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

Abstract

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.

• Authors: Harry Towbin, Kenneth W Bair, James A DeCaprio, Michael J Eck, Sunkyu Kim, Frederick R Kinder, Anthony Morollo, Dieter R Mueller, Patrick Schindler, Hyun Kyu Song, Jan van Oostrum, Richard W Versace, Hans Voshol, Jeanette Wood, Sonya Zabludoff, Penny E Phillips
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 52 Pg. 52964-71 (Dec 26 2003) ISSN: 0021-9258 [Print] United States
• PMID: 14534293 (Publication Type: Journal Article)

Chemical References

• 14-3-3 Proteins
• 3,4,5-trihydroxy-2--methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl)non-6-enamide
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Azepines
• Cyclohexanes
• Enzyme Inhibitors
• Fatty Acids, Unsaturated
• Glycoproteins
• Peptides
• Protein Isoforms
• Proteome
• RNA, Small Interfering
• Sesquiterpenes
• Cobalt
• fumagillin
• Tyrosine 3-Monooxygenase
• Aminopeptidases
• METAP2 protein, human
• Methionyl Aminopeptidases

Topics

• 14-3-3 Proteins
• Aminopeptidases (antagonists & inhibitors, chemistry, genetics)
• Angiogenesis Inhibitors (pharmacology)
• Antineoplastic Agents (pharmacology)
• Azepines (pharmacology)
• 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, genetics)
• Humans
• 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)