lanosterol
Summary
Lanosterol is a tetracyclic triterpenoid that serves as the first sterol intermediate in cholesterol biosynthesis, formed from squalene via squalene epoxide cyclization. It is a key precursor from which cholesterol is synthesized through a series of demethylation and reduction reactions.
Detail
Lanosterol biosynthesis pathway: Acetyl-CoA → HMG-CoA → mevalonate → isopentenyl pyrophosphate (IPP) → squalene → squalene epoxide (via squalene epoxidase, O2-dependent) → lanosterol (via squalene epoxidase/lanosterol synthase, a cyclization step). Lanosterol is then converted to cholesterol through approximately 19 additional enzymatic steps involving demethylation (removal of three methyl groups), double bond migration, and reduction reactions, occurring primarily in the smooth endoplasmic reticulum.
Clinical significance: Lanosterol synthase and downstream enzymes are targets of interest in cholesterol-lowering and antifungal therapy. In fungi, lanosterol is converted to ergosterol (the fungal membrane sterol analogous to cholesterol) via a different pathway. Azole antifungals (fluconazole, ketoconazole, itraconazole) inhibit lanosterol 14-α-demethylase (a cytochrome P450 enzyme, CYP51), blocking conversion of lanosterol to ergosterol, which disrupts fungal cell membrane integrity—this is a classic USMLE pharmacology point distinguishing fungal vs. human sterol pathways.
Additionally, lanosterol has been studied experimentally for its potential to reverse cataract formation by disaggregating crystallin protein aggregates in the lens, an area of ongoing research interest.
Key enzyme to remember: HMG-CoA reductase (rate-limiting step, target of statins) acts upstream of lanosterol, while CYP51 (lanosterol demethylase) is the azole antifungal target downstream in fungi.
Sources
- First Aid for the USMLE Step 1
- Lippincott's Illustrated Reviews: Biochemistry
- Katzung's Basic and Clinical Pharmacology
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
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