Mechanistic analysis of carbon–carbon bond formation by deoxypodophyllotoxin synthase

Haoyu Tang, Min Hao Wu, Hsiao Yu Lin, Meng Ru Han, Yueh Hua Tu, Zhi Jie Yang, Tun Cheng Chien*, Nei Li Chan, Wei Chen Chang

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

摘要

Deoxypodophyllotoxin contains a core of four fused rings (A to D) with three consecutive chiral centers, the last being created by the attachment of a peripheral trimethoxyphenyl ring (E) to ring C. Previous studies have suggested that the iron(II)- and 2-oxoglutarate–dependent (Fe/2OG) oxygenase, deoxypodophyllotoxin synthase (DPS), catalyzes the oxidative coupling of ring B and ring E to form ring C and complete the tetracyclic core. Despite recent efforts to deploy DPS in the preparation of deoxypodophyllotoxin analogs, the mechanism underlying the regio- and stereoselectivity of this cyclization event has not been elucidated. Herein, we report 1) two structures of DPS in complex with 2OG and (±)-yatein, 2) in vitro analysis of enzymatic reactivity with substrate analogs, and 3) model reactions addressing DPS’s catalytic mechanism. The results disfavor a prior proposal of on-pathway benzylic hydroxylation. Rather, the DPS-catalyzed cyclization likely proceeds by hydrogen atom abstraction from C7', oxidation of the benzylic radical to a carbocation, Friedel–Crafts-like ring closure, and rearomatization of ring B by C6 deprotonation. This mechanism adds to the known pathways for transformation of the carbon-centered radical in Fe/2OG enzymes and suggests what types of substrate modification are likely tolerable in DPS-catalyzed production of deoxypodophyllotoxin analogs.

原文英語
文章編號e2113770119
期刊Proceedings of the National Academy of Sciences of the United States of America
119
發行號1
DOIs
出版狀態已發佈 - 2022 1月 4

ASJC Scopus subject areas

  • 多學科

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