Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases.

Li, Xuan; Chang, Yie‐Hwa

doi:10.1073/pnas.92.26.12357

Cited by 282 publications

(238 citation statements)

References 30 publications

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“…These two enzymes are both associated with the ribosome and could compensate for each other (5). MetAP1 and MetAP2 double-null yeast strains are nonviable, but the MetAP1-or MetAP2-null strain is viable, albeit with a slower growth rate (5,6). In addition, overall protein N-myristoylation is unaffected in endothelial cells treated with the selective MetAP2 inhibitor TNP-470, suggesting that MetAP1 activity can generally compensate when MetAP2 is inactive (6).…”

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confidence: 87%

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Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

Wang

Tucker

Stavropoulos

et al. 2008

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

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This laboratory and others have shown that agents that inhibit the in vitro catalytic activity of methionine aminopeptidase-2 (MetAP2) are effective in blocking angiogenesis and tumor growth in preclinical models. However, these prototype MetAP2 inhibitors are clearly not optimized for therapeutic use in the clinic. We have discovered an orally active class of MetAP2 inhibitors, the anthranilic acid sulfonamides exemplified by A-800141, which is highly specific for MetAP2. This orally bioavailable inhibitor exhibits an antiangiogenesis effect and a broad anticancer activity in a variety of tumor xenografts including B cell lymphoma, neuroblastoma, and prostate and colon carcinomas, either as a single agent or in combination with cytotoxic agents. We also have developed a biomarker assay to evaluate in vivo MetAP2 inhibition in circulating mononuclear cells and in tumors. This biomarker assay is based on the N-terminal methionine status of the MetAP2-specific substrate GAPDH in these cells. In cell cultures in vitro, the sulfonamide MetAP2 inhibitor A-800141 caused the formation of GAPDH variants with an unprocessed N-terminal methionine. A-800141 blocked tumor growth and MetAP2 activity in a similar dose-response in mouse models, demonstrating the antitumor effects seen for A-800141 are causally connected to MetAP2 inhibition in vivo. The sulfonamide MetAP2 inhibitor and GAPDH biomarker in circulating leukocytes may be used for the development of a cancer treatment.angiogenesis ͉ biomarker ͉ cancer therapy ͉ GAPDH ͉ MetAP2

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confidence: 87%

“…The differential physiological responsibilities of MetAP1 and MetAP2 are not clearly understood. These two enzymes are both associated with the ribosome and could compensate for each other (5). MetAP1 and MetAP2 double-null yeast strains are nonviable, but the MetAP1-or MetAP2-null strain is viable, albeit with a slower growth rate (5,6).…”

mentioning

confidence: 99%

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

Wang

Tucker

Stavropoulos

et al. 2008

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

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“…Fumagillin and ovalicin are also strikingly selective inhibitors of endothelial cell proliferation, whereas bengamides inhibit proliferation of all cell types tested, including both endothelial and epithelial cells. In lower organisms, viability requires at least one functional MetAp isoform (26); given that bengamides inhibit the only two known human isoforms of MetAps, their breadth of cytotoxic activity might have been predicted. However, despite the lack of specificity in vitro, tumor-specific activity was seen with bengamides in vivo, as demonstrated by the striking antitumor activity in xenograft models at well tolerated doses (3).…”

Section: Discussionmentioning

confidence: 99%

Proteomics-based Target Identification

Towbin

Bair

DeCaprio

et al. 2003

Journal of Biological Chemistry

140

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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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“…Although only one MetAP gene is present in the genome of most, but not all, prokaryotes, at least two types of MetAPs, type I and type II, are known in eukaryotic cells. In budding yeast Saccharomyces cerevisiae, deletion of either ScMetAP1 or ScMetAP2 resulted in a slow-growth phenotype compared with the wild-type strain, whereas the double mutant is nonviable, indicating the redundant yet essential functions of both types of MetAP (1,2). In multicellular organisms MetAP2 has been shown to be essential for the proliferation and development of specific tissues (3,4).…”

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confidence: 99%

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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Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases.

Cited by 282 publications

References 30 publications

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor

Proteomics-based Target Identification

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

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