title: Activation and inhibition of CTP synthase from Trypanosoma brucei, the causative agent of African sleeping sickness.
abstract: CTP Synthase from Trypanosoma brucei (TbCTPS) catalyzes the conversion of UTP to CTP and is a recognized target for the development of antiprotozoal agents. GTP activates glutamine-dependent CTP formation catalyzed by TbCTPS at concentrations below 0.2 mM, but inhibits this activity at concentrations above 0.2 mM. TbCTPS catalyzes ammonia-dependent CTP formation, which is inhibited by purine derivatives such as GTP, guanosine, caffeine, and uric acid with IC(50) values of 460, 380, 480, and 100 μM, respectively. These observations suggest that the purine ring may serve as a useful scaffold for the development of inhibitors of trypanosomal CTP synthase.
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Steeves
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Bearne
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D011687:Purines; D011994:Recombinant Proteins; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; C030985:purine