<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Zheng,J.</style></author><author><style face="normal" font="default" size="100%">Rubin,E.J.</style></author><author><style face="normal" font="default" size="100%">Bifani,P.</style></author><author><style face="normal" font="default" size="100%">Vanessa Mathys</style></author><author><style face="normal" font="default" size="100%">Lim,V.</style></author><author><style face="normal" font="default" size="100%">Au,M.</style></author><author><style face="normal" font="default" size="100%">Jang,J.</style></author><author><style face="normal" font="default" size="100%">Nam,J.</style></author><author><style face="normal" font="default" size="100%">Dick,T.</style></author><author><style face="normal" font="default" size="100%">Walker,J.R.</style></author><author><style face="normal" font="default" size="100%">Pethe,K.</style></author><author><style face="normal" font="default" size="100%">L. Camacho</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis33991</style></title><secondary-title><style face="normal" font="default" size="100%">J.Biol.Chem.</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">0</style></keyword><keyword><style  face="normal" font="default" size="100%">a</style></keyword><keyword><style  face="normal" font="default" size="100%">acid</style></keyword><keyword><style  face="normal" font="default" size="100%">Activity</style></keyword><keyword><style  face="normal" font="default" size="100%">Agent</style></keyword><keyword><style  face="normal" font="default" size="100%">Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Aminosalicylic Acid</style></keyword><keyword><style  face="normal" font="default" size="100%">an</style></keyword><keyword><style  face="normal" font="default" size="100%">antagonists &amp; inhibitors</style></keyword><keyword><style  face="normal" font="default" size="100%">Antitubercular Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">article</style></keyword><keyword><style  face="normal" font="default" size="100%">AS</style></keyword><keyword><style  face="normal" font="default" size="100%">Bacterial Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Benzoic Acid</style></keyword><keyword><style  face="normal" font="default" size="100%">biosynthesis</style></keyword><keyword><style  face="normal" font="default" size="100%">Clinical</style></keyword><keyword><style  face="normal" font="default" size="100%">Dihydropteroate Synthase</style></keyword><keyword><style  face="normal" font="default" size="100%">disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Diseases</style></keyword><keyword><style  face="normal" font="default" size="100%">DRUG</style></keyword><keyword><style  face="normal" font="default" size="100%">drugs</style></keyword><keyword><style  face="normal" font="default" size="100%">electronic</style></keyword><keyword><style  face="normal" font="default" size="100%">evidence</style></keyword><keyword><style  face="normal" font="default" size="100%">Folate</style></keyword><keyword><style  face="normal" font="default" size="100%">Folic Acid</style></keyword><keyword><style  face="normal" font="default" size="100%">Folic Acid Antagonists</style></keyword><keyword><style  face="normal" font="default" size="100%">Folic-acid</style></keyword><keyword><style  face="normal" font="default" size="100%">Functional</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Knockdown Techniques</style></keyword><keyword><style  face="normal" font="default" size="100%">genetics</style></keyword><keyword><style  face="normal" font="default" size="100%">identification</style></keyword><keyword><style  face="normal" font="default" size="100%">im</style></keyword><keyword><style  face="normal" font="default" size="100%">Institute</style></keyword><keyword><style  face="normal" font="default" size="100%">IS</style></keyword><keyword><style  face="normal" font="default" size="100%">IT</style></keyword><keyword><style  face="normal" font="default" size="100%">journal</style></keyword><keyword><style  face="normal" font="default" size="100%">Laboratories</style></keyword><keyword><style  face="normal" font="default" size="100%">mechanism</style></keyword><keyword><style  face="normal" font="default" size="100%">metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">Pa</style></keyword><keyword><style  face="normal" font="default" size="100%">PAS</style></keyword><keyword><style  face="normal" font="default" size="100%">pharmacokinetics</style></keyword><keyword><style  face="normal" font="default" size="100%">pharmacology</style></keyword><keyword><style  face="normal" font="default" size="100%">prevent</style></keyword><keyword><style  face="normal" font="default" size="100%">Prodrugs</style></keyword><keyword><style  face="normal" font="default" size="100%">protein</style></keyword><keyword><style  face="normal" font="default" size="100%">Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">report</style></keyword><keyword><style  face="normal" font="default" size="100%">Research</style></keyword><keyword><style  face="normal" font="default" size="100%">Research Support</style></keyword><keyword><style  face="normal" font="default" size="100%">resistance</style></keyword><keyword><style  face="normal" font="default" size="100%">SB - IM</style></keyword><keyword><style  face="normal" font="default" size="100%">strain</style></keyword><keyword><style  face="normal" font="default" size="100%">Tetrahydrofolate Dehydrogenase</style></keyword><keyword><style  face="normal" font="default" size="100%">Tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">use</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2013</style></year><pub-dates><date><style  face="normal" font="default" size="100%">9/8/2013</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">23456</style></number><volume><style face="normal" font="default" size="100%">288</style></volume><pages><style face="normal" font="default" size="100%">23447 - 23456</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity. Interestingly, PAS is recognized by DHPS as efficiently as its natural substrate para-amino benzoic acid. Chemical inhibition of DHPS or mutation in DHFS prevents the formation of the antimetabolite, thereby conferring resistance to PAS. In addition, we identified a bifunctional enzyme (riboflavin biosynthesis protein (RibD)), a putative functional analog of DHFR in a knock-out strain. This finding is further supported by the identification of PAS-resistant clinical isolates encoding a RibD overexpression mutation displaying cross-resistance to genuine DHFR inhibitors. Our findings reveal that a metabolite of PAS inhibits DHFR in the folate pathway. RibD was shown to act as a functional analog of DHFR, and as for DHFS, both were shown to be associated in PAS resistance in laboratory strains and clinical isolates</style></abstract><issue><style face="normal" font="default" size="100%">32</style></issue><custom1><style face="normal" font="default" size="100%">38480</style></custom1><section><style face="normal" font="default" size="100%">23447</style></section></record></records></xml>