Physiological and Biochemical Pathways
This domain tests the mechanistic base beneath clinical decisions: how fuel becomes ATP, how one-carbon metabolism links B vitamins to methylation, how biotransformation phases handle xenobiotics, and how fatty acid balance shapes inflammation.
Energy and macronutrient pathways
- Glycolysis nets 2 ATP and 2 NADH per glucose; pyruvate dehydrogenase (thiamine-dependent) feeds acetyl-CoA into the TCA cycle, which yields NADH/FADH2 for oxidative phosphorylation, roughly 30–32 ATP per glucose.
- Fatty acid beta-oxidation generates acetyl-CoA; hepatic ketogenesis via HMG-CoA synthase produces acetoacetate, beta-hydroxybutyrate, and acetone, which spare glucose for the brain during fasting.
- Gluconeogenesis draws on glycerol, lactate (Cori cycle), and glucogenic amino acids; fatty acids cannot be converted to glucose except for odd-chain fatty acids.
- The urea cycle clears nitrogen; B6 and biotin-dependent carboxylases are common exam targets.
One-carbon metabolism and methylation
Methionine synthase needs B12 and folate to convert homocysteine to methionine, generating SAMe for methylation. Elevated methylmalonic acid is specific to B12 deficiency; elevated homocysteine alone implicates folate. Serum B12 can look normal despite tissue deficiency, so use MMA or holotranscobalamin when suspicion is high.
Biotransformation and eicosanoids
Phase I cytochrome P450 oxidation can create reactive intermediates; phase II conjugation (glucuronidation, sulfation, glutathione conjugation, methylation) increases water solubility for excretion. Cruciferous vegetables induce CYP1A2. Omega-6 arachidonic acid yields pro-inflammatory series-2 prostaglandins and series-4 leukotrienes; EPA shifts production toward series-3 prostanoids and resolvins through competition for desaturases.
Worked example
A patient has homocysteine 22 micromol/L, serum B12 350 pg/mL, and methylmalonic acid 0.9 micromol/L. Because MMA is elevated, tissue B12 deficiency is present despite the unremarkable serum B12, so treat with B12 and reassess. If MMA were normal, the isolated hyperhomocysteinemia would point to folate insufficiency.
Traps
Assuming a normal serum B12 excludes deficiency; treating a heterozygous MTHFR variant as a disease requiring methylfolate; confusing nutritional ketosis with ketoacidosis; mixing up NADH and NAD+ in redox steps; ignoring thiamine before glucose loading in malnourished patients.