Abstract
Selenium is an essential micronutrient in diverse organisms. Two routes are known for its insertion into proteins and nucleic acids, via selenocysteine and 2-selenouridine, respectively1. However, despite its importance, pathways for specific incorporation of selenium into small molecules have remained elusive. Here we use a genome-mining strategy in various microorganisms to uncover a widespread three-gene cluster that encodes a dedicated pathway for producing selenoneine, the selenium analogue of the multifunctional molecule ergothioneine2,3. We elucidate the reactions of all three proteins and uncover two novel selenium–carbon bond-forming enzymes and the biosynthetic pathway for production of a selenosugar, which is an unexpected intermediate en route to the final product. Our findings expand the scope of biological selenium utilization, suggest that the selenometabolome is more diverse than previously thought, and set the stage for the discovery of other selenium-containing natural products.
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Data availability
Experimental data supporting the conclusions of this study are available within the article and its Supplementary information. Sequences were retrieved from the NCBI Conserved Domain Database (https://www.ncbi.nlm.nih.gov/cdd/) and the NCBI Non-redundant Protein Database (https://www.ncbi.nlm.nih.gov/protein/). NCBI accession numbers of analysed proteins from V. paradoxus DSM 30034 are as follows: WP_062361878.1 (SenA), WP_080642484.1 (SenB), WP_062361881.1 (SenC), WP_062366250.1 (EgtD) and WP_062366249.1 (EgtB). Raw experimental data and complete bioinformatic datasets can be made available on reasonable request.
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Acknowledgements
We thank Andy K. L. Nguy for helpful discussions and the Edward C. Taylor 3rd Year Fellowship in Chemistry (to C.M.K.), the Life Sciences Research Foundation Postdoctoral Fellowship sponsored by the Open Philanthropy Project (to J.H.), the Swiss National Science Foundation Early “Postdoc Mobility” Fellowship (no. P2EZP2_187995 to N.H.), the National Science Foundation CAREER Award (no. 1847932 to M.R.S.), and the US National Institutes of Health (GM129496 to M.R.S.) for financial support.
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C.M.K. and M.R.S. conceived the idea for the study. C.M.K. designed and performed the bioinformatic search and all experiments described in the paper. J.H. synthesized and purified SeGlcNAc and 2AG. N.H. conceived the selenoxide elimination. C.M.K. and M.R.S. analysed the data and prepared the manuscript.
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This file contains Supplementary Tables 1–8; coding DNA sequences and amino acid sequences of recombinant proteins; Supplementary Figs. 1–11 and Supplementary Schemes 1–4.
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Kayrouz, C.M., Huang, J., Hauser, N. et al. Biosynthesis of selenium-containing small molecules in diverse microorganisms. Nature 610, 199–204 (2022). https://doi.org/10.1038/s41586-022-05174-2
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DOI: https://doi.org/10.1038/s41586-022-05174-2
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