ArticleNature communications2017
Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
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- Chemotype- and Target-Driven Genome Mining for a New Natural Product Inhibitor of Bacterial Peptide Deformylase.Journal of the American Chemical Society · 2025Article
- Identification of the lydiamycin biosynthetic gene cluster in a plant pathogen guides structural revision and identification of molecular target.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Enzyme Inhibitors as Multifaceted Tools in Medicine and Agriculture.Molecules (Basel, Switzerland) · 2024Review
- Hydroxylamine production byScience advances · 2024Article
- Chemistry and biology of specialized metabolites produced byNatural product reports · 2024Review
- Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis.Organic letters · 2023Article
- Non-Canonical Amino Acids in Analyses of Protease Structure and Function.International journal of molecular sciences · 2023Review
- Metabolic engineering ofEngineering microbiology · 2022Review
- Discovery of unusual dimeric piperazyl cyclopeptides encoded by aProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Dirammox Is Widely Distributed and Dependently Evolved inFrontiers in microbiology · 2022Article
- Bioproduction of L-piperazic acid in gram scale using Aureobasidium melanogenum.Microbial biotechnology · 2021Article
- Glycine-derived nitronates bifurcate to O-methylation or denitrification in bacteria.Nature chemistry · 2021Article
- Reproducible molecular networking of untargeted mass spectrometry data using GNPS.Nature protocols · 2020Article
- Genetic platforms for heterologous expression of microbial natural products.Natural product reports · 2019Review
- Highlights of Streptomyces genetics.Heredity · 2019Review
- The hidden enzymology of bacterial natural product biosynthesis.Nature reviews. Chemistry · 2019Article
- Biosynthetic reconstitution of deoxysugar phosphoramidate metalloprotease inhibitors using an N-P-bond-forming kinase.Chemical science · 2019Article
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Authors and funding
13 authors.
Funding
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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