학술논문
Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.
Document Type
article
Author
Xie, Stanley; Metcalfe, Riley; Dunn, Elyse; Morton, Craig; Huang, Shih-Chung; Puhalovich, Tanya; Du, Yawei; Wittlin, Sergio; Nie, Shuai; Luth, Madeline; Ma, Liting; Kim, Mi-Sook; Pasaje, Charisse; Kumpornsin, Krittikorn; Giannangelo, Carlo; Houghton, Fiona; Churchyard, Alisje; Famodimu, Mufuliat; Barry, Daniel; Gillett, David; Dey, Sumanta; Kosasih, Clara; Newman, William; Niles, Jacquin; Lee, Marcus; Baum, Jake; Ottilie, Sabine; Creek, Darren; Williamson, Nicholas; Parker, Michael; Brand, Stephen; Langston, Steven; Dick, Lawrence; Griffin, Michael; Gould, Alexandra; Tilley, Leann; Winzeler, Elizabeth
Source
Science. 376(6597)
Subject
Language
Abstract
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.