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 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.
It is said that carbon, the most abundant element in organic matter, supplies life’s quantity, whereas nitrogen supplies its quality. It is therefore unsurprising that many natural products that contain basic nitrogens (alkaloids) are coveted for their benefit to human health. However, nitrogen is known to mire many chemical syntheses because of its basicity and susceptibility to oxidation. This challenge may be heightened by the presence of more than one nitrogen atom in a targeted complex alkaloid, but can be met by the selective introduction and removal of functional groups that mitigate basicity, as highlighted herein with the first chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C through 13C feeding studies, supports the existence of a common bicyclo[2.2.2]diazaoctane containing biogenetic precursor to these compounds as has been proposed previously.
The first strategy that provides reverse-prenylated indole alkaloids that bear a characteristic bicyclo[2.2.2]diazaoctane as well as those that lack this structural motif is reported.
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