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Expanding the Ajudazol Cytotoxin Scaffold: Insights from Genome Mining, Biosynthetic Investigations, and Novel Derivatives. | LitMetric

Expanding the Ajudazol Cytotoxin Scaffold: Insights from Genome Mining, Biosynthetic Investigations, and Novel Derivatives.

J Nat Prod

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University, 66123 Saarbrücken, Saarland, Germany.

Published: November 2022

AI Article Synopsis

Article Abstract

Myxobacteria have proven to be a rich source of natural products, but their biosynthetic potential seems to be underexplored given the high number of biosynthetic gene clusters present in their genomes. In this study, a truncated ajudazol biosynthetic gene cluster in sp. SBCb004 was identified using mutagenesis and metabolomics analyses and a set of novel ajudazols (named ajudazols C-J, -, respectively) were detected and subsequently isolated. Their structures were elucidated using comprehensive HR-MS and NMR spectroscopy. Unlike the known ajudazols A () and B (), which utilize acetyl-CoA as the biosynthetic starter unit, these novel ajudazols were proposed to incorporate 3,3-dimethylacrylyl CoA as the starter. Ajudazols C-J (-, respectively) are characterized by varying degrees of hydroxylation, desaturation, and different glycosylation patterns. Two P450-dependent enzymes and one glycosyltransferase are shown to be responsible for the hydroxylation at C-8, the desaturation at C-15 and C-33, and the transfer of a d--glucopyranose, respectively, based on mutagenesis results. One of the cytochrome P450-dependent enzymes and the glycosyltransferase were found to be encoded by genes located outside the biosynthetic gene cluster. Ajudazols C-H (-, respectively) exhibit cytotoxicity against various cancer cell lines.

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http://dx.doi.org/10.1021/acs.jnatprod.2c00637DOI Listing

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