A flavin-monooxygenase catalyzing oxepinone formation and the complete biosynthesis of vibralactone

Ke-Na Feng, Yue Zhang, Mingfang Zhang, Yan-Long Yang, Ji-Kai Liu, Lifeng Pan () and Ying Zeng ()
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Ke-Na Feng: Chinese Academy of Sciences
Yue Zhang: Chinese Academy of Sciences
Mingfang Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yan-Long Yang: Chinese Academy of Sciences
Ji-Kai Liu: South-Central Minzu University
Lifeng Pan: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ying Zeng: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Oxepinone rings represent one of structurally unusual motifs of natural products and the biosynthesis of oxepinones is not fully understood. 1,5-Seco-vibralactone (3) features an oxepinone motif and is a stable metabolite isolated from mycelial cultures of the mushroom Boreostereum vibrans. Cyclization of 3 forms vibralactone (1) whose β-lactone-fused bicyclic core originates from 4-hydroxybenzoate, yet it remains elusive how 4-hydroxybenzoate is converted to 3 especially for the oxepinone ring construction in the biosynthesis of 1. In this work, using activity-guided fractionation together with proteomic analyses, we identify an NADPH/FAD-dependent monooxygenase VibO as the key enzyme performing a crucial ring-expansive oxygenation on the phenol ring to generate the oxepin-2-one structure of 3. The crystal structure of VibO reveals that it forms a dimeric phenol hydroxylase-like architecture featured with a unique substrate-binding pocket adjacent to the bound FAD. Computational modeling and solution studies provide insight into the likely VibO active site geometry, and suggest possible involvement of a flavin-C4a-OO(H) intermediate.

Date: 2023
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DOI: 10.1038/s41467-023-39108-x

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