A research team led by Professor Zhang Fan from the School of Pharmaceutical Sciences at Av性爱 (WHU) has published a breakthrough study in Angewandte Chemie International Edition, revealing the biosynthetic pathway of Forazoline A, a marine-derived natural antifungal compound.
FrazP2, a cytochrome P450, catalyzes cyclohexane ring formation in the marine antifungal forazoline A via radical-mediated cyclization, paving the way for engineering novel analogues.
Known for its potent activity and unique mode of action, Forazoline A's complex biosynthesis had remained unclear, particularly the formation of its core cyclohexane ring.
Using genome mining, heterologous expression, gene knockout, and isotope labeling, the team identified three cytochrome P450 enzymes involved in the process. Among them, FrazP2 was found to catalyze the cyclization of a 1,3,6-triene precursor into the cyclohexane ring – a key step in building Forazoline A's molecular framework. High-resolution crystal structure analysis of the FrazP2–substrate complex, combined with molecular dynamics simulations and quantum chemical calculations, revealed that the enzyme mediates this noncanonical cyclization via a novel "oxidation–proton transfer–cyclization" mechanism, expanding current understanding of P450 enzyme function.
The team also engineered ring-opened Forazoline derivatives that showed four-eight times greater antifungal activity than the natural compound. These findings highlight the role of molecular flexibility in improving membrane permeability and offer promising directions for the design of next-generation antifungal drugs.
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