Decrypting the programming of β-methylation in virginiamycin M biosynthesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 03 2023
10 03 2023
Historique:
received:
04
10
2022
accepted:
27
02
2023
entrez:
10
3
2023
pubmed:
11
3
2023
medline:
15
3
2023
Statut:
epublish
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.
Identifiants
pubmed: 36899003
doi: 10.1038/s41467-023-36974-3
pii: 10.1038/s41467-023-36974-3
pmc: PMC10006238
doi:
Substances chimiques
Virginiamycin
11006-76-1
malonic acid
9KX7ZMG0MK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1327Informations de copyright
© 2023. The Author(s).
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