Microsomal fatty-acid elongation cycle (ELOVL -> HSD17B12 -> HACD1/2 -> TECR)

Most fatty acids longer than the C16 palmitate made by cytosolic fatty-acid synthase are produced by the microsomal elongation system, a four-reaction cycle on the cytosolic face of the endoplasmic-reticulum membrane that adds two carbons per turn. Each round begins with the rate-limiting, substrate-selective condensation of an acyl-CoA with malonyl-CoA to a 3-oxoacyl-CoA (releasing CO2), catalysed by one of seven fatty-acid elongases (ELOVL1-7) whose chain-length and saturation preferences define which fatty acids a cell makes: ELOVL1/3/6 handle saturated and monounsaturated substrates (ELOVL6 the C16->C18 lipogenic step, ELOVL1 the C22->C26 very-long-chain step for sphingolipids/myelin, ELOVL3 skin/brown-fat lipids), ELOVL2/5 the C20/C22 polyunsaturated fatty acids en route to DHA, ELOVL7 C18-C20 substrates, and ELOVL4 the unique ultra-long-chain (C26-C38) fatty acids of retina, skin and brain. The 3-oxoacyl-CoA is then reduced by the NADPH-dependent 3-ketoacyl-CoA reductase HSD17B12 (KAR) to (3R)-3-hydroxyacyl-CoA, dehydrated by the 3-hydroxyacyl-CoA dehydratases HACD1/HACD2 to (2E)-enoyl-CoA, and reduced by the NADPH-dependent trans-2-enoyl-CoA reductase TECR to the two-carbon-extended saturated acyl-CoA, which re-enters the cycle. The reductase/dehydratase/reductase enzymes are shared across all ELOVLs; substrate specificity resides in the elongase. Inherited defects span the products: ELOVL1 (IKSHD ichthyosis/spastic quadriplegia), ELOVL4 (Stargardt-like macular dystrophy, SCA34, ichthyosis), HACD1 (congenital myopathy), TECR (intellectual disability), reflecting the roles of very-long-chain and ultra-long-chain fatty acids in skin barrier, myelin, retina and muscle.