2.50
Hdl Handle:
http://hdl.handle.net/10033/346872
Title:
Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors.
Authors:
Rachid, Shwan; Huo, Liujie; Herrmann, Jennifer; Stadler, Marc ( 0000-0002-7284-8671 ) ; Köpcke, Bärbel; Bitzer, Jens; Müller, Rolf
Abstract:
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 Chembiochem
Journal:
Chembiochem : a European journal of chemical biology
Issue Date:
11-Apr-2011
URI:
http://hdl.handle.net/10033/346872
DOI:
10.1002/cbic.201100024
PubMed ID:
21387511
Type:
Article
Language:
en
ISSN:
1439-7633
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorRachid, Shwanen
dc.contributor.authorHuo, Liujieen
dc.contributor.authorHerrmann, Jenniferen
dc.contributor.authorStadler, Marcen
dc.contributor.authorKöpcke, Bärbelen
dc.contributor.authorBitzer, Jensen
dc.contributor.authorMüller, Rolfen
dc.date.accessioned2015-03-19T12:45:32Zen
dc.date.available2015-03-19T12:45:32Zen
dc.date.issued2011-04-11en
dc.identifier.citationMining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors. 2011, 12 (6):922-31 Chembiochemen
dc.identifier.issn1439-7633en
dc.identifier.pmid21387511en
dc.identifier.doi10.1002/cbic.201100024en
dc.identifier.urihttp://hdl.handle.net/10033/346872en
dc.description.abstractThe 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.en
dc.language.isoenen
dc.subject.meshBiosynthetic Pathwaysen
dc.subject.meshCell Line, Tumoren
dc.subject.meshHumansen
dc.subject.meshLactonesen
dc.subject.meshMultigene Familyen
dc.subject.meshProtease Inhibitorsen
dc.subject.meshProteasome Endopeptidase Complexen
dc.subject.meshProteasome Inhibitorsen
dc.subject.meshPyrrolesen
dc.subject.meshStreptomycesen
dc.titleMining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors.en
dc.typeArticleen
dc.identifier.journalChembiochem : a European journal of chemical biologyen

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