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).
Organ Systems
cardiovascular
nervous
digestive
Pathway Steps
α-linolenic acid (ALA, 18:3n-3) → 18:4n-3 — via FADS2 / Δ6-desaturase — RATE-LIMITING for both n-3 and n-6 arms. Δ6-desaturase (FADS2) is the rate-limiting first step shared by BOTH the n-3 and n-6 families, so ALA and linoleic acid compete for it — high dietary LA (Western seed oils) throttles ALA→EPA/DHA conversion, and FADS variants strongly shape endogenous PUFA status.
18:4n-3 → eicosatetraenoic acid (20:4n-3) — via ELOVL5 elongation. ELOVL5 elongates by two carbons. The whole elongation/desaturation chain is slow in humans, so endogenous EPA/DHA synthesis from plant ALA is limited (often <5–10%) — the rationale for preformed marine EPA/DHA.
eicosatetraenoic acid (20:4n-3) → EPA (20:5n-3) — via FADS1 / Δ5-desaturase. Δ5-desaturase (FADS1) makes EPA, substrate for the less-inflammatory series-3 eicosanoids and resolvins. FADS1/2 sit in a gene cluster whose variants explain much of the inter-individual difference in EPA/DHA levels and fish-oil response.
EPA (20:5n-3) → DHA (22:6n-3) — via Sprecher pathway: ELOVL5 → 24:5n-3 → FADS2 → 24:6n-3 → peroxisomal β-oxidation → DHA. DHA synthesis is roundabout (the Sprecher pathway): elongation to 24:6n-3 then peroxisomal β-oxidation back to 22:6n-3 — humans have no direct Δ4-desaturase. This further limits endogenous DHA, which is critical for brain and retina.
linoleic acid (LA, 18:2n-6) → γ-linolenic acid (GLA, 18:3n-6) — via FADS2 / Δ6-desaturase (same enzyme as n-3 arm; competitive). The n-6 arm uses the same Δ6-desaturase as n-3 (the point of competition). This step is often cited as limiting, the basis for GLA-supplying oils (evening primrose, borage) that bypass it.
GLA (18:3n-6) → dihomo-γ-linolenic acid (DGLA, 20:3n-6) — via ELOVL5 elongation; DGLA → series-1 (anti-inflammatory) prostaglandins. ELOVL5 elongates GLA to DGLA, precursor of the series-1 (anti-inflammatory) prostaglandin PGE1 — so DGLA is an anti-inflammatory node, balanced against its onward conversion to arachidonic acid.
DGLA (20:3n-6) → arachidonic acid (AA, 20:4n-6) — via FADS1 / Δ5-desaturase — AA enters arachidonic_acid_cascade as PG/LT substrate. Δ5-desaturase makes arachidonic acid, which feeds the pro-inflammatory eicosanoid cascade (see arachidonic_acid_cascade). The dietary n-3:n-6 ratio shifts membrane AA vs EPA and thus the inflammatory tone of eicosanoid signaling.
Known Modulators
ala (substrate) — n-3 arm entry — Δ6-desaturase substrate. Endogenous conversion to EPA <5%, to DHA <0.5% — direct supplementation poorly efficient