title: Understanding the selectivity of fumagillin for the methionine aminopeptidase type II.
abstract: The aim of this study is to explain the selectivity of the antiangiogenic drug fumagillin for the eukaryotic enzyme methionine aminopeptidase type II (MetAP-II, EC 3.4.11.18) over the structurally very similar MetAP-I. A homology model for the human MetAP-I is constructed and molecular dynamics simulations are performed on this model with and without a docked fumagillin molecule. These simulations are compared with analogous simulations that were performed on the experimentally determined structure of the human MetAP-II enzyme. We observe an increased flexibility of the active site histidine that is covalently modified by fumagillin in the MetAP-I enzyme. The MetAP-I active site residues, particularly the fumagillin-binding histidine, have a lower probability to be in a conformation that is prone to react with the drug than their MetAP-II counterparts. This result offers an explanation for the selectivity of fumagillin for the eukaryotic MetAP-II enzyme.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, University of the Saarland FR 8.5, PO Box 151150, D-66111 Saarbruecken, Germany. cdpk@mx.uni-sb.de
authors.forename: Christian D P
authors.initials: CD
authors.lastname: Klein
authors.forename: G
authors.initials: G
authors.lastname: Folkers
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000187:drug effects* / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D003510:Cyclohexanes; D004926:Escherichia coli / Q000201:enzymology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology*; D006639:Histidine / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000187:drug effects* / Q000378:metabolism*; D063208:Methionyl Aminopeptidases; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012717:Sesquiterpenes; D055672:Static Electricity; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; D006639:Histidine; C026211:fumagillin; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases