Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors.
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Authors
Rachid, ShwanHuo, Liujie
Herrmann, Jennifer
Stadler, Marc
Köpcke, Bärbel
Bitzer, Jens
Müller, Rolf
Issue Date
2011-04-11
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The cinnabaramides and salinosporamides are mixed PKS/NRPS natural products isolated from a terrestrial streptomycete and a marine actinomycete, respectively. They interfere with the proteasome and thus potentially inhibit the growth of cancer cells. The compounds exhibit a γ-lactam-β-lactone bicyclic ring structure attached to a cyclohexenyl unit and a PKS side chain. As a first step towards improving anticancer activity and permitting genetic approaches to novel analogues, we have cloned and characterized the cinnabaramide biosynthetic genes from Streptomyces sp. JS360. In addition to the expected PKS and NRPS genes, the cluster encodes functionalities for the assembly of the hexyl side chain precursor. The corresponding enzymes exhibit relaxed substrate specificities towards a number of synthesized precursors, enabling production of novel chlorinated cinnabaramides. These were isolated and analyzed for activity, revealing that derivatives bearing a chlorine atom in the PKS side chain show higher inhibitory potentials towards the proteasome's proteolytic subunits (especially the trypsin and chymotrypsin units) and higher cytotoxicities towards human tumor cell lines than the parent cinnabaramide A. Although their activities towards the proteasome were weaker than that of salinosporamide A, the cinnabaramides were found to inhibit the growth of various fungi with greater potency.Citation
Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors. 2011, 12 (6):922-31 ChembiochemPubMed ID
21387511Type
ArticleLanguage
enISSN
1439-7633ae974a485f413a2113503eed53cd6c53
10.1002/cbic.201100024
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