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Metronidazole is currently the first-line drug despite adverse effects and concerns on the emergence of drug resistance. Fumagillin, a fungal metabolite from\n                    <jats:italic>Aspergillus fumigatus,<\/jats:italic>\n                    and its structurally related natural and synthetic compounds have been previously explored as potential anti-angiogenesis inhibitors for cancers, anti-microbial, and anti-obese compounds. Although fumagillin was used for human amebiasis in clinical trials in 1950s, the mode of action of fumagillin remains elusive until now. In this report, we showed that fumagillin covalently binds to methionine aminopeptidase 2 (MetAP2) and non-covalently but abundantly binds to patatin family phospholipase A (PLA). Susceptibility against fumagillin of the amebic strains in which expression of\n                    <jats:italic>E. histolytica MetAP2<\/jats:italic>\n                    (\n                    <jats:italic>EhMetAP2<\/jats:italic>\n                    ) gene was silenced increased compared to control strain. Conversely, overexpression of EhMetAP2 mutants that harbors amino acid substitutions responsible for resistance to ovalicin, a fumagillin analog, in human MetAP2, also resulted in decrease in fumagillin susceptibility. In contrast, neither gene silencing nor overexpression of\n                    <jats:italic>E. histolytica<\/jats:italic>\n                    PLA (EhPLA) affected fumagillin susceptibility. These data suggest that EhPLA is not essential and not the target of fumagillin for its amebicidal activity. Taken together, our data have demonstrated that EhMetAP2 is the primary target for amebicidal activity of fumagillin, and EhMetAP2 represents a rational explorable target for the development of alternative therapeutic agents against amebiasis.\n                  <\/jats:p>","DOI":"10.1128\/aac.00560-23","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T10:31:02Z","timestamp":1698143462000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Fumagillin inhibits growth of the enteric protozoan parasite\n                    <i>Entamoeba histolytica<\/i>\n                    by covalently binding to and selectively inhibiting methionine aminopeptidase 2"],"prefix":"10.1128","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3527-3100","authenticated-orcid":false,"given":"Natsuki","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of 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