The malbrancheamides are complex fungal indole alkaloids with therapeutic potential as calmodulin antagonists, and the halogenation of the indole ring significantly contributes to the biological activity of these molecules. MalA has been characterized as an iterative late-stage halogenase that provides the halogen moieties to produce brominated and chlorinated malbrancheamide analogs. We have delved into the mechanism of enzymatic halogenation through structural and computational studies, and utilized this knowledge base to engineer a range of MalA variants for selective halogenation on the natural substrate premalbrancheamide. To demonstrate the utility of halogenation biocatalysts, we analyzed the substrate scope of MalA and various mutants on 1,000 substrates from the Novartis compound library. Halogenation was achieved on a broad range of substrates with variation in number of products, degree of halogenation, and percent conversion. Crystal structures of the wild-type enzyme compared to variants have aided the visualization of how these mutations change the binding pocket and provide insight into the accommodation of unnatural substrates.

Structure-guided development of a biocatalyst for late-stage halogenation

2019 Spring National Meeting

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