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The purine salvage pathway is redundant and contains two routes to guanosine\u20105\u2032\u2010monophosphate (<jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content>) formation: conversion from xanthosine\u20105\u2032\u2010monophosphate (<jats:styled-content style=\"fixed-case\">XMP<\/jats:styled-content>) by <jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content> synthase (<jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content>) or direct salvage of guanine by hypoxanthine\u2010guanine phosphoribosyltransferase (<jats:styled-content style=\"fixed-case\">HGPRT<\/jats:styled-content>). We show recombinant <jats:styled-content style=\"fixed-case\"><jats:italic>T<\/jats:italic><\/jats:styled-content><jats:italic>.\u2009brucei<\/jats:italic>\u2005<jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content> efficiently catalyzes <jats:styled-content style=\"fixed-case\">GMP<\/jats:styled-content> formation. Genetic knockout of <jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content> in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of <jats:italic>gmps<\/jats:italic> null cells was only rescued by supraphysiological guanine concentrations (100\u2009\u03bcM) or by expression of an extrachromosomal copy of <jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content>. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake\/metabolic conversion mechanism. In mice, <jats:italic>gmps<\/jats:italic> null parasites were unable to establish an infection demonstrating that <jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content> is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate <jats:styled-content style=\"fixed-case\">GMPS<\/jats:styled-content> as a potential therapeutic target for treatment of human <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>frican trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche.<\/jats:p>","DOI":"10.1111\/mmi.13083","type":"journal-article","created":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T07:45:34Z","timestamp":1433490334000},"page":"1006-1020","source":"Crossref","is-referenced-by-count":35,"title":["<scp>GMP<\/scp> synthase is essential for viability and infectivity of <scp><i>T<\/i><\/scp><i>rypanosoma brucei<\/i> despite a redundant purine salvage pathway"],"prefix":"10.1111","volume":"97","author":[{"given":"Qiong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Texas Southwestern Medical Center at Dallas  6001 Forest Park Rd Dallas TX 75390\u20109041 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