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

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

doi:10.1074/jbc.M309039200

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

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

Research output: Contribution to journal › Article › peer-review

150 Citations (Scopus)

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, 14-3-3γ, 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 14-3-3γ. 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.

Original language	English
Pages (from-to)	52964-52971
Number of pages	8
Journal	Journal of Biological Chemistry
Volume	278
Issue number	52
DOIs	https://doi.org/10.1074/jbc.M309039200
Publication status	Published - 2003 Dec 26
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1074/jbc.M309039200

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Towbin, H., Bair, K. W., DeCaprio, J. A., Eck, M. J., Kim, S., Kinder, F. R., Morollo, A., Mueller, D. R., Schindler, P., Song, H. K., Van Oostrum, J., Versace, R. W., Voshol, H., Wood, J., Zabludoff, S., & Phillips, P. E. (2003). Proteomics-based target identification: Bengamides as a new class of methionine aminopeptidase inhibitors. Journal of Biological Chemistry, 278(52), 52964-52971. https://doi.org/10.1074/jbc.M309039200

Towbin, H, Bair, KW, DeCaprio, JA, Eck, MJ, Kim, S, Kinder, FR, Morollo, A, Mueller, DR, Schindler, P, Song, HK, Van Oostrum, J, Versace, RW, Voshol, H, Wood, J, Zabludoff, S & Phillips, PE 2003, 'Proteomics-based target identification: Bengamides as a new class of methionine aminopeptidase inhibitors', Journal of Biological Chemistry, vol. 278, no. 52, pp. 52964-52971. https://doi.org/10.1074/jbc.M309039200

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title = "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, 14-3-3γ, 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 14-3-3γ. 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.",

author = "Harry Towbin and Bair, {Kenneth W.} and DeCaprio, {James A.} and Eck, {Michael J.} and Sunkyu Kim and Kinder, {Frederick R.} and Anthony Morollo and Mueller, {Dieter R.} and Patrick Schindler and Song, {Hyun Kyu} and {Van Oostrum}, Jan and Versace, {Richard W.} and Hans Voshol and Jeanette Wood and Sonya Zabludoff and Phillips, {Penny E.}",

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T2 - Bengamides as a new class of methionine aminopeptidase inhibitors

AU - Towbin, Harry

AU - Bair, Kenneth W.

AU - DeCaprio, James A.

AU - Eck, Michael J.

AU - Kim, Sunkyu

AU - Kinder, Frederick R.

AU - Morollo, Anthony

AU - Mueller, Dieter R.

AU - Schindler, Patrick

AU - Song, Hyun Kyu

AU - Van Oostrum, Jan

AU - Versace, Richard W.

AU - Voshol, Hans

AU - Wood, Jeanette

AU - Zabludoff, Sonya

AU - Phillips, Penny E.

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AB - 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, 14-3-3γ, 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 14-3-3γ. 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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Proteomics-based target identification: Bengamides as a new class of methionine aminopeptidase inhibitors

Abstract

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UN SDGs

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