Fungal ergosterol biosynthesis

Category: biosynthesis

Overview

Ergosterol is the fungal-specific membrane sterol (analog of mammalian cholesterol). Selective antifungal toxicity targets enzymes unique to fungi: azoles (fluconazole, itraconazole, voriconazole, posaconazole, ketoconazole, miconazole, clotrimazole) inhibit CYP51 (sterol-14α-demethylase) — depleting ergosterol + accumulating toxic 14α-methylsterols. Off-target hit on mammalian CYP3A4 explains the massive DDI surface for systemic azoles (itraconazole 20× midazolam AUC, etc.). Terbinafine + allylamines inhibit squalene epoxidase upstream → toxic squalene buildup. Hydroxypyridones (ciclopirox) chelate Fe/Al cofactors of multiple fungal enzymes. Polyenes (amphotericin B, nystatin) bind ergosterol directly → membrane pores.

Organ Systems

• integumentary
• immune-hematologic

Pathway Steps

1. lanosterol → ergosterol — via CYP51 (sterol-14α-demethylase) + downstream desaturases/reductases; azole-blockade target. Fungi convert lanosterol to ergosterol — their characteristic membrane sterol (the fungal analog of cholesterol) — via steps including CYP51 (14α-demethylase). Azole antifungals inhibit CYP51, and this fungal-specific sterol is what gives antifungals selectivity over human cells.
2. squalene → lanosterol — via squalene epoxidase + lanosterol synthase; terbinafine blocks the epoxidase step. Earlier in the pathway, squalene is epoxidized (squalene epoxidase) and cyclized to lanosterol. Allylamines (terbinafine) inhibit squalene epoxidase, both depleting ergosterol and accumulating toxic squalene — a fungicidal action used for dermatophyte infections.

Known Modulators

• itraconazole (inhibitor) — fungal CYP51 (+ mammalian CYP3A4 strong). systemic azole; canonical CYP3A4 perpetrator authored Wave 2a v1.1 (triazolam 27×, lovastatin 20× — contraindicated); HFrEF contraindication
• voriconazole (inhibitor) — fungal CYP51 (+ CYP3A4). invasive aspergillosis first-line; CYP2C19 polymorphic clearance + CYP3A4 perpetrator (multi-DDI authored — sirolimus 11× AUC contraindicated, omeprazole 4×)
• posaconazole (inhibitor) — fungal CYP51 (+ CYP3A4). broadest azole spectrum (Mucor + Zygomyces); food + low gastric pH required for tablet absorption (delayed-release formulation)
• terbinafine (inhibitor) — fungal squalene epoxidase. allylamine; onychomycosis first-line; CYP2D6 inhibitor (DDI authored Wave 2a v1.1: desipramine 5×); hepatotoxicity baseline LFTs
• clotrimazole (inhibitor) — fungal CYP51 (topical/oral azole). topical for cutaneous candidiasis + tinea; oral troches for oropharyngeal thrush
• miconazole (inhibitor) — fungal CYP51. topical/intravaginal azole; minimal systemic absorption from intravaginal route (local-acting)
• ciclopirox (inhibitor) — fungal Fe/Al-cofactor enzymes (broad). hydroxypyridone; topical nail lacquer for onychomycosis (poor PK as nail-penetration is the limit)
• efinaconazole (inhibitor) — fungal CYP51 (topical). topical onychomycosis solution; superior nail penetration vs ciclopirox

References

• PMID 21321146