## Hemoglobin S Structure **Key Point:** Hemoglobin S results from a single nucleotide substitution in the β-globin gene (GAG → GTG), causing glutamic acid (a hydrophilic, negatively charged amino acid) to be replaced by valine (a hydrophobic amino acid) at position 6 of the β-globin chain. ### Molecular Basis - **Codon change:** GAG (glutamic acid) → GTG (valine) - **Position:** 6th amino acid of β-globin - **Chemical consequence:** Loss of negative charge and increased hydrophobicity - **Polymerization result:** Under low oxygen tension, deoxygenated HbS molecules polymerize due to hydrophobic interactions between valine residues on adjacent molecules ### Clinical Significance - This single amino acid change causes the entire pathophysiology of sickle cell disease - The polymerized HbS distorts RBCs into the characteristic sickle shape - Leads to hemolysis, vaso-occlusion, and tissue infarction **High-Yield:** This is the most commonly tested mutation in hemoglobin disorders. The glutamic acid → valine substitution at β6 is pathognomonic for HbS. **Mnemonic:** **GALS** — Glutamic Acid to valine at position 6 in Sickle hemoglobin (remember: Loss of negative charge → Sickling).
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