Understanding the selectivity of fumagillin for the methionine aminopeptidase type II.
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.
Klein
Christian D P
CD
Pharmaceutical and Medicinal Chemistry, University of the Saarland FR 8.5, PO Box 151150, D-66111 Saarbruecken, Germany. cdpk@mx.uni-sb.de
Folkers
G
G
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
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