Work

A Bifunctional Cytochrome P450 Enzyme Catalyzes Hydroxylation and Aryl‐Aryl Ether Formation in the Biosynthesis of Emestrin

Year: 2025

Type: article

Abstract: Emestrins, a subgroup of epipolythiodioxopiperazines, are originated from cyclo-l-Phe-l-Phe and feature a dihydrooxepine ring. They contain typically a 15-membered lactone ring with an aryl-aryl ether linkage. Despite considerable progress in elucidating epipolythiodioxopiperazine biosynthesis, the enzymatic mechanism for the ether bond formation in emestrins remains uncharacterized. We identified a putative gene cluster (eme) in the fungus Emericella quadrilineata with three unknown P450 enzymes, EmeE, EmeR, and EmeO. Gene deletion, feeding experiments, and in vitro assays proved that EmeE and EmeR install regioselective and stereospecific hydroxyl groups at the ß-positions of the diketopiperazine ring. EmeO acts as a bifunctional enzyme for the construction of the lactone ring via an aryl-aryl ether bond formation and simultaneous hydroxylation between phenolic and nonphenolic aromatic rings. To the best of our knowledge, such enzymatic reactions have not been reported prior to this study.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.202503453

Authors: Yu‐Chuan Chen, Jing‐Jing Wu, Ming‐Hua Chen, Shu‐Ming Li

Institutions: Philipps University of Marburg, Chinese Academy of Medical Sciences & Peking Union Medical College

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: hybrid

Estimated APC paid: $4,640