produced)
• 2 1,3-BPG → 2 3-Phosphoglycerate (Phosphoglycerate kinase, 2 ATP produced)
• 2 3-PG → 2 2-Phosphoglycerate (Phosphoglycerate mutase)
• 2 2-PG → 2 Phosphoenolpyruvate (Enolase)
• 2 PEP → 2 Pyruvate (Pyruvate kinase, 2 ATP produced)

Glycogenesis (Synthesis)

Stores excess glucose as glycogen when blood glucose is high.

• Glucose-6-P → Glucose-1-P (Phosphoglucomutase)
• Glucose-1-P + UTP → UDP-glucose + PPi (UDP-glucose pyrophosphorylase)
• UDP-glucose → Glycogen (Glycogen synthase)
• Branching enzyme creates α-1,6 glycosidic bonds

Gluconeogenesis

Synthesis of glucose from non-carbohydrate sources.

• Precursors: Lactate, Pyruvate, Glycerol, Glucogenic amino acids
• Key enzymes bypass irreversible glycolysis steps:
• Pyruvate → Oxaloacetate → Phosphoenolpyruvate
• Fructose-1,6-BP → Fructose-6-P (Fructose-1,6-bisphosphatase)
• Glucose-6-P → Glucose (Glucose-6-phosphatase, liver only)

Aerobic Pathway

Pyruvate dehydrogenase complex: Pyruvate + CoA + NAD+ → Acetyl-CoA + CO₂ + NADH

This is the bridge between glycolysis and the TCA cycle.

Anaerobic Pathway (Lactate Fermentation)

Lactate dehydrogenase: Pyruvate + NADH → Lactate + NAD+

Regenerates NAD+ to allow glycolysis to continue when oxygen is limited.

The 8 Reactions

1. Citrate Synthase: Acetyl-CoA + Oxaloacetate → Citrate + CoA
2. Aconitase: Citrate → Isocitrate (Isomerization)
3. Isocitrate Dehydrogenase: Isocitrate → α-Ketoglutarate + CO₂ + NADH
4. α-Ketoglutarate Dehydrogenase: α-KG → Succinyl-CoA + CO₂ + NADH
5. Succinyl-CoA Synthetase: Succinyl-CoA → Succinate + GTP
6. Succinate Dehydrogenase: Succinate → Fumarate + FADH₂
7. Fumarase: Fumarate → Malate
8. Malate Dehydrogenase: Malate → Oxaloacetate + NADH

Macronutrient Integration

The TCA cycle integrates all macronutrient metabolism:

• Carbohydrates: Enter as Acetyl-CoA (from pyruvate)
• Fatty Acids: Enter as Acetyl-CoA (from β-oxidation)
• Amino Acids: Enter at multiple points (Acetyl-CoA, α-KG, Succinyl-CoA, Fumarate, Oxaloacetate)

Anabolic Functions

• Gluconeogenesis: Oxaloacetate → Phosphoenolpyruvate → Glucose
• Lipogenesis: Citrate exported to cytosol → Acetyl-CoA → Fatty acids
• Amino Acid Synthesis: α-KG and Oxaloacetate as carbon skeletons

The Four Complexes

• Complex I (NADH-CoQ oxidoreductase): NADH → NAD+ + 4 H+ pumped
• Complex II (Succinate-CoQ oxidoreductase): FADH₂ → FAD + 0 H+ pumped
• Complex III (CoQH₂-cytochrome c oxidoreductase): CoQH₂ → CoQ + 4 H+ pumped
• Complex IV (Cytochrome c oxidase): Cytochrome c → O₂ + 2 H+ pumped

Electron Carriers

• Coenzyme Q (Ubiquinone): Hydrophobic, mobile in membrane
• Cytochrome c: Hydrophilic, mobile in intermembrane space

ATP Synthesis (Oxidative Phosphorylation)

ATP Synthase: Uses proton gradient (chemiosmotic coupling) to synthesize ATP

For every 4 H+ that flow through ATP Synthase → 1 ATP synthesized

Oxygen as Terminal Electron Acceptor

At Complex IV: O₂ + 4e⁻ + 4H+ → 2 H₂O

This is why oxygen is essential for aerobic metabolism. Without oxygen, the ETC stops, NADH and FADH₂ cannot be reoxidized, and the TCA cycle halts.

Uncoupling

Uncoupling Proteins (UCP): Allow protons to flow back into the matrix without producing ATP

Brown Adipose Tissue: Uses UCP1 for thermogenesis (heat production) instead of ATP synthesis