Flavoenzyme CrmK-mediated Substrate Recycling in Caerulomycin Biosynthesis

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Aug 30

PMID 30155134

Citations 7

Authors

Yiguang Zhu

Marie-Eve Picard

Qingbo Zhang

Julie Barma

Xavier Murphy Despres

Xiangui Mei

Liping Zhang

Jean-Baptiste Duvignaud

Manon Couture

Weiming Zhu

Rong Shi

Changsheng Zhang

Affiliations

Soon will be listed here.

Abstract

Substrate salvage or recycling is common and important for primary metabolism in cells but is rare in secondary metabolism. Herein we report flavoenzyme CrmK-mediated shunt product recycling in the biosynthesis of caerulomycin A (CRM A ), a 2,2'-bipyridine-containing natural product that is under development as a potent novel immunosuppressive agent. We demonstrated that the alcohol oxidase CrmK, belonging to the family of bicovalent FAD-binding flavoproteins, catalyzed the conversion of an alcohol into a carboxylate an aldehyde. The CrmK-mediated reactions were not to biosynthesis but played an unexpectedly important role by recycling shunt products back to the main pathway of . Crystal structures and site-directed mutagenesis studies uncovered key residues for FAD-binding, substrate binding and catalytic activities, enabling the proposal for the CrmK catalytic mechanism. This study provides the first biochemical and structural evidence for flavoenzyme-mediated substrate recycling in secondary metabolism.

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