Human Methionine Aminopeptidase 1 (MetAP1) as a New Anticancer Target

摘要

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. Human methionine aminopeptidase II (hMetAP2) has been identified as the pharmacological target of fumagillin, a natural anti-angiogenic compound originating from fungi. Furthermore, studies on Bengamides, inhibitors of both human MetAPI and II, have revealed significant antitumor effects. These data suggest hMetAPl may play an important role in tumor cell growth. During the period of this report, a high throughput screen for selective inhibitors of human methionine aminopeptidase I (hMetAP1) was performed. Several selective lead compounds have been identified with a core structure of pyridine-2- carboxylic acid. These compounds also inhibited MCF-7 cell proliferation with micromolar IC(sub 50) and induced a G2/M phase cell cycle delay. In spite of rescue for cell proliferation by hMetAP1 overexpression, gene-specific silencing (RNAi) of hMetAP1 did not recapitulate the cell cycle effect by drug inhibition. A recent report on mitochondrial hMetAP isoform is in attention and named as hMetAP3. hMetAP3 has been cloned and expressed in E.coli. hMetAP1 selective inhibitors showed equal potency toward hMetAP3 in enzymatic assay in vitro. Study of hMetAP3 function is currently ongoing.