Decrypting the programming of β-methylation in virginiamycin M biosynthesis.
Fiche publication
Date publication
mars 2023
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GRUEZ Arnaud, Dr JACOB Christophe, Pr WEISSMAN Kira
Tous les auteurs :
Collin S, Cox RJ, Paris C, Jacob C, Chagot B, Weissman KJ, Gruez A
Lien Pubmed
Résumé
During biosynthesis by multi-modular trans-AT polyketide synthases, polyketide structural space can be expanded by conversion of initially-formed electrophilic β-ketones into β-alkyl groups. These multi-step transformations are catalysed by 3-hydroxy-3-methylgluratryl synthase cassettes of enzymes. While mechanistic aspects of these reactions have been delineated, little information is available concerning how the cassettes select the specific polyketide intermediate(s) to target. Here we use integrative structural biology to identify the basis for substrate choice in module 5 of the virginiamycin M trans-AT polyketide synthase. Additionally, we show in vitro that module 7, at minimum, is a potential additional site for β-methylation. Indeed, analysis by HPLC-MS coupled with isotopic labelling and pathway inactivation identifies a metabolite bearing a second β-methyl at the expected position. Collectively, our results demonstrate that several control mechanisms acting in concert underpin β-branching programming. Furthermore, variations in this control - whether natural or by design - open up avenues for diversifying polyketide structures towards high-value derivatives.
Référence
Nat Commun. 2023 03 10;14(1):1327