Cholesterol biosynthesis I — sterol commitment (squalene -> lanosterol); FDFT1/SQLE/LSS

The sterol-commitment segment of cholesterol biosynthesis converts the isoprenoid intermediate farnesyl diphosphate into the first cyclic sterol, lanosterol, committing carbon away from the branched isoprenoid pool (dolichol, ubiquinone, prenylation) and irreversibly toward sterols. Squalene synthase (FDFT1) performs the first committed step: a reductive head-to-head condensation of two farnesyl-diphosphate molecules (via presqualene diphosphate) to the C30 hydrocarbon squalene. Squalene monooxygenase / epoxidase (SQLE), an FAD flavoprotein and the second rate-limiting, cholesterol-feedback- regulated enzyme of the pathway, oxidises squalene to (S)-2,3-epoxysqualene using O2 and NADPH. Lanosterol synthase (LSS, oxidosqualene cyclase) then carries out the remarkable polycyclization of 2,3-epoxysqualene to lanosterol, the tetracyclic sterol scaffold from which cholesterol (and, in other tissues, downstream sterols) is made by the post-lanosterol demethylation/reduction steps. All three enzymes are endoplasmic-reticulum-membrane proteins. Inherited defects: FDFT1 deficiency (squalene synthase deficiency, a congenital cholesterol-biosynthesis disorder with dysmorphism/developmental delay) and LSS mutations (hypotrichosis with juvenile cataract / congenital cataract, and a palmoplantar keratoderma); SQLE is a validated antifungal/anticancer drug target rather than a Mendelian-disease gene.