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 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.
Towbin
Harry
H
Novartis Pharma AG, CH-4036 Basle, Switzerland.
Bair
Kenneth W
KW
DeCaprio
James A
JA
Eck
Michael J
MJ
Kim
Sunkyu
S
Kinder
Frederick R
FR
Morollo
Anthony
A
Mueller
Dieter R
DR
Schindler
Patrick
P
Song
Hyun Kyu
HK
van Oostrum
Jan
J
Versace
Richard W
RW
Voshol
Hans
H
Wood
Jeanette
J
Zabludoff
Sonya
S
Phillips
Penny E
PE
D048948:14-3-3 Proteins; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003035:Cobalt / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D063208:Methionyl Aminopeptidases; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D020543:Proteome; D034741:RNA, Small Interfering / Q000378:metabolism; D012717:Sesquiterpenes; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D048948:14-3-3 Proteins; C438868:3,4,5-trihydroxy-2--methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl)non-6-enamide; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001381:Azepines; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006023:Glycoproteins; D010455:Peptides; D020033:Protein Isoforms; D020543:Proteome; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D003035:Cobalt; C026211:fumagillin; D014446:Tyrosine 3-Monooxygenase; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases