Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors

Franziska Leipoldt, Javier Santos-Aberturas, Dennis P. Stegmann, Felix Wolf, Andreas Kulik, Rodney Lacret, Désirée Popadić, Daniela Keinhörster, Norbert Kirchner, Paulina Bekiesch, Harald Gross, Andrew W. Truman () and Leonard Kaysser ()
Additional contact information
Franziska Leipoldt: Eberhard Karls University Tübingen
Javier Santos-Aberturas: John Innes Centre, Colney Lane
Dennis P. Stegmann: Eberhard Karls University Tübingen
Felix Wolf: Eberhard Karls University Tübingen
Andreas Kulik: Microbiology/Biotechnology, Eberhard Karls University Tübingen
Rodney Lacret: John Innes Centre, Colney Lane
Désirée Popadić: John Innes Centre, Colney Lane
Daniela Keinhörster: Eberhard Karls University Tübingen
Norbert Kirchner: Eberhard Karls University Tübingen
Paulina Bekiesch: Eberhard Karls University Tübingen
Harald Gross: Eberhard Karls University Tübingen
Andrew W. Truman: John Innes Centre, Colney Lane
Leonard Kaysser: Eberhard Karls University Tübingen

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Metalloproteinase inhibitors often feature hydroxamate moieties to facilitate the chelation of metal ions in the catalytic center of target enzymes. Actinonin and matlystatins are potent metalloproteinase inhibitors that comprise rare N-hydroxy-2-pentyl-succinamic acid warheads. Here we report the identification and characterization of their biosynthetic pathways. By gene cluster comparison and a combination of precursor feeding studies, heterologous pathway expression and gene deletion experiments we are able to show that the N-hydroxy-alkyl-succinamic acid warhead is generated by an unprecedented variation of the ethylmalonyl-CoA pathway. Moreover, we present evidence that the remarkable structural diversity of matlystatin congeners originates from the activity of a decarboxylase-dehydrogenase enzyme with high similarity to enzymes that form epoxyketones. We further exploit this mechanism to direct the biosynthesis of non-natural matlystatin derivatives. Our work paves the way for follow-up studies on these fascinating pathways and allows the identification of new protease inhibitors by genome mining.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-017-01975-6 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:8:y:2017:i:1:d:10.1038_s41467-017-01975-6

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

DOI: 10.1038/s41467-017-01975-6

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 ().