MAP1D, a novel methionine aminopeptidase family member is overexpressed in colon cancer

Leszczyniecka, Magdalena; Bhatia, Umesh; Cueto, Maria; Nirmala, Nanguneri; Towbin, Harry; Vattay, Anthony; Wang, B; Zabludoff, Sonya; Phillips, Penny E.

doi:10.1038/sj.onc.1209383

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…Besides the two well-studied human MetAPs, there is another less-known human MetAP named MetAP1D, which is of mitochondrial origin. 28 It was only biochemically characterized, 29 and its structural information is not available. Therefore, selective inhibitors of human MetAPs are desired to provide the research tools to elucidate the mechanism of individual human MetAP in cancer pathogenesis and to generate novel leads as anticancer agents.…”

Section: Resultsmentioning

confidence: 99%

Structural Analysis of Bengamide Derivatives as Inhibitors of Methionine Aminopeptidases

Xü

Lü

2012

J. Med. Chem.

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Natural product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases (MetAPs) for their cellular effects. Several derivatives were designed, synthesized, and evaluated as MetAP inhibitors. Here, we present four new X-ray structures of human MetAP1 in complex with the inhibitors. Together with the previous structures of bengamide derivatives with human MetAP2 and tubercular MtMetAP1c, analysis of the interactions of these inhibitors at the active site provides structural basis for further modification of these bengamide inhibitors for improved potency and selectivity as anticancer and antibacterial therapeutics.

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Section: Resultsmentioning

confidence: 99%

Structural Analysis of Bengamide Derivatives as Inhibitors of Methionine Aminopeptidases

Xü

Lü

2012

J. Med. Chem.

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“…103) or prevention of malignant progression following p53-dependent activation 159 . OMA1 is also upregulated by p53, increasing cisplatin chemosensitivity in gynaecological cancer cells 160 , whereas the aminopeptidase METAP1D is overexpressed in colon cancer, and its downregulation decreases the tumorigenic potential of colorectal cancer cells 161 . Finally, several SNPs in IMMP2L have been associated with genetic susceptibility to differentiated thyroid cancer 162 .…”

Section: Mitoproteases and Human Diseasesmentioning

confidence: 99%

New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

461

424

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Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.

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“…N-terminal methionine processing is accomplished by the action of two intracellular metalloproteases: methionine aminopeptidase 1 and 2 (MetAP1 and MetAP2) (2,3). Recently, evidence for an additional mammalian enzyme, MAP1D (or MetAP3), has been shown (4). Although very little is known about the new protein, it appears to be localized in the mitochondria and to resemble MetAP1 in several respects, including high amino acid homology and similar inhibitor sensitivity.…”

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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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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MAP1D, a novel methionine aminopeptidase family member is overexpressed in colon cancer

Cited by 28 publications

References 31 publications

Structural Analysis of Bengamide Derivatives as Inhibitors of Methionine Aminopeptidases

Structural Analysis of Bengamide Derivatives as Inhibitors of Methionine Aminopeptidases

New roles for mitochondrial proteases in health, ageing and disease

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

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