Potent Inhibitors of tRNA-Guanine Transglycosylase,an Enzyme Linked to the Pathogenicity of the Shigella Bacterium:Charge-Assisted Hydrogen Bonding

摘要

tRNA-Guanine transglycosylase(TGT,EC 2.4.2.29)is a tRNA-modifying enzyme common to nearly all organisms including humans.In bacteria,TGT catalyzes the exchange of guanine in position 34 by preQ_1,whereas eukaryotic TGT accelerates the replacement by queuine.This difference in substrate specificity offers the possibility for selective inhibition of the bacterial enzyme,which has been linked to the pathogenicity of Shigella,the causative agent of bacillary dysentery(Shigellosis),a diarrheal disease responsible for more than a million deaths annually.As substantial crystallographic and biochemical information about the bacterial enzyme is available,TGT represents an ideal target for structure-based drug design to facilitate the development of selective antibiotics against bacillary dysentery.