21.2 Carbohydrate Metabolism

Glycolysis

Glycolysis is the cytosolic pathway that converts one molecule of glucose (6C) to two molecules of pyruvate (3C), yielding a net 2 ATP (4 produced, 2 consumed) and 2 NADH. It proceeds in two phases: the energy-investment phase (hexokinase, phosphoglucose isomerase, phosphofructokinase-1, aldolase, triose phosphate isomerase) consumes 2 ATP; the energy-payoff phase (glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, phosphoglycerate mutase, enolase, pyruvate kinase) produces 4 ATP and 2 NADH.

Regulation of Glycolysis

Three rate-limiting, irreversible steps control glycolytic flux:

1. Hexokinase / glucokinase — hexokinase has low Km and is inhibited by its product glucose-6-phosphate (feedback); glucokinase (liver, pancreas) has high Km, is inducible by insulin, and is not product-inhibited, allowing the liver to buffer postprandial glucose.
2. Phosphofructokinase-1 (PFK-1) — the principal rate-limiting enzyme. PFK-1 is activated by fructose-2,6-bisphosphate (F2,6BP) and AMP; inhibited by ATP and citrate. F2,6BP is produced by PFK-2, a bifunctional enzyme whose kinase domain is activated by insulin (dephosphorylated) and phosphatase domain by glucagon (phosphorylated).
3. Pyruvate kinase — activated by fructose-1,6-bisphosphate (feed-forward), inhibited by ATP, alanine; the liver isozyme is inactivated by glucagon-mediated phosphorylation.

Under anaerobic conditions, pyruvate is reduced to lactate by lactate dehydrogenase, regenerating NAD+ so glycolysis continues. In aerobic conditions, pyruvate enters mitochondria for oxidation via pyruvate dehydrogenase and the TCA cycle.

Gluconeogenesis

Gluconeogenesis synthesizes glucose from non-carbohydrate precursors (lactate, glycerol, alanine and other gluconeogenic amino acids, propionyl-CoA) primarily in the liver and, during prolonged fasting, the kidney. It reverses glycolysis except at three irreversible steps, which require separate bypass enzymes:

• Pyruvate → oxaloacetate (pyruvate carboxylase, biotin-dependent, activated by acetyl-CoA), then oxaloacetate → phosphoenolpyruvate (PEPCK)
• Fructose-1,6-bisphosphate → fructose-6-phosphate (fructose-1,6-bisphosphatase, inhibited by AMP and F2,6BP)
• Glucose-6-phosphate → glucose (glucose-6-phosphatase, ER-localized; absent in muscle, explaining why muscle glycogen cannot directly raise blood glucose)

Two ATP and two GTP are consumed per molecule of glucose synthesized (six high-energy phosphates total). Gluconeogenesis is upregulated by glucagon and glucocorticoids and downregulated by insulin. The Cori cycle trades muscle lactate to the liver for glucose; the glucose-alanine cycle transports amino nitrogen from muscle to liver as alanine, which is transaminated to pyruvate for gluconeogenesis.

Glycogen Metabolism

Glycogen, the storage form of glucose, is a branched α-1,4-linked glucose polymer with α-1,6 branches every ~8–12 residues. Liver glycogen (≈100 g) maintains blood glucose; muscle glycogen (≈400 g) fuels muscle contraction.

Glycogenesis is catalyzed by glycogen synthase (α-1,4 linkages) and the branching enzyme. Glycogen synthase is activated by insulin (dephosphorylation) and by glucose-6-phosphate allosterically. Glycogenolysis uses glycogen phosphorylase (α-1,4 cleavage to glucose-1-phosphate) and the debranching enzyme. Glycogen phosphorylase is activated by glucagon (liver) and epinephrine (muscle) via the cAMP/PKA phosphorylation cascade and by AMP (muscle). Inherited defects cause disease: McArdle disease (muscle glycogen phosphorylase deficiency → exercise intolerance, myoglobinuria); Pompe disease (lysosomal acid α-glucosidase deficiency → lysosomal glycogen accumulation, cardiomyopathy); Cori disease (debranching enzyme deficiency); von Gierke disease (glucose-6-phosphatase deficiency → severe fasting hypoglycemia, hepatomegaly, lactic acidosis).

Pentose Phosphate Pathway

The pentose phosphate pathway (PPP), operating in the cytosol, branches from glucose-6-phosphate and serves two purposes: generating NADPH (for reductive biosynthesis and antioxidant defense) and ribose-5-phosphate (for nucleotide synthesis). The oxidative phase uses glucose-6-phosphate dehydrogenase (G6PD, the rate-limiting step, NADP+-dependent), lactonase, and 6-phosphogluconate dehydrogenase to produce 2 NADPH, CO2, and ribulose-5-phosphate. The non-oxidative phase interconverts sugars via transketolase (thiamine-dependent) and transaldolase. G6PD deficiency, the most common enzyme deficiency worldwide, limits NADPH production; red blood cells, which rely solely on glutathione/NADPH for antioxidant defense, are vulnerable to oxidative stress from fava beans, sulfa drugs, primaquine — producing hemolytic anemia.

Galactose and Fructose Metabolism

Galactose enters glycolysis via the Leloir pathway: galactokinase → galactose-1-phosphate → (via galactose-1-phosphate uridyltransferase, GALT) UDP-galactose, which interconverts with UDP-glucose. Classic galactosemia (GALT deficiency) causes hepatomegaly, jaundice, cataracts, and intellectual disability; galactokinase deficiency produces cataracts only. Fructose enters glycolysis in the liver via fructokinase → fructose-1-phosphate → (aldolase B) dihydroxyacetone phosphate + glyceraldehyde; this bypasses PFK-1, the main regulatory point. Hereditary fructose intolerance (aldolase B deficiency) causes accumulation of fructose-1-phosphate, trapping phosphate and causing hypoglycemia and liver damage. Fructose metabolism also bypasses phosphofructokinase regulation and contributes to lipogenesis, which is why high fructose intake promotes fatty liver. The PA-CAT Bulletin of Information, rev. 20240815, lists Carbohydrate Metabolism within the Biochemistry blueprint; hormonal regulation (insulin/glucagon) of these pathways is a high-yield topic.