Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors

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 mobili...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-12, Vol.278 (52), p.52964-52971
Main Authors: Towbin, Harry, Bair, Kenneth W, DeCaprio, James A, Eck, Michael J, Kim, Sunkyu, Kinder, Frederick R, Morollo, Anthony, Mueller, Dieter R, Schindler, Patrick, Song, Hyun Kyu, van Oostrum, Jan, Versace, Richard W, Voshol, Hans, Wood, Jeanette, Zabludoff, Sonya, Phillips, Penny E
Format: Article
Language:English
Subjects:
14-3-3 Proteins
Aminopeptidases - antagonists & inhibitors
Aminopeptidases - chemistry
Aminopeptidases - genetics
Angiogenesis Inhibitors - pharmacology
Antineoplastic Agents - pharmacology
Azepines - pharmacology
bengamides
Binding Sites
Cell Division
Cell Line, Tumor
Cloning, Molecular
Cobalt - chemistry
Crystallography, X-Ray
Cyclohexanes
Dose-Response Relationship, Drug
Electrophoresis, Gel, Two-Dimensional
Enzyme Inhibitors - pharmacology
Fatty Acids, Unsaturated - pharmacology
Glycoproteins - chemistry
Glycoproteins - genetics
Humans
LAF389
Methionyl Aminopeptidases
Models, Chemical
Models, Molecular
Peptides - chemistry
Protein Binding
Protein Isoforms
Protein Structure, Tertiary
Proteome
RNA, Small Interfering - metabolism
Sesquiterpenes
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Tyrosine 3-Monooxygenase - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M309039200