Enzymatic Reductive Dehalogenation Controls the Biosynthesis of Marine Bacterial Pyrroles

Abstract

Enzymes capable of performing dehalogenating reactions have attracted tremendous contemporary attention due to their potential application in the bioremediation of anthropogenic polyhalogenated persistent organic pollutants. Nature, in particular the marine environment, is also a prolific source of polyhalogenated organic natural products. The study of the biosynthesis of these natural products has furnished a diverse array of halogenation biocatalysts, but thus far no examples of dehalogenating enzymes have been reported from a secondary metabolic pathway. Here we show that the penultimate step in the biosynthesis of the highly brominated marine bacterial product pentabromopseudilin is catalyzed by an unusual debrominase Bmp8 that utilizes a redox thiol mechanism to remove the C-2 bromine atom of 2,3,4,5-tetrabromopyrrole to facilitate oxidative coupling to 2,4-dibromophenol. To the best of our knowledge, Bmp8 is first example of a dehalogenating enzyme from the established genetic and biochemical context of a natural product biosynthetic pathway.

Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum Ca2+ Dynamics

“…23–27 Recently, the biosynthetic pathways for a number of brominated pyrroles, bipyrroles and phenols have been also elucidated. 1,19,21,28 Tetrabromopyrrole ( 31 ) isolated from Pseudoalteromonas bacteria has been shown to elicit specific development cues to coral larvae necessary for metamorphosis and benthic attachment of Orbicella franksi and Acropora palmata onto crustose coralline algae. 29,30 Remarkably, high levels of several halopyrroles, including tetrabromopyrrole ( 31 ), are produced as disinfection byproducts (DBPs) during treatment of drinking water, agricultural irrigation water and saline wastewater, and are considered as emerging pollutants because of their cytotoxicity, genotoxicity, carcinogenicity and developmental toxicity.…”

Active Site Binding Is Not Sufficient for Reductive Deiodination by Iodotyrosine Deiodinase

“…hhIYD may also contribute to secondary metabolism in analogy to a recently discovered reductive debrominase that is required for the biosynthesis of a marine natural product. 55 …”

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

“…(Figure 35A). 38,49,372 This requisite dehalogenative transformation was recently shown to be enzymatically catalyzed by the unique thioredoxin-like reductive dehalogenase, Bmp8, encoded in the biosynthetic gene cluster responsible for the production of 29 . 372 Of note, Bmp8 is the first, and to date only example of a dehalogenase enzyme that performs a dedicated role in the biosynthesis of a natural product.…”