Master Biochemistry
for FMGE

Core Concepts

Biochemistry is the study of chemical processes within and relating to living organisms. It underpins all physiological functions and disease states. High-yield areas for FMGE include:

• Carbohydrate Metabolism:
  • Glycolysis: Glucose → Pyruvate. Energy production. Key enzyme: PFK-1. Aerobic vs. Anaerobic metabolism (Lactate).
  • Gluconeogenesis: Non-carb precursors → Glucose (liver, kidney). Activated by glucagon, cortisol. Imp. enzymes: Pyruvate carboxylase, PEPCK, F-1,6-BPase, G-6-Phosphatase.
  • Glycogenesis & Glycogenolysis: Synthesis/breakdown of glycogen. Regulated by insulin/glucagon. GSDs – e.g., Von Gierke (G-6-Pase), McArdle (Muscle Glycogen Phosphorylase).
  • HMP Shunt (Pentose Phosphate Pathway): Produces NADPH (reductive biosynthesis, antioxidant) and Ribose-5-Phosphate. Key enzyme: G-6-PD. G6PD deficiency: Hemolytic anemia with oxidant stress.
  • TCA Cycle (Krebs Cycle): Central hub for aerobic metabolism, generates ATP, NADH, FADH2.
  • Fructose & Galactose Metabolism: Inborn errors include Hereditary Fructose Intolerance (aldolase B def), Galactosemia (GALT def).
• Lipid Metabolism:
  • Fatty Acid Synthesis & Beta-oxidation: Synthesis (cytosol), Breakdown (mitochondria, Carnitine shuttle).
  • Ketone Bodies: Acetoacetate, β-hydroxybutyrate. Synthesized in liver during fasting/starvation. Diabetic Ketoacidosis (DKA).
  • Cholesterol Synthesis: Key enzyme HMG-CoA Reductase.
  • Lipoproteins: Chylomicrons, VLDL, LDL, HDL. Transport lipids. Disorders: Familial Hypercholesterolemias.
• Protein & Amino Acid Metabolism:
  • Urea Cycle: Detoxifies ammonia to urea. Disorders: Hyperammonemia.
  • Amino Acid Catabolism: Carbon skeletons feed into TCA/gluconeogenesis. Nitrogen removed via transamination/deamination.
  • Disorders: Phenylketonuria (PKU - Phenylalanine hydroxylase def), Maple Syrup Urine Disease (MSUD), Alkaptonuria (Homogentisate oxidase def).
• Nucleic Acid Metabolism:
  • Purine & Pyrimidine Synthesis/Degradation. Salvage pathways.
  • Disorders: Gout (hyperuricemia), Lesch-Nyhan syndrome (HGPRT def).
• Enzymology:
  • Enzyme Kinetics: Michaelis-Menten (Km, Vmax). Factors: pH, temp, substrate conc.
  • Inhibition: Competitive (Vmax unchanged, Km ↑), Non-competitive (Vmax ↓, Km unchanged).
  • Regulation: Allosteric, covalent modification.
• Vitamins & Minerals:
  • Fat-soluble (A, D, E, K): Functions, deficiency. Vit D (Ca/P), Vit K (clotting).
  • Water-soluble (B complex, C): Functions, deficiency. B1 (pyruvate dehydrogenase), B3 (NAD/NADP), B12 & Folate (one-carbon).
  • Minerals: Ca, P, Na, K, Mg, Fe, Cu, Zn.
• Molecular Biology:
  • DNA Replication, Transcription, Translation: Central dogma.
  • Mutations: Point, frameshift.
  • Recombinant DNA: PCR, Gel electrophoresis, Blotting (Southern-DNA, Northern-RNA, Western-Protein).
• Hormones & Signal Transduction: Insulin/Glucagon regulate blood glucose. Steroid hormones.
• Clinical Biochemistry Markers: LFTs, RFTs, Cardiac enzymes (CK-MB, Troponins), Electrolytes, ABG.

Clinical Presentation

• Often non-specific: Failure to thrive, developmental delay, neurological dysfunction (seizures, hypotonia), recurrent infections.
• Specific signs: Unusual body/urine odor (e.g., MSUD, PKU), hepatosplenomegaly, jaundice, cardiomyopathy, acidosis/alkalosis.
• Triggered by stress: Fasting, infection, certain foods/drugs can exacerbate symptoms in metabolic disorders.

Diagnosis (Gold Standard)

Primarily based on identifying abnormal metabolites or enzyme deficiencies:

• Newborn Screening (NBS): Tandem Mass Spectrometry (MS/MS) for amino acidopathies, organic acidemias, fatty acid oxidation defects.
• Specific Enzyme Assays: Confirm enzyme deficiency in affected tissues (e.g., fibroblasts, WBCs).
• Genetic Testing: Targeted gene sequencing or whole exome sequencing (WES) to identify causative mutations.
• Metabolic Panels: Plasma amino acids, urine organic acids, serum acylcarnitines, plasma lactate/ammonia, CSF studies.

Management (First Line)

Focuses on dietary modification, removing toxic substances, and supplementing deficient products:

• Dietary Restrictions: Limiting intake of problematic precursors (e.g., phenylalanine in PKU, lactose/galactose in galactosemia).
• Cofactor Supplementation: High-dose vitamins/cofactors if the enzyme defect is responsive (e.g., B6 in some homocystinurias, B12 for methylmalonic acidemia).
• Enzyme Replacement Therapy (ERT): For specific lysosomal storage disorders.
• Symptomatic Support: Addressing acute metabolic crises (e.g., IV glucose for hypoglycemia, dialysis for hyperammonemia).

Exam Red Flags