title: Inhibition of Helicobacter pylori Glu-tRNAGlnamidotransferase by novel analogues of the putative transamidation intermediate.
abstract: Glutaminyl-tRNAGlnin Helicobacter pylori is formed by an indirect route requiring a noncanonical glutamyl-tRNA synthetase and a tRNA-dependent heterotrimeric amidotransferase (AdT) GatCAB. Widespread use of this pathway among prominent human pathogens, and its absence in the mammalian cytoplasm, identify AdT as a target for the development of antimicrobial agents. We present here the inhibitory properties of three dipeptide-like sulfone-containing compounds analogous to the transamidation intermediates, which are competitive inhibitors of AdT with respect to Glu-tRNAGln. Molecular docking revealed that AdT inhibition by these compounds depends on π-π stacking interactions between their aromatic groups and Tyr81 of the GatB subunit. The properties of these inhibitors indicate that the 3'-terminal adenine of Glu-tRNAGlnplays a major role in binding to the AdT transamidation active site.
authors: Département de Biochimie, de Microbiologie et de Bio-informatique, Faculté des Sciences et de Génie, Université Laval, Québec, Canada. van-hau.pham.1@ulaval.ca.|Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Canada. van-hau.pham.1@ulaval.ca.|The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada. van-hau.pham.1@ulaval.ca.
authors: Van Hau
authors: VH
authors: Pham
authors: Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Canada.
authors: Halim
authors: H
authors: Maaroufi
authors: The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada.|Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec, Canada.
authors: Christian
authors: C
authors: Balg
authors: Département de Biochimie, de Microbiologie et de Bio-informatique, Faculté des Sciences et de Génie, Université Laval, Québec, Canada.|Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Canada.|The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada.
authors: Sébastien P
authors: SP
authors: Blais
authors: CHU de Québec, Centre de Recherche en Infectiologie, Université Laval, Québec, Canada.
authors: Nancy
authors: N
authors: Messier
authors: CHU de Québec, Centre de Recherche en Infectiologie, Université Laval, Québec, Canada.
authors: Paul H
authors: PH
authors: Roy
authors: The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada.|Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec, Canada.
authors: François
authors: F
authors: Otis
authors: The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada.|Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec, Canada.
authors: Normand
authors: N
authors: Voyer
authors: Département de Biochimie, de Microbiologie et de Bio-informatique, Faculté des Sciences et de Génie, Université Laval, Québec, Canada. Jacques.Lapointe@bcm.ulaval.ca.|Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Canada. Jacques.Lapointe@bcm.ulaval.ca.|The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada. Jacques.Lapointe@bcm.ulaval.ca.
authors: Jacques
authors: J
authors: Lapointe
authors: The Quebec Network for Research on Protein Function, Structure and Engineering (PROTEO), Université Laval, Québec, Canada. Robert.Chenevert@chm.ulaval.ca.|Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec, Canada. Robert.Chenevert@chm.ulaval.ca.
authors: Robert
authors: R
authors: Chênevert
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000201:enzymology*; D019884:Nitrogenous Group Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding
chemical_list: D001426:Bacterial Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D019884:Nitrogenous Group Transferases; C047694:glutamyl-tRNA(Gln) amidotransferase
keywords: GatCAB; competitive inhibitors; molecular docking; pathogenic bacteria; protein biosynthesis; transition state analogues