Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin

Griffith, Eric C.; Su, Zhuang; Turk, Benjamin E.; Chen, Shaoping; Chang, Yie Hwa; Wu, Zheng; Biemann, K.; Liu, Jun O.

doi:10.1016/s1074-5521(97)90198-8

Cited by 412 publications

(327 citation statements)

References 37 publications

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“…The application of another immunosuppressive natural product, rapamycin, has shed significant light on the TOR kinases in myriad signaling processes from cytokine signaling to nutrient sensing (20). Similarly, the identification of MetAP2 as the cellular target for the fumagillin family of antiangiogenic natural products has helped to reveal a unique function of this otherwise universally expressed general-processing enzyme in endothelial cells (5,6) and T cells (21). However, in contrast to MetAP2, study of the cellular functions of MetAP1 has been hampered in part by the lack of an inhibitor with sufficient selectivity.…”

Section: Discussionmentioning

confidence: 99%

“…Human MetAP2 has been identified as the primary target of the fumagillin family of natural products that potently inhibit angiogenesis (5,6). A synthetic analog of fumagillin, TNP-470, with higher potency and lower toxicity, has entered clinical trials for a variety of cancers (7,8).…”

mentioning

confidence: 99%

“…A synthetic analog of fumagillin, TNP-470, with higher potency and lower toxicity, has entered clinical trials for a variety of cancers (7,8). Much evidence now exists supporting the notion that HsMetAP2 plays an important role in endothelial cell proliferation and is likely to mediate inhibition of endothelial cells by fumagillin and related analogs (5,6,9).…”

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confidence: 99%

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Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Addlagatta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Processing of the N-terminal initiator methionine is an essential cellular process conserved from prokaryotes to eukaryotes. The enzymes that remove N-terminal methionine are known as methionine aminopeptidases (MetAPs). Human MetAP2 has been shown to be required for the proliferation of endothelial cells and angiogenesis. The physiological function of MetAP1, however, has remained elusive. In this report we demonstrate that a family of inhibitors with a core structure of pyridine-2-carboxylic acid previously developed for the bacterial and yeast MetAP1 is also specific for human MetAP1 (HsMetAP1), as confirmed by both enzymatic assay and high-resolution x-ray crystallography. Treatment of tumor cell lines with the MetAP1-specific inhibitors led to an accumulation of cells in the G2͞M phase, suggesting that HsMetAP1 may play an important role in G2͞M phase transition. Overexpression of HsMetAP1, but not HsMetAP2, conferred resistance of cells to the inhibitors, and the inhibitors caused retention of N-terminal methionine of a known MetAP substrate, suggesting that HsMetAP1 is the cellular target for the inhibitors. In addition, when HsMetAP1 was knocked down by gene-specific siRNA, cells exhibited slower progression during G2͞M phase, a phenotype similar to cells treated with MetAP1 inhibitors. Importantly, MetAP1 inhibitors were able to induce apoptosis of leukemia cell lines, presumably as a consequence of their interference with the G2͞M phase checkpoint. Together, these results suggest that MetAP1 plays an important role in G2͞M phase of the cell cycle and that it may serve as a promising target for the discovery and development of new anticancer agents.aminopeptidase inhibitors ͉ angiogenesis ͉ apoptosis

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Addlagatta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Both MetAp1 and 2 were inhibited by LAF389, thus establishing MetAps as direct targets of LAF389. Fumagillin, a well known covalently reacting inhibitor specific for MetAp2 (20,21), was tested in parallel in these assays. For MetAp2, the IC 50 of LAF389 was 800 nM in this assay format, compared with 30 nM for fumagillin.…”

Section: Laf389 Inhibits Methionine Aminopeptidases Directly-mentioning

confidence: 99%

“…LAF389 Has Pronounced Activity on Endothelial CellsFumagillin selectively inhibits endothelial cell proliferation, and structure-activity relation studies of fumagillin analogues have shown that its anti-proliferative effect correlates well with MetAp2 enzyme inhibition (21,22). Therefore, it was of interest to test whether LAF389 could inhibit endothelial cell proliferation.…”

Section: Laf389 Inhibits Methionine Aminopeptidases Directly-mentioning

confidence: 99%

Proteomics-based Target Identification

Towbin

Bair

DeCaprio

et al. 2003

Journal of Biological Chemistry

144

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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 proteomicsbased 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, 14-3-3␥, 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 14-3-3␥. 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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Selective inhibition of endothelial cell proliferation by fumagillin is not due to differential expression of methionine aminopeptidases

2000

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The angiogenesis inhibitors fumagillin and TNP-470 selectively inhibit the proliferation of endothelial cells, as compared with most other cell types. The mechanism of this selective inhibition remains uncertain, although methionine aminopeptidase-2 (MetAP2) has recently been found to be a target for fumagillin or TNP-470, which inactivates MetAP2 enzyme activity through covalent modification. Primary cultures of human endothelial cells and six other non-endothelial cell types were treated with fumagillin to determine its effect on cell proliferation. Only the growth of endothelial cells was completely inhibited at low concentrations of fumagillin. MetAP1 and MetAP2 levels in these cells were investigated to determine whether differential enzyme expression plays a role in the selective action of fumagillin. Western blot analysis and RT-PCR data showed that MetAP1 and MetAP2 were both expressed in these different types of cells, thus, ruling out differential expression of MetAP1 and MetAP2 as an explanation for the cell specificity of fumagillin. Expression of MetAP2, but not of MetAP1, is regulated. Treatment of human microvascular endothelial cells (HMVEC) with fumagillin resulted in threefold increases of MetAP2 protein in the cells, while MetAP1 remained constant. Similar upregulation of MetAP2 by exposure to fumagillin was also observed in non-endothelial cells, eliminating this response as an explanation for cell specificity. Taken together, these results indicate that while MetAP2 plays a critical role in the effect of fumagillin on endothelial cell proliferation, differential endogenous expression or fumagillin-induced upregulation of methionine aminopeptidases is not responsible for this observed selective inhibition.

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Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin

Abstract: The protein MetAP2 is a common molecular target for both AGM-1470 and ovalicin. This finding suggests that MetAP2 may play a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs.

Cited by 412 publications

References 37 publications

Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression

Proteomics-based Target Identification

Selective inhibition of endothelial cell proliferation by fumagillin is not due to differential expression of methionine aminopeptidases

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