A unique mechanism involving cocatalysis of enzyme and nonenzyme to form β-carboline and spirotryprostatins in Aspergillus fumigatus.

Authors

Hai Gao, Deng Yu, Qiao Luo, Yanan Wang, Ling Lu, Weiming Zhu, Yi Wang

Published in

Science advances. Volume 11. Issue 41. Pages eadz2319. Oct 10, 2025. Epub Oct 10, 2025.

Abstract

Environmental stress represents an effective strategy for discovering natural products from microorganisms, but the processes involved remain unclear. Under acidic conditions, a previously unidentified class of β-carbolines (βCs), termed secofumitremorgins (SFs), with potent antiangiogenic activity in zebrafish models was found and identified via nuclear magnetic resonance, Marfey's analysis, and quantum calculations. Using gene knockout, heterologous expression, precursor feeding, isotope tracing, molecular docking, and site-directed mutagenesis, a unique biosynthetic pathway for SFs was characterized, beyond the Pictet-Spenglerase-mediated biosynthetic process. Furthermore, an unreported pH-regulated mechanism was unveiled, where P450 (FtmG) facilitated new fumitremorgin intermediate formation, enabling spontaneous, nonenzymatic generation of βCs and spirotryprostatins under distinct pH conditions. Notably, this work provides detailed experimental evidence and reaction mechanisms for synergistic enzymatic and nonenzymatic catalysis driving metabolite diversification under pH stress. The findings expand biosynthetic paradigms for indole alkaloids and highlight the therapeutic potential of pH-elicited βCs, advancing strategies for natural product discovery.

PMID:
41071895
Bibliographic data and abstract were imported from PubMed on 11 Oct 2025.

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