Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Aug 5

PMID 28777910

Citations 35

Authors

Amy E Fraley

Marc Garcia-Borras

Ashootosh Tripathi

Dheeraj Khare

Eduardo V Mercado-Marin

Hong Tran

Qingyun Dan

Gabrielle P Webb

Katharine R Watts

Phillip Crews

Richmond Sarpong

Robert M Williams

Janet L Smith

K N Houk

David H Sherman

Affiliations

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Abstract

Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from both Malbranchea aurantiaca and Malbranchea graminicola that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the two flavin-dependent halogenases involved in the late-stage halogenation of malbrancheamide in two different fungal strains. MalA and MalA' catalyze the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogues were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA' in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases and provides new insights into a potentially unique reaction mechanism.

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