期刊
CHEMBIOCHEM
卷 15, 期 5, 页码 757-765出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300676
关键词
biosynthesis; myxobacteria; Nannocystis pusilla; phenylnannolone A; polyketides
资金
- NRW International Research Graduate School Biotech-Pharma
- German Centre for Infection Research (DZIF)
- DFG Research Unit [FOR 854]
- Novo Nordisk Fonden [NNF10CC1016517] Funding Source: researchfish
The myxobacterial strain Nannocystis pusilla B150 synthesizes the structurally new polyketides phenylnannolone A-C. Apart from some common volatiles and siderophores, these are the first natural products from the genus Nannocystis. Phenylnannolone A shows inhibitory activity towards the ABCB1 gene product P-glycoprotein and reverses daunorubicin resistance in cancer cells. To decipher the biochemical reactions leading to the formation of phenylnannolone A, the putative biosynthetic genes were identified (phn1, phn2). Phn2 is a polyketide synthase (PKS) with an NRPS-like loading module, and its domain order is consistent with the phenylnannolone A structure. The functionality and substrate selectivity of the loading module were determined by means of a -O-18(4)-ATP pyrophosphate exchange and a phosphopantetheine ejection assay. A specific activation of cinnamic acid by the AMP-ligase was detected. Phn1 is a putative butyryl-CoA carboxylase (BCC), providing ethylmalonyl-CoA for the formation of the ethyl-substituted part of phenylnannolone A. Phn1 is the first BCC found in biosynthetic genes for an ethyl-substituted natural compound. Biosynthesis of phenylnannolone A, putatively encoded by phn1 and phn2, thus utilizes the first biosynthetic machinery in which both a BCC and a PKS are involved.
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