Master Biochemistry
for PMDC NLE Step 1

Core Concepts

Biochemistry is the study of the chemical processes within living organisms. For NLE Step 1, focus on medically relevant aspects including metabolism, enzymes, molecular biology, and nutrient roles.

• Macromolecules:
  • Carbohydrates: Glucose metabolism (Glycolysis, TCA cycle, Gluconeogenesis, Glycogenesis, Glycogenolysis, Pentose Phosphate Pathway). Understand key regulatory enzymes (e.g., PFK-1, FBPase-1, Glycogen Synthase, Glycogen Phosphorylase).
  • Lipids: Fatty acid synthesis & beta-oxidation, cholesterol synthesis & regulation (HMG-CoA Reductase), lipoprotein metabolism (VLDL, LDL, HDL, chylomicrons, receptors). Ketone body synthesis & utilization.
  • Proteins & Amino Acids: Protein structure (primary to quaternary), protein synthesis (translation), amino acid metabolism (synthesis, degradation, Urea Cycle for nitrogen disposal), essential vs. non-essential AAs.
  • Nucleic Acids: DNA structure, replication (DNA polymerases, ligase, helicase), transcription (RNA polymerases, promoters, enhancers), translation (ribosomes, tRNAs, genetic code, start/stop codons). DNA repair mechanisms.
• Enzymes: Catalytic function, active site, enzyme kinetics (Michaelis-Menten: Km, Vmax), types of inhibition (competitive, non-competitive, uncompetitive, irreversible), allosteric regulation, cofactors & coenzymes (vitamins).
• Metabolism & Energy: ATP as energy currency, Electron Transport Chain & Oxidative Phosphorylation (components, inhibitors, uncouplers), integration of metabolic pathways (fed vs. fasted state), hormonal regulation (Insulin, Glucagon, Cortisol, Thyroid hormones).
• Molecular Biology: Central Dogma, gene expression regulation (transcriptional, post-transcriptional, translational, post-translational), mutations (point, frameshift, missense, nonsense), epigenetics basics.
• Vitamins & Minerals: Roles of fat-soluble (A, D, E, K) and water-soluble (B complex, C) vitamins, trace minerals (Fe, Zn, Cu, Se, I). Deficiencies and toxicities.

Clinical Presentation

• Inborn Errors of Metabolism (IEMs): Variable presentations from neonatal to adult life. Often involve developmental delay, neurological dysfunction (seizures, lethargy), organomegaly, feeding difficulties, hypotonia, specific odors (e.g., maple syrup urine disease), or pigment changes. Examples: Phenylketonuria (PKU), Glycogen Storage Diseases (GSDs), Lysosomal Storage Diseases (LSDs), Urea Cycle Disorders, Fatty Acid Oxidation Defects.
• Nutritional Deficiencies:
  • Vitamin A: Night blindness, xerophthalmia.
  • Vitamin D: Rickets (children), osteomalacia (adults).
  • Vitamin C: Scurvy (bleeding gums, poor wound healing).
  • Thiamine (B1): Beriberi (cardiac, neurological).
  • Niacin (B3): Pellagra (dermatitis, diarrhea, dementia).
  • Iron: Microcytic hypochromic anemia, fatigue.
• Endocrine Disorders: Metabolic dysregulation. E.g., Diabetes Mellitus (hyperglycemia, polyuria, polydipsia, weight loss), Hypothyroidism (fatigue, weight gain, bradycardia).
• Mitochondrial Disorders: Multisystemic, often neurological & muscular symptoms, lactic acidosis.

Diagnosis (Gold Standard)

Diagnosis relies on identifying abnormal metabolites or enzyme activities.

• Metabolite Screening: Plasma amino acids, urine organic acids, acylcarnitine profile (tandem mass spectrometry for IEMs).
• Enzyme Assays: Specific enzyme activity measurement in patient samples (e.g., fibroblasts, leukocytes, liver biopsy) for GSDs, LSDs, etc.
• Genetic Testing: DNA sequencing for specific gene mutations associated with IEMs or other genetic conditions affecting biochemical pathways.
• Biochemical Challenges: Oral glucose tolerance test (diabetes), protein loading tests (urea cycle disorders).
• Specific Biomarkers: Blood glucose, HbA1c (diabetes), thyroid hormones, liver enzymes, lipids (cholesterol, triglycerides), ammonia (urea cycle disorders), lactate (mitochondrial disorders).

Management (First Line)

Management is specific to the biochemical defect, aiming to restore metabolic balance.

• Dietary Modification: Restriction of substrate (e.g., phenylalanine in PKU, galactose in galactosemia), supplementation of deficient products, or specific nutrients.
• Cofactor/Vitamin Supplementation: High-dose vitamins for cofactor-responsive IEMs (e.g., biotin for biotinidase deficiency, B6 for homocystinuria).
• Enzyme Replacement Therapy (ERT): For certain Lysosomal Storage Diseases (e.g., Gaucher, Fabry).
• Substrate Reduction Therapy: To decrease production of toxic metabolites.
• Symptomatic & Supportive Care: To manage complications (e.g., anticonvulsants for seizures, diuretics for edema).
• Detoxification: Ammonia scavengers (e.g., sodium benzoate, sodium phenylacetate) for urea cycle disorders.

Exam Red Flags