Linking Biomolecule Structure to Disease

Sickle Cell Anaemia — Primary Structure Mutation:

Normal HbA: beta-chain position 6 = Glutamate (Glu, polar, charged at pH 7) Sickle HbS: beta-chain position 6 = Valine (Val, non-polar, hydrophobic)

Single amino acid substitution (Glu → Val) changes:

• Primary structure → altered surface properties
• Deoxygenated HbS polymerises (Val creates hydrophobic patch) → rigid fibres → sickle-shaped RBCs
• Demonstrates: primary structure entirely determines protein function

Lactose Intolerance — Enzyme Deficiency:

Missing: Lactase (beta-galactosidase) in brush border of small intestine Substrate: Lactose (beta-1,4 Gal-Glc disaccharide) Consequence: Undigested lactose → colonic fermentation → $CO_{2}$ + $H_{2}$ gas + organic acids → bloating, cramps, osmotic diarrhoea

Phenylketonuria (PKU) — Amino Acid Metabolism:

Missing enzyme: Phenylalanine hydroxylase (PAH) Result: Phenylalanine accumulates → phenylpyruvate → intellectual disability if untreated Treatment: Low-Phe diet from birth

Galactosaemia — Monosaccharide Metabolism:

Missing: Galactose-1-phosphate uridylyltransferase Result: Galactose-1-phosphate accumulates → liver damage, intellectual disability, cataracts Source: Galactose from lactose in milk Treatment: Lactose-free diet

Beriberi/Niacin linking carbohydrate metabolism:

Thiamine (B1) → TPP → pyruvate dehydrogenase → acetyl-CoA → Krebs cycle Niacin (B3) → N$AD^{+}$ → electron carrier in Krebs cycle and glycolysis Deficiency of either → energy crisis in high-demand tissues (nervous system, heart)