Category: biosynthesis
Where omega_fatty_acid_metabolism covers the clinical-effect arm (cardio outcomes, anti-inflammation), this pathway covers the *biosynthetic* arm — how the two essential 18-carbon precursors (ALA, n-3; LA, n-6) elongate + desaturate into the bioactive long-chain PUFAs (EPA, DHA, AA). The key kinetic insight: ALA + LA SHARE the same Δ6-desaturase (FADS2) + elongase (ELOVL5) + Δ5-desaturase (FADS1) enzymes — they compete competitively. High dietary LA (modern Western diet, seed-oil heavy) saturates Δ6-desaturase → very low ALA → EPA conversion (typically <5% in humans, <0.5% to DHA). Step 1: ALA → 18:4n-3 via FADS2 (Δ6-desaturase, the rate-limiting step for both arms). Step 2: 18:4n-3 → 20:4n-3 via ELOVL5 elongation. Step 3: 20:4n-3 → EPA (20:5n-3) via FADS1 (Δ5-desaturase). Step 4: EPA → DPA (22:5n-3) → 24:6n-3 → DHA (22:6n-3) via Sprecher pathway (further elongation + Δ6-desaturation + peroxisomal β-oxidation chain shortening). Step 5 (parallel n-6): LA → GLA → DGLA → AA via the same Δ6, ELOVL5, Δ5 enzymes. Therapeutic implication: direct EPA/DHA supplementation bypasses the rate-limiting Δ6 step → much more efficient than ALA supplementation for raising tissue n-3 content; GLA supplementation (borage, evening primrose) bypasses Δ6 on the n-6 side → raises DGLA → PGE1 (anti-inflammatory) without raising AA (most of the AA flux goes via 1-series prostaglandin precursor anyway). FADS1/FADS2 SNPs (rs174537, rs174546) explain large interindividual variation in conversion efficiency — populations with high-LA dietary history (most Western Europeans) carry "fast" variants; populations with marine diet (Inuit, Greenland) carry "slow" variants. Cross-links: [[omega_fatty_acid_metabolism]], [[arachidonic_acid_cascade]], [[nrf2_keap1_antioxidant_response]] (PUFA peroxidation produces electrophiles that activate Nrf2).