Master Biochemistry & Nutrition
for USMLE Step 1

Core Concepts

Biochemistry and Nutrition for USMLE Step 1 primarily focuses on metabolic pathways, enzyme regulation, and the role of vitamins and minerals. Understanding these processes is crucial for diagnosing and managing metabolic disorders.

• Carbohydrate Metabolism:
  • Glycolysis: Glucose to pyruvate; key regulated enzyme is PFK-1. Produces ATP, NADH.
  • Gluconeogenesis: Pyruvate to glucose (liver); key regulated enzyme is Fructose-1,6-bisphosphatase. Requires ATP, GTP.
  • Glycogen Metabolism: Synthesis (Glycogenesis, Glycogen Synthase) and breakdown (Glycogenolysis, Glycogen Phosphorylase). Regulated by insulin/glucagon.
  • Pentose Phosphate Pathway (PPP): Produces NADPH (for reductive reactions, e.g., glutathione reduction, fatty acid synthesis) and ribose-5-phosphate (nucleotide synthesis). Key enzyme is Glucose-6-phosphate Dehydrogenase (G6PD).
  • Metabolic Disorders:
    • Glycogen Storage Diseases (GSDs): e.g., Type I (Von Gierke – G6Pase def), Type II (Pompe – lysosomal α-glucosidase def), Type V (McArdle – muscle glycogen phosphorylase def).
    • Fructose Intolerance: Aldolase B deficiency.
    • Galactosemia: Galactose-1-phosphate Uridyltransferase (GALT) deficiency.
• Lipid Metabolism:
  • Fatty Acid Oxidation (β-oxidation): Produces Acetyl-CoA, NADH, FADH2. Carnitine shuttle required for long-chain fatty acids into mitochondria.
  • Fatty Acid Synthesis: Occurs in cytosol, requires NADPH (from PPP), Acetyl-CoA.
  • Ketogenesis: Liver converts Acetyl-CoA to ketone bodies (β-hydroxybutyrate, acetoacetate) during fasting/starvation.
  • Cholesterol Synthesis: Rate-limiting step catalyzed by HMG-CoA Reductase.
  • Lipoprotein Metabolism: Chylomicrons (dietary fat), VLDL (endogenous fat), LDL (cholesterol delivery), HDL (reverse cholesterol transport). Key enzymes: LPL, HTGL, LCAT, CETP.
  • Disorders: Carnitine deficiency, Familial Hypercholesterolemia (LDL receptor defect), Tangier disease (ABCA1 defect).
• Amino Acid & Protein Metabolism:
  • Urea Cycle: Converts ammonia to urea (liver). Rate-limiting step: Carbamoyl Phosphate Synthetase I (CPSI).
  • Amino Acid Catabolism: Transamination, oxidative deamination. Products feed into TCA cycle or gluconeogenesis.
  • Disorders:
    • Phenylketonuria (PKU): Phenylalanine Hydroxylase deficiency.
    • Maple Syrup Urine Disease (MSUD): Branched-chain α-ketoacid dehydrogenase deficiency (valine, isoleucine, leucine).
    • Homocystinuria: Cystathionine β-synthase deficiency (most common).
    • Alkaptonuria: Homogentisate oxidase deficiency.
• Nucleotide Metabolism:
  • Purine/Pyrimidine Synthesis & Salvage pathways.
  • Disorders:
    • Gout: Hyperuricemia, often due to overproduction or underexcretion of uric acid. Can be linked to Lesch-Nyhan Syndrome (HGPRT deficiency).
• Vitamins & Minerals:
  • Fat-Soluble (ADEK):
    • A: Vision (retinal), growth, immune. Def: Night blindness, xerophthalmia.
    • D: Calcium/phosphate homeostasis. Def: Rickets (children), osteomalacia (adults).
    • E: Antioxidant. Def: Hemolytic anemia, neurological dysfunction.
    • K: Clotting factors (II, VII, IX, X), bone. Def: Bleeding diathesis.
  • Water-Soluble (B complex, C):
    • B1 (Thiamine): TPP cofactor (PDH, α-KGDH, transketolase). Def: Beriberi (wet/dry), Wernicke-Korsakoff.
    • B2 (Riboflavin): FAD, FMN cofactor. Def: Cheilosis, glossitis, corneal vascularization.
    • B3 (Niacin): NAD+, NADP+ cofactor. Def: Pellagra (3 Ds: Dermatitis, Diarrhea, Dementia).
    • B5 (Pantothenic Acid): Coenzyme A. Def: Dermatitis, enteritis, alopecia.
    • B6 (Pyridoxine): PLP cofactor (transamination, decarboxylation). Def: Convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemia.
    • B7 (Biotin): Carboxylation reactions. Def: Dermatitis, enteritis, alopecia.
    • B9 (Folate): Tetrahydrofolate (THF) cofactor (1-carbon transfers, purine/thymidine synthesis). Def: Megaloblastic anemia, neural tube defects.
    • B12 (Cobalamin): Methylmalonyl-CoA mutase, Methionine synthase. Def: Megaloblastic anemia, subacute combined degeneration.
    • C (Ascorbate): Hydroxylation (collagen synthesis), antioxidant. Def: Scurvy (bleeding gums, impaired wound healing).
  • Minerals:
    • Iron: Heme synthesis. Def: Microcytic anemia.
    • Calcium/Phosphorus: Bone, signaling. Def: Tetany, rickets/osteomalacia.
    • Iodine: Thyroid hormones. Def: Goiter, hypothyroidism.
    • Zinc: Cofactor for >100 enzymes. Def: Poor wound healing, dysgeusia, impaired immunity.
    • Copper: Cofactor (cytochrome c oxidase, lysyl oxidase). Def: Anemia, neurological issues. Wilson's disease (copper overload).
• Enzyme Kinetics:
  • Michaelis-Menten: Km (affinity), Vmax (max rate).
  • Inhibition: Competitive (↑Km, Vmax unchanged), Noncompetitive (↓Vmax, Km unchanged), Uncompetitive (↓Km, ↓Vmax).

Clinical Presentation

• Hypoglycemia +/- Hepatomegaly: GSDs (especially Type I), Fructose intolerance, Galactosemia.
• Developmental Delay, Seizures, Intellectual Disability: PKU, MSUD, Homocystinuria, Urea Cycle Disorders.
• Acidosis (Metabolic): Lactic acidosis (PDH def, GSD I, severe hypoxia), Ketoacidosis (MSUD), Propionic/Methylmalonic acidemia.
• Hyperammonemia: Urea Cycle Disorders, Liver failure.
• Cataracts, Jaundice, Hepatomegaly, Vomiting (infant): Galactosemia.
• Dark Urine/Diapers: Alkaptonuria (turns black on standing).
• Neurological Symptoms: Vitamin B1, B6, B12 deficiencies, MSUD, Homocystinuria, Wilson's disease.
• Anemia: Iron, B6, B9, B12 deficiencies, G6PD deficiency (hemolytic).
• Bleeding/Bruising: Vitamin K, C deficiencies.
• Bone Deformities/Pain: Vitamin D deficiency (Rickets/Osteomalacia).
• Dermatitis, Diarrhea, Dementia: Niacin (B3) deficiency (Pellagra).
• Gums (Swollen, Bleeding): Vitamin C deficiency (Scurvy).
• Night Blindness, Dry Eyes: Vitamin A deficiency.

Diagnosis (Gold Standard)

Diagnosis typically involves a combination of biochemical tests and genetic confirmation.

• Newborn Screening: Tandem mass spectrometry for amino acidopathies (PKU, MSUD), organic acidemias, fatty acid oxidation disorders.
• Enzyme Activity Assay: Direct measurement of deficient enzyme in fibroblasts, lymphocytes, or specific tissues (e.g., muscle biopsy for McArdle's).
• Genetic Testing: Confirmatory for most inherited metabolic disorders.
• Urine Organic Acids: Elevated specific metabolites (e.g., phenylpyruvate in PKU, branched-chain keto acids in MSUD).
• Plasma Amino Acids: Elevated specific amino acids (e.g., phenylalanine in PKU, ammonia in urea cycle defects).
• Acylcarnitine Profile: For fatty acid oxidation disorders and organic acidemias.
• Liver Biopsy: For definitive diagnosis of certain GSDs (e.g., Von Gierke).
• Schilling Test: To determine cause of B12 deficiency (pernicious anemia vs. malabsorption).

Management (First Line)

Management strategies are highly specific to the disorder and often involve dietary modification, supplementation, and supportive care.

• Dietary Restriction:
  • PKU: Low-phenylalanine diet.
  • MSUD: Restriction of branched-chain amino acids (leucine, isoleucine, valine).
  • Galactosemia/Fructose Intolerance: Avoidance of galactose/fructose.
  • Urea Cycle Disorders: Low-protein diet, nitrogen scavengers (e.g., sodium phenylacetate).
• Enzyme Replacement Therapy (ERT): Available for some lysosomal storage diseases (e.g., Pompe disease).
• Vitamin/Cofactor Supplementation:
  • Vitamin deficiencies: Oral or parenteral replacement (e.g., B12 for pernicious anemia).
  • Homocystinuria: High-dose B6, B9, B12.
  • PDH Deficiency: High-dose thiamine (B1).
• Symptomatic/Supportive Care: Management of acute crises (e.g., hyperammonemia, metabolic acidosis).
• Avoidance of Triggers: For G6PD deficiency, avoid oxidant drugs (e.g., primaquine, sulfa drugs).

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