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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
52
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pubmed:dateCreated |
2003-12-22
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pubmed:databankReference |
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pubmed:abstractText |
LAF389 is a synthetic analogue of bengamides, a class of marine natural products that produce inhibitory effects on tumor growth in vitro and in vivo. A proteomics-based approach has been used to identify signaling pathways affected by bengamides. LAF389 treatment of cells resulted in altered mobility of a subset of proteins on two-dimensional gel electrophoresis. Detailed analysis of one of the proteins, 14-3-3gamma, showed that bengamide treatment resulted in retention of the amino-terminal methionine, suggesting that bengamides directly or indirectly inhibited methionine aminopeptidases (MetAps). Both known MetAps are inhibited by LAF389. Short interfering RNA suppression of MetAp2 also altered amino-terminal processing of 14-3-3gamma. A high resolution structure of human MetAp2 co-crystallized with a bengamide shows that the compound binds in a manner that mimics peptide substrates. Additionally, the structure reveals that three key hydroxyl groups on the inhibitor coordinate the di-cobalt center in the enzyme active site.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/14-3-3 Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/3,4,5-trihydroxy-2--methoxy-8,8-dime...,
http://linkedlifedata.com/resource/pubmed/chemical/Aminopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Angiogenesis Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Azepines,
http://linkedlifedata.com/resource/pubmed/chemical/Cobalt,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclohexanes,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acids, Unsaturated,
http://linkedlifedata.com/resource/pubmed/chemical/Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/METAP2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Isoforms,
http://linkedlifedata.com/resource/pubmed/chemical/Proteome,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Sesquiterpenes,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine 3-Monooxygenase,
http://linkedlifedata.com/resource/pubmed/chemical/fumagillin,
http://linkedlifedata.com/resource/pubmed/chemical/methionyl aminopeptidase
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:BairKenneth WKW,
pubmed-author:DeCaprioJames AJA,
pubmed-author:EckMichael JMJ,
pubmed-author:KimSunkyuS,
pubmed-author:KinderFrederick RFR,
pubmed-author:MorolloAnthonyA,
pubmed-author:MuellerDieter RDR,
pubmed-author:PhillipsPenny EPE,
pubmed-author:SchindlerPatrickP,
pubmed-author:SongHyun KyuHK,
pubmed-author:TowbinHarryH,
pubmed-author:VersaceRichard WRW,
pubmed-author:VosholHansH,
pubmed-author:WoodJeanetteJ,
pubmed-author:ZabludoffSonyaS,
pubmed-author:van OostrumJanJ
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pubmed:issnType |
Print
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pubmed:day |
26
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
52964-71
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:14534293-14-3-3 Proteins,
pubmed-meshheading:14534293-Aminopeptidases,
pubmed-meshheading:14534293-Angiogenesis Inhibitors,
pubmed-meshheading:14534293-Antineoplastic Agents,
pubmed-meshheading:14534293-Azepines,
pubmed-meshheading:14534293-Binding Sites,
pubmed-meshheading:14534293-Cell Division,
pubmed-meshheading:14534293-Cell Line, Tumor,
pubmed-meshheading:14534293-Cloning, Molecular,
pubmed-meshheading:14534293-Cobalt,
pubmed-meshheading:14534293-Crystallography, X-Ray,
pubmed-meshheading:14534293-Cyclohexanes,
pubmed-meshheading:14534293-Dose-Response Relationship, Drug,
pubmed-meshheading:14534293-Electrophoresis, Gel, Two-Dimensional,
pubmed-meshheading:14534293-Enzyme Inhibitors,
pubmed-meshheading:14534293-Fatty Acids, Unsaturated,
pubmed-meshheading:14534293-Glycoproteins,
pubmed-meshheading:14534293-Humans,
pubmed-meshheading:14534293-Models, Chemical,
pubmed-meshheading:14534293-Models, Molecular,
pubmed-meshheading:14534293-Peptides,
pubmed-meshheading:14534293-Protein Binding,
pubmed-meshheading:14534293-Protein Isoforms,
pubmed-meshheading:14534293-Protein Structure, Tertiary,
pubmed-meshheading:14534293-Proteome,
pubmed-meshheading:14534293-RNA, Small Interfering,
pubmed-meshheading:14534293-Sesquiterpenes,
pubmed-meshheading:14534293-Spectrometry, Mass, Matrix-Assisted Laser...,
pubmed-meshheading:14534293-Tyrosine 3-Monooxygenase
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pubmed:year |
2003
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pubmed:articleTitle |
Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors.
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pubmed:affiliation |
Novartis Pharma AG, CH-4036 Basle, Switzerland.
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pubmed:publicationType |
Journal Article
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