The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2 Journal Article
| Authors: | Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. G.; Crews, C. M. |
| Article Title: | The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2 |
| Abstract: | The inhibition of new blood vessel formation (angiogenesis) is an effective means of limiting both the size and metastasis of solid tumors. The leading anti-angiogenic compound, TNP-470, has proven to be effective in in vitro and in animal model studies, and is currently being tested in phase III antitumor clinical trials. Despite many detailed pharmacological studies, little is known of the molecular mode of action of TNP-470. Using a derivative of the TNP-470 parent compound, the fungal metabolite, fumagillin, we have purified a mammalian protein that is selectively and covalently bound by this natural product. This fumagillin binding protein was found to be a metalloprotease, methionine aminopeptidase (MetAP-2), that is highly conserved between human and Saccharomyces cerevisiae. In the absence of MetAP-1, a distantly related methionine aminopeptidase, MetAP-2 function is essential for vegetative growth in yeast. We demonstrate that fumagillin selectively inhibits the S. cerevisiae MetAP-2 protein in vivo. The binding is highly specific as judged by the failure of fumagillin to inhibit MetAP-1 in vivo. Hence, these results identify MetAP-2 as an important target of study in the analysis of the potent biological activities of fumagillin. |
| Keywords: | controlled study; human cell; angiogenesis inhibitor; animals; enzyme inhibition; drug potency; neovascularization, pathologic; endothelium cell; amino acid sequence; molecular sequence data; sequence homology, amino acid; kinetics; drug mechanism; umbilical vein; saccharomyces cerevisiae; sequence alignment; binding sites; cattle; antibiotics, antineoplastic; mammals; methionine; fungus growth; metalloproteinase; cytostasis; fumagillol chloroacetylcarbamate; biotin; cyclohexanes; sesquiterpenes; metastasis inhibition; covalent bond; fatty acids, unsaturated; aminopeptidase; metalloendopeptidases; fumagillin; humans; human; priority journal; article; aminopeptidases; drug binding protein |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 94 |
| Issue: | 12 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1997-06-10 |
| Start Page: | 6099 |
| End Page: | 6103 |
| Language: | English |
| DOI: | 10.1073/pnas.94.12.6099 |
| PUBMED: | 9177176 |
| PROVIDER: | scopus |
| PMCID: | PMC21008 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
