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Inhibition of Helicobacter pylori Glu‐t RNA G ln amidotransferase by novel analogues of the putative transamidation intermediate
Author(s) -
Pham Van Hau,
Maaroufi Halim,
Balg Christian,
Blais Sébastien P.,
Messier Nancy,
Roy Paul H.,
Otis François,
Voyer Normand,
Lapointe Jacques,
Chênevert Robert
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12380
Subject(s) - glutamine amidotransferase , heterotrimeric g protein , chemistry , biochemistry , docking (animal) , stereochemistry , amino acid , glutamine , medicine , g protein , receptor , nursing
Glutaminyl‐t RNA G ln in Helicobacter pylori is formed by an indirect route requiring a noncanonical glutamyl‐t RNA synthetase and a t RNA ‐dependent heterotrimeric amidotransferase (AdT) Gat CAB . 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‐t RNA G ln . 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‐t RNA G ln plays a major role in binding to the AdT transamidation active site.