Genome mining reveals uncommon alkylpyrones as type III PKS products from myxobacteria
Type III polyketide synthases (PKSs) are comparatively small homodimeric enzymes affording natural products with diverse structures and functions. While type III PKS biosynthetic pathways have been studied thoroughly in plants, their counterparts from bacteria and fungi are to date scarcely characterized. This gap is exemplified by myxobacteria from which no type III PKS-derived small molecule has previously been isolated. In this study, we conducted a genomic survey of myxobacterial type III PKSs and report the identification of uncommon alkylpyrones as the products of type III PKS biosynthesis from the myxobacterial model strain Myxococcus xanthus DK1622 through a self-resistance-guided screening approach focusing on genes encoding pentapetide repeat proteins, proficient to confer resistance to topoisomerase inhibitors. Using promoter-induced gene expression in the native host as well as heterologous expression of biosynthetic type III PKS genes, sufficient amounts of material could be obtained for structural elucidation and bioactivity testing, revealing potent topoisomerase activity in vitro.
KeywordsMyxobacteria Genome mining Natural products Type III polyketide synthase Self-resistance
The authors thank Alexander Popoff for recording the NMR spectra of the alkylpyrones, Viktoria Schmitt and Jennifer Herrmann for performing bioactivity assays, Ronald Garcia for microbiological assistance and Nestor Zaburannyi for bioinformatic support. Joachim J. Hug was supported by a PhD fellowship of the Boehringer Ingelheim Fonds.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 13.Funa N, Funabashi M, Yoshimura E et al (2005) A novel quinone-forming monooxygenase family involved in modification of aromatic polyketides. J Biol Chem 280(15):14514–14523Google Scholar
- 26.Kashefi K, Hartzell PL (1995) Genetic suppression and phenotypic masking of a Myxococcus xanthus frzF-defect. Mol Microbiol 15(3):483–494Google Scholar
- 32.Miyanaga A, Funa N, Awakawa T et al (2008) Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis. Proc Natl Acad Sci USA 105(3):871–876Google Scholar
- 37.Sambrook J, Russell DW (2001) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
- 40.Schuz R, Heller W, Hahlbrock K (1983) Substrate specificity of chalcone synthase from Petroselinum hortense. Formation of phloroglucinol derivatives from aliphatic substrates. J Biol Chem 258(11):6730–6734Google Scholar
- 43.Sone Y, Nakamura S, Sasaki M et al. (2018) Identification and characterization of bacterial enzymes catalyzing the synthesis of 1,8-dihydroxynaphthalene, a key precursor of dihydroxynaphthalene melanin, from Sorangium cellulosum. Appl Environ Microbiol. AEM-00258-18. https://doi.org/10.1128/aem.00258-18