biostudies-literatureSarksian RNational Center for Research ResourcesNCRR NIH HHSHoward Hughes Medical InstituteNational Institute of General Medical SciencesNIGMS NIH HHS2551-2558https://www.ebi.ac.uk/biostudies/studies/S-EPMC9486935biostudies-literatureUnknown17(9)The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active stereoisomers. Lanthipeptides are post-translationally modified peptidic natural products that contain macrocyclic thioethers featuring lanthionine (Lan) and/or methyllanthionine (MeLan) residues with defined stereochemistry. In this report, we compare two class I lanthipeptide biosynthetic gene clusters (BGCs), <i>coi</i> and <i>olv</i>, that represent two families of lanthipeptide gene clusters found in Actinobacteria. The precursor peptides and BGCs are quite similar with genes encoding a dehydratase, cyclase, and methyltransferase (MT). We illustrate that the precursor peptide CoiA1 is converted by these enzymes into a polyACS chemical biologyDivergent Evolution of Lanthipeptide Stereochemistry.PMC9486935S10 RR027109 AS10 RR027109R37 GM058822van der Donk WASarksian RfalseDivergent Evolution of Lanthipeptide Stereochemistry.The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active stereoisomers. Lanthipeptides are post-translationally modified peptidic natural products that contain macrocyclic thioethers featuring lanthionine (Lan) and/or methyllanthionine (MeLan) residues with defined stereochemistry. In this report, we compare two class I lanthipeptide biosynthetic gene clusters (BGCs), <i>coi</i> and <i>olv</i>, that represent two families of lanthipeptide gene clusters found in Actinobacteria. The precursor peptides and BGCs are quite similar with genes encoding a dehydratase, cyclase, and methyltransferase (MT). We illustrate that the precursor peptide CoiA1 is converted by these enzymes into a poly2022-01-01T00:00:00Z2022 Sep2025-04-05T10:25:32.246Z2025-04-05T10:25:32.246ZS-EPMC94869353600188010.1021/acschembio.2c00492