Carbohydrate Metabolism

Carbohydrates are the primary fuel source for most cells. Glucose catabolism — from glycolysis through the TCA cycle to oxidative phosphorylation — is among the most conserved metabolic pathway in biology, and its dysregulation underlies major diseases including diabetes mellitus and cancer.

Glycolysis: Ten Steps, Two Phases

Glycolysis occurs in the cytoplasm and converts one glucose molecule into two molecules of pyruvate, with a net yield of 2 ATP and 2 NADH. The pathway has two phases. The investment phase (steps 1–5) consumes 2 ATP: hexokinase phosphorylates glucose to glucose-6-phosphate (G6P), phosphoglucose isomerase converts G6P to fructose-6-phosphate (F6P), and phosphofructokinase-1 (PFK-1) phosphorylates F6P to fructose-1,6-bisphosphate (F1,6BP) — the committed, rate-limiting step. Aldolase cleaves F1,6BP into two triose phosphates. The payoff phase (steps 6–10, ×2 for each triose) produces 4 ATP and 2 NADH via substrate-level phosphorylation and oxidative steps, yielding pyruvate. PFK-1 is the primary regulatory point: allosterically inhibited by ATP and citrate (energy surplus) and activated by AMP, ADP, and fructose-2,6-bisphosphate (F2,6BP) — the most potent activator, whose levels are controlled hormonally by insulin (activates PFK-2 → raises F2,6BP) and glucagon/epinephrine (via PKA → activates FBPase-2 → lowers F2,6BP).

Fate of Pyruvate

Under aerobic conditions, pyruvate enters the mitochondrial matrix and is oxidatively decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex (PDC), requiring cofactors TPP, lipoic acid, FAD, NAD+, and CoA, and yielding 1 NADH and 1 CO2 per pyruvate. PDC is inhibited by its products (acetyl-CoA and NADH) and by phosphorylation via PDH kinase; it is activated by Ca2+ and insulin. Under anaerobic conditions, pyruvate is reduced to lactate by lactate dehydrogenase (LDH), regenerating NAD+ to allow glycolysis to continue. This is the basis of the Cori cycle: lactate produced in exercising muscle travels to the liver and is converted back to glucose via gluconeogenesis.

The TCA Cycle

Acetyl-CoA (2C) condenses with oxaloacetate (4C) to form citrate (6C) — catalysed by citrate synthase. The cycle proceeds through isocitrate, alpha-ketoglutarate (–CO2, +NADH), succinyl-CoA (–CO2, +NADH), succinate (+GTP, +FADH2), fumarate, malate, and back to oxaloacetate (+NADH). Per acetyl-CoA: 3 NADH, 1 FADH2, 1 GTP, 2 CO2. The TCA cycle serves both catabolic and anabolic roles: intermediates are withdrawn as biosynthetic precursors (anaplerosis replenishes them, e.g., pyruvate carboxylase converts pyruvate → oxaloacetate).

Gluconeogenesis

Gluconeogenesis synthesises glucose from non-carbohydrate precursors — lactate, glycerol, and glucogenic amino acids — occurring mainly in the liver and kidney cortex. Three irreversible glycolytic steps require unique bypass enzymes: pyruvate carboxylase + PEPCK (bypass pyruvate kinase), fructose-1,6-bisphosphatase (bypass PFK-1), and glucose-6-phosphatase (bypass hexokinase; present only in liver, kidney cortex, and small intestine — explaining why only these tissues release free glucose). Gluconeogenesis costs 6 ATP equivalents per glucose and is stimulated by glucagon and cortisol, inhibited by insulin.

Glycogen Metabolism

Glycogen is a branched polymer of glucose (α-1,4 linkages, α-1,6 branches every 8–12 residues) stored in liver and muscle. Glycogen synthase extends chains; branching enzyme creates branches. Glycogen phosphorylase (rate-limiting step of glycogenolysis) cleaves glucose-1-phosphate from non-reducing ends. Hormonal regulation: glucagon/epinephrine → PKA → phosphorylase kinase → active phosphorylase a + inhibition of glycogen synthase; insulin reverses this via protein phosphatase 1.

Clinical Relevance

Type 2 diabetes involves insulin resistance in peripheral tissues and inappropriate hepatic gluconeogenesis, elevating blood glucose. Glycogen storage diseases (GSDs) result from enzyme deficiencies: Pompe disease (acid alpha-glucosidase deficiency) causes lysosomal glycogen accumulation with cardiomyopathy; McArdle disease (muscle phosphorylase deficiency) causes exercise intolerance and myoglobinuria. Lactic acidosis occurs when pyruvate cannot enter the TCA cycle (thiamine deficiency/Wernicke encephalopathy, septic shock, metformin toxicity). The Warburg effect — preferential aerobic glycolysis in cancer cells — is exploited in FDG-PET tumour imaging.