A Novel and Prevalent Pathway in Microbial Selenium Metabolism

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, respectively. However, despite its importance, pathways for specific incorporation of selenium into small molecules have remained elusive. We herein use a genome mining strategy to uncover a widespread three-gene cluster in varied microorganisms that encodes a dedicated pathway for producing selenoneine, the selenium-analog of the multifunctional molecule ergothioneine. We elucidate the reactions of all three proteins and uncover two novel selenium-carbon bond-forming enzymes and the first biosynthetic pathway for production of a selenosugar, an unexpected intermediate on 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.