2. Academic Validation
  3. Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors

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

  • Nat Commun. 2017 Dec 6;8(1):1965. doi: 10.1038/s41467-017-01975-6.
Franziska Leipoldt 1 2,  Javier Santos-Aberturas 3,  Dennis P Stegmann 1 2,  Felix Wolf 1 2,  Andreas Kulik 4,  Rodney Lacret 3,  Désirée Popadić 3 5,  Daniela Keinhörster 1,  Norbert Kirchner 1 2,  Paulina Bekiesch 1 6,  Harald Gross 1 2,  Andrew W Truman 7,  Leonard Kaysser 8 9
Affiliations

Affiliations

  • 1 Pharmaceutical Biology, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 2 German Center for Infection Research (DZIF), Partner site Tübingen, 72076, Tübingen, Germany.
  • 3 Department of Molecular Microbiology, John Innes Centre, Colney Lane, Norwich, NR4 7UH, UK.
  • 4 Interfaculty Institute of Microbiology and Infection Medicine, Microbiology/Biotechnology, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 5 Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, D-79104, Freiburg i. Br., Germany.
  • 6 Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria.
  • 7 Department of Molecular Microbiology, John Innes Centre, Colney Lane, Norwich, NR4 7UH, UK. andrew.truman@jic.ac.uk.
  • 8 Pharmaceutical Biology, Eberhard Karls University Tübingen, 72076, Tübingen, Germany. leonard.kaysser@pharm.uni-tuebingen.de.
  • 9 German Center for Infection Research (DZIF), Partner site Tübingen, 72076, Tübingen, Germany. leonard.kaysser@pharm.uni-tuebingen.de.
PMID: 29213087 DOI: 10.1038/s41467-017-01975-6
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.

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