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Peer-reviewedCC BYJournal of the American Chemical Society

Widespread Biosynthesis of Thiohistidine Dipeptides in Bacteria.

  • Marissa L Abbott1
  • Jacob T Leeman1
  • Chase M Kayrouz1
  • Kendra A Ireland2
  • Katherine M Davis2
  • Mohammad R Seyedsayamdost1,3
  1. 1Department of Chemistry, Princeton University, Princeton, New Jersey08544, United States.
  2. 2Department of Chemistry, Emory University, Atlanta, Georgia30322, United States.
  3. 3Department of Molecular Biology, Princeton University, Princeton, New Jersey08544, United States.
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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.

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Cite

BibTeXRIS
BibTeX
@article{abbott2026widespread,
  title = {{Widespread Biosynthesis of Thiohistidine Dipeptides in Bacteria.}},
  author = {Marissa L Abbott and Jacob T Leeman and Chase M Kayrouz and Kendra A Ireland and Katherine M Davis and Mohammad R Seyedsayamdost},
  journal = {Journal of the American Chemical Society},
  year = {2026},
  month = oct,
  doi = {10.1021/jacs.6c03714},
  url = {https://europepmc.org/article/MED/42913589},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Widespread Biosynthesis of Thiohistidine Dipeptides in Bacteria.
AU  - Marissa L Abbott
AU  - Jacob T Leeman
AU  - Chase M Kayrouz
AU  - Kendra A Ireland
AU  - Katherine M Davis
AU  - Mohammad R Seyedsayamdost
PY  - 2026
DA  - 2026/10/01
JO  - Journal of the American Chemical Society
DO  - 10.1021/jacs.6c03714
UR  - https://europepmc.org/article/MED/42913589
AB  - 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.
SN  - 0002-7863
SN  - 1520-5126
ER  -