Trifunctional flavoenzyme-catalyzed asymmetric 4-alkyl-butenolide assembly in avenolide biosynthesis

Wenrui LiInstitute of Mechanics

Jinlian ZhaoInstitute of Mechanics

Weibo ZengYunnan University

Ruifei ZhangInstitute of Mechanics

Peng YuInstitute of Mechanics

Yuting FanInstitute of Mechanics

Jianan LiInstitute of Mechanics

Wenzhao WANGInstitute of Mechanics

Mervyn J. BibbAustralian Regenerative Medicine Institute

Shanshan ZhouInstitute of Acoustics

Nature Communications·February 7, 2026

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Abstract

Butenolides are important features of many bioactive compounds. Current petrochemical-based methods for asymmetric butenolide synthesis are unsustainable. Biocatalysis could enable cheaper, greener, and more sustainable alternatives. However, known butenolide biosynthetic pathways are complex and challenging to harness. Here we show that avenolide, a 4-alkylbutenolide that regulates avermectin production in Streptomyces avermitilis, is assembled from a fatty acyl thioester by a multifunctional flavoenzyme and an iterative cytochrome P450. The flavoenzyme catalyzes homochiral 4-alkylbutenolide formation via successive desaturation, hydroxylation, and lactonization reactions, using dioxygen as the sole stoichiometric reagent. This lays the foundation for development of sustainable biocatalytic asymmetric butenolide synthesis.

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