About: Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

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About: Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs
Creator	Janowski, Robert Mucha, Artur Giurg, Mirosław Talma, Michał Westerhoff, Hans Węglarz-Tomczak, Ewelina
Source	Medline; PMC
abstract	The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X(2) are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound (K(i) in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D's action on tumors and suggests new avenues and molecules for medical applications.
has issue date	2018-06-29(xsd:dateTime)
bibo:doi	10.18632/oncotarget.25532
bibo:pmid	30034623
has license	cc-by
sha1sum (hex)	a03f649135d42858e9619d36c614d8faff51dafb
schema:url	https://doi.org/10.18632/oncotarget.25532
resource representing a document's title	Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs
has PubMed Central identifier	PMC6047675
has PubMed identifier	30034623
schema:publication	Oncotarget
resource representing a document's body	covid:a03f649135d42858e9619d36c614d8faff51dafb#body_text
is schema:about of	named entity 'actinomycin D' named entity 'ORIGINAL' named entity 'molecular' named entity 'MetAP2' covid:arg/a03f649135d42858e9619d36c614d8faff51dafb named entity 'CC BY 3.0' named entity 'actinomycin' named entity 'distribution' named entity 'author' named entity 'DISTRIBUTION' named entity 'permits' named entity 'CC BY' named entity 'APN' named entity 'UNRESTRICTED' named entity 'License' named entity 'targets' named entity 'analogs' named entity 'original' named entity 'PROVIDED' named entity 'SOURCE' named entity 'AUTHOR' named entity 'Neutral' named entity 'discovered' named entity 'METAP2' named entity 'ANALOGS' named entity 'SIMPLE' named entity 'NEWLY DISCOVERED' named entity 'USE' named entity 'REPRODUCTION' named entity 'LICENSE' named entity 'MEDIUM' named entity 'ITS' named entity 'NEUTRAL' named entity 'ACTINOMYCIN D' named entity 'ANTICANCER' named entity 'TARGETS' named entity 'APN' named entity 'MOLECULAR' nodeID://b56156898 nodeID://b56160474 nodeID://b56186278 nodeID://b56205486 nodeID://b56218922 nodeID://b56226074 nodeID://b56231378 nodeID://b56266082 nodeID://b56267366 nodeID://b56310206 nodeID://b56355458 nodeID://b56356138 nodeID://b56381118
is wasQuotedFrom of	covid:arg/a03f649135d42858e9619d36c614d8faff51dafb/0 covid:arg/a03f649135d42858e9619d36c614d8faff51dafb/1 covid:arg/a03f649135d42858e9619d36c614d8faff51dafb/2
is part of of	The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X(2) are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound (K(i) in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D's action on tumors and suggests new avenues and molecules for medical applications. Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs covid:a03f649135d42858e9619d36c614d8faff51dafb#body_text

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