Decrypting the programming of β-methylation in virginiamycin M biosynthesis

Sabrina Collin, Russell J. Cox, Cédric Paris, Christophe Jacob, Benjamin Chagot (), Kira J. Weissman () and Arnaud Gruez ()
Additional contact information
Sabrina Collin: Université de Lorraine, CNRS, IMoPA
Russell J. Cox: OCI & BMWZ, Leibniz Universität Hannover
Cédric Paris: Université de Lorraine, LIBio
Christophe Jacob: Université de Lorraine, CNRS, IMoPA
Benjamin Chagot: Université de Lorraine, CNRS, IMoPA
Kira J. Weissman: Université de Lorraine, CNRS, IMoPA
Arnaud Gruez: Université de Lorraine, CNRS, IMoPA

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36974-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36974-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36974-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().