5wgr

Publication Abstract from PubMed

Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from Malbranchea aurantiaca 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 flavin-dependent halogenase involved in the late-stage halogenation of malbrancheamide. MalA catalyzes the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogs 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.

Function and structure of MalA/MalA', iterative halogenases for late-stage C-H functionalization of indole alkaloids.,Fraley AE, Garcia-Borras M, Tripathi A, Khare D, Mercado-Marin EV, Tran H, Dan Q, Webb G, Watts K, Crews P, Sarpong R, Williams RM, Smith JL, Houk KN, Sherman DH J Am Chem Soc. 2017 Aug 4. doi: 10.1021/jacs.7b06773. PMID:28777910^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.