title: Methionine aminopeptidase 2 is a key regulator of apoptotic like cell death in Leishmania donovani.
abstract: We investigate the role of methionine aminopeptidase 2 (MAP2) in miltefosine induced programmed cell death (PCD) in promastigote form of L. donovani. We report that TNP-470, an inhibitor of MAP2, inhibits programmed cell death in miltefosine treated promastigotes. It inhibits the biochemical features of metazoan apoptosis, including caspase3/7 protease like activity, oligonucleosomal DNA fragmentation, collapse of mitochondrial transmembrane potential, and increase in cytosolic pool of calcium ions but did not prevent the cell death and phosphatidyl serine externalization. The data suggests that the MAP2 is involved in the regulation of PCD in parasite. Moreover, TNP-470 shows the leishmanicidal activity (IC50= 15 µM) and in vitro inhibition of LdMAP2 activity (Ki= 13.5 nM). Further studies on MAP2 and identification of death signaling pathways provide valuable information that could be exploited to understand the role of non caspase proteases in PCD of L. donovani.
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India.
authors.forename: Kartikeya
authors.initials: K
authors.lastname: Tiwari
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, 781039, India. vdubey@iitg.ernet.in.
authors.forename: Vikash Kumar
authors.initials: VK
authors.lastname: Dubey
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016923:Cell Death; D003001:Cloning, Molecular; D003510:Cyclohexanes / Q000494:pharmacology*; D053938:DNA Fragmentation; D005786:Gene Expression Regulation / Q000187:drug effects; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D003510:Cyclohexanes; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D010767:Phosphorylcholine; C039128:miltefosine; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol