title: Design, synthesis and activity of bisubstrate, transition-state analogues and competitive inhibitors of aspartate transcarbamylase.
abstract: Aspartate transcarbamylase initiates the de novo biosynthetic pathway for the production of the pyrimidine nucleotides, precursors of nucleic acids. This pathway is particularly active in rapidly growing cells and tissues. Thus, this enzyme has been tested as a potential target for antiproliferative drugs. In the present work, on the basis of its structural and mechanistic properties, a series of substrate analogues, including potential suicide-pseudosubstrates was synthesized and their putative inhibitory effects were tested using E. coli aspartate transcarbamylase as a model. Two of these compounds appear to be very efficient inhibitors of this enzyme.
authors.affiliation: INCM FR CNRS 1742, UMR CNRS-UHP Nancy I 7565, Université Henri Poincaré, institut nanceien de chimie moléculaire, laboratoire de chimie organique biomoléculaire, Vandoeuvre-lès-Nancy, France. claude.grison@lco2.uhp-nancy.fr
authors.forename: Claude
authors.initials: C
authors.lastname: Grison
authors.forename: Philippe
authors.initials: P
authors.lastname: Coutrot
authors.forename: Corinne
authors.initials: C
authors.lastname: Comoy
authors.forename: Laurence
authors.initials: L
authors.lastname: Balas
authors.forename: Stéphane
authors.initials: S
authors.lastname: Joliez
authors.forename: Guido
authors.initials: G
authors.lastname: Lavecchia
authors.forename: Patrick
authors.initials: P
authors.lastname: Oliger
authors.forename: Bernadette
authors.initials: B
authors.lastname: Penverne
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Guy
authors.initials: G
authors.lastname: Hervé
mesh_terms: D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001667:Binding, Competitive; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D007700:Kinetics; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D001221:Aspartate Carbamoyltransferase