Widespread Biosynthesis of Thiohistidine Dipeptides in Bacteria

Abstract

Abstract Natural products have been paramount in inspiring novel chemistry as well as providing therapeutic agents and chemical tools for biological applications. A recently emerging class of natural products, the thio/seleno-imidazoles (TSIs), contains C–S or C–Se bonds that are installed by nonheme iron sulfoxide and selenoxide synthases (NHISSs). These TSIs, which include ergothioneine, are ubiquitous, but little is known about the broader TSI chemical space or co-occurrence with other biosynthetic enzymes. Here, we use NHISSs as a bioinformatic hook to identify a widespread family of biosynthetic gene clusters that encode a combination of NHISS and ATP-grasp enzymes. This search strategy enabled the discovery of two 2-thiohistidine-containing dipeptide natural products, one of which we isolated from the original microbial host. Structural and biochemical analyses of the corresponding biosynthetic enzymes revealed a novel NHISS active site architecture and an ATP-grasp enzyme with unprecedented substrate selectivity for 2-thiohistidine. Together, these results expand the known enzymology and distribution of TSIs and establish 2-thiohistidine as a biosynthetically encoded building block, enabling future discovery and functional investigation into this new natural product family.

The authors' abstract, as published at the source. Journal of the American Chemical Society, 2026 · DOI ↗