6.3.4.2 1,3,7,9-tetramethyluric - 39970 6.3.4.2 1,3,7-trimethyluric acid - 39969 6.3.4.2 1,3-dimethyluric acid pH-dependent inhibition, overview 39967 6.3.4.2 1,7-dimethyluric acid pH-dependent inhibition, overview 39968 6.3.4.2 1-methyluric acid - 23326 6.3.4.2 2',3'-dialdehyde adenosine 5'-triphosphate irreversible inhibitor of CTPS 14077 6.3.4.2 2'-deoxy-GTP no guanosine, kact: 1.5/sec, KA: 0.21 mM, Ki: 0.36 mM; the GTP analogue is capable of inhibiting Gln-dependent CTP formation at over 0.15 mM 5697 6.3.4.2 2'-deoxy-guanosine - 36605 6.3.4.2 2,6-diaminopurine riboside - 13381 6.3.4.2 2-aminopurine riboside - 8690 6.3.4.2 2-Thiocytidine 5'-triphosphate - 29416 6.3.4.2 2-thiouridine 5'-triphosphate - 13025 6.3.4.2 3'-deoxy-guanosine - 36463 6.3.4.2 3,7-dimethyluric acid - 23325 6.3.4.2 3-Deazauridine 5'-triphosphate - 91408 6.3.4.2 4-thiouridine 5'-triphosphate - 52277 6.3.4.2 5-bromoUTP - 13421 6.3.4.2 6-diazo-5-oxo-L-norleucine reduces the parasite CTP level even further and inhibits trypanosome proliferation in vitro and in Trypanosoma brucei-infected mice 839 6.3.4.2 6-diazo-5-oxo-L-norleucine - 839 6.3.4.2 6-thio-GTP the GTP analogue is capable of inhibiting Gln-dependent CTP formation at over 0.15 mM 18833 6.3.4.2 6-thioguanine - 1253 6.3.4.2 6-thioguanosine - 9517 6.3.4.2 6-thioguanosine 5'-triphosphate no guanosine, kact: 8.5/sec, KA: 0.035 mM, Ki: 0.27 mM 18242 6.3.4.2 7-deazaguanosine - 135715 6.3.4.2 8-oxoguanosine - 24481 6.3.4.2 8-oxoguanosine 5'-triphosphate - 36461 6.3.4.2 acivicin irreversible inhibition by the glutamine analogue acivin. The acivicin inhibition of Trypanosoma brucei CTPS is more pronounced when the enzyme is preincubated with the drug in the presence of nucleotide substrates than in the absence of substrates 2824 6.3.4.2 acycloguanosine - 4406 6.3.4.2 acycloguanosine monophosphate - 36465 6.3.4.2 adenine - 144 6.3.4.2 adenosine - 122 6.3.4.2 adenosine 5'-[beta,gamma-imido]triphosphate poor inhibitor compared to ATPgammaS 8034 6.3.4.2 adenylyl-iminodiphosphate competitive with ATP 115169 6.3.4.2 alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid reduces the parasite CTP level even further and inhibits trypanosome proliferation in vitro and in Trypanosoma brucei-infected mice 115241 6.3.4.2 ATPgammaS - 1860 6.3.4.2 Caffeine - 882 6.3.4.2 Co2+ above 2 mM 23 6.3.4.2 CTP IC50: 0.3 mM 60 6.3.4.2 CTP product inhibition of wild-type enzyme, mutant E161K is less sensitive to CTP product inhibition 60 6.3.4.2 CTP cooperative inhibition 60 6.3.4.2 CTP IC50: 0.32 mM 60 6.3.4.2 CTP mixed inhibition 60 6.3.4.2 CTP - 60 6.3.4.2 CTP IC50 for the native enzyme: 0.12 in presence of 0.5 mM ATP, 0.22 mM in presence of 1 mM ATP. IC50 for the phosphorylated enzyme: 0.21 mM in presence of 0.5 mM ATP, 0.31 mM in presence of 1 mM ATP 60 6.3.4.2 CTP allosteric inhibition 60 6.3.4.2 CTP feedback inhibitor; IC50: 0.05 mM 60 6.3.4.2 CTP IC50: 0.15 mM 60 6.3.4.2 CTP the enzyme from T lymphoblast S49 cells is refractory to complete inhibition by CTP 60 6.3.4.2 CTP allosteric regulation, product inhibition 60 6.3.4.2 Cu2+ inhibition is not reversed by EDTA, in presence of dithiothreitol inhibition at concentrations below 0.2 mM 19 6.3.4.2 cyclopentenyl cytosine the inhibitor has a cytostatic effect on lymphoblasts of children with acute lymphocytic leukemia 52492 6.3.4.2 cyclopentenyl cytosine a highly specific inhibitor of CTPS1, in vivo inhibition leads to alterations in the cell nuclei and microtubule network, overview 52492 6.3.4.2 cyclopentylcytosine triphosphate - 115510 6.3.4.2 D,L-2-amino-4-phosphonobutyrate - 51995 6.3.4.2 dCTP very weak inhibitor 179 6.3.4.2 DELTA1-Pyrroline-5-carboxylate weak 3810 6.3.4.2 dideoxy-GTP - 36464 6.3.4.2 DL-DELTA1-pyrroline 5-carboxylate 0.125 mM, complete inhibition of ammonium chloride-dependent CTP synthesis 127608 6.3.4.2 GDP - 53 6.3.4.2 Gln inhibition of hydroxylamine-dependent N4-OH CTP synthesis in presence of GTP 378 6.3.4.2 glutamate gamma-semialdehyde potent linear mixed-type inhibitor, competitive with respect to ammonia, no inhibition of the mutant enzyme C379A 33430 6.3.4.2 GMP - 162 6.3.4.2 GTP inhibition of N4-OH-CTP synthesis 37 6.3.4.2 GTP inhibition of glutamine-dependent CTP formation above 0.15 mM, inhibition of glutamine-dependent CTP formation in a concentration-dependent manner 37 6.3.4.2 GTP 0.1 mM guanosine, kact: 10.3/sec, KA: 0.088 mM, Ki: 0.22 mM; 0.2 mM guanosine, kact: 8.2/sec, KA: 0.078 mM, Ki: 0.12 mM; allosteric effector, structural requirements for activation are stringent, but requirements for inhibition are lax. GTP promotes Gln hydrolysis but inhibits Gln-dependent CTP formation at concentrations of over 0.15 mM; no guanosine, kact: 10.6/sec, KA: 0.081 mM, Ki: 0.28 mM 37 6.3.4.2 GTP GTP acts a positive allosteric effector for Gln-dependent CTP formation. However, at concentrations exceeding 0.15 mM, GTP inhibits Gln-dependent CTP formation. Moreover, GTP is an inhibitor of NH3-dependent CTP formation at all concentrations 37 6.3.4.2 GTP inhibits glutamine-dependent CTP formation at concentrations above 0.2 mM 37 6.3.4.2 guanosine - 296 6.3.4.2 guanosine 5'-tetraphosphate no guanosine, kact: 4/sec, KA: 0.19 mM, Ki: 0.5 mM; the GTP analogue is capable of inhibiting Gln-dependent CTP formation at over 0.15 mM 1789 6.3.4.2 HgCl2 - 110 6.3.4.2 Inosine - 167 6.3.4.2 ITP no guanosine, kact: 5.2/sec, KA: 2.9 mM, Ki: 4.5 mM; the GTP analogue is capable of inhibiting Gln-dependent CTP formation at over 0.15 mM 229 6.3.4.2 L-2-pyrrolidone 5-carboxylate weak competitive inhibition of the reaction with ammonia as substrate, no significant inhibition with glutamine as substrate 115935 6.3.4.2 Mn2+ above 2 mM 11 6.3.4.2 additional information enzyme loses activity at ionic strengths higher than 0.4 M 2 6.3.4.2 additional information GTP analogues inhibite NH3-and Gln-dependent CTP-formation, often in a cooperative manner, to a similar extent as they activate it with IC50 values of 0.2-0.5 mM, the inhibition appears to be due solely to the purine base, binding structures and kinetics, overview. Inhibitor structure-activity study, overview 2 6.3.4.2 additional information incubation of EcCTPS modified by CysNO and HcyNO with 5 mM DTT for 30 min at 37°C reveals that 88% and 97%, respectively, of the original activity can be recovered; it is shown that in the presence of 1 mM Gln, S-nitroso-L-cysteine reduces the enzymatic activity by 88% and by 32% in the presence of 10 mM Gln. Similar studies with S-nitroso-L-homocysteine result in reduction of the activity by 43% and 19%, respectively. The results suggest that the substrate Gln competitively protects the active site of EcCTPS from the modification with S-nitroso-L-cysteine and S-nitroso-L-homocysteine.; no inhibition by S-nitrosoglutathione presumably due to its inability to enter the actve site of the enzyme 2 6.3.4.2 additional information inhibition by xanthine and derivatives, no inhibition by allantoin, an intact purine ring with anionic character favors inhibition. In general, methylation of the purine does not significantly affect inhibition 2 6.3.4.2 N-methylguanosine - 36462 6.3.4.2 NEM - 89 6.3.4.2 NH4Cl substrate inhibition , a significant part of the inhibition can be shown to be due to the increase in ionic strength with increasing substrate concentrations 329 6.3.4.2 Ni2+ in presence of dithiothreitol inhibition at concentrations below 0.2 mM 38 6.3.4.2 O-methylguanosine - 11775 6.3.4.2 O-methylguanosine 5'-triphosphate no guanosine, kact: 2.8/sec, KA: 0.13 mM, Ki: 0.29 mM 18243 6.3.4.2 O6-methyl-GTP the GTP analogue is capable of inhibiting Gln-dependent CTP formation at over 0.15 mM 38396 6.3.4.2 p-chloromercuribenzenesulfonic acid - 3485 6.3.4.2 paraxanthine pH-dependent inhibition, overview 3927 6.3.4.2 PCMB 0.01 mM, 50% inhibition 78 6.3.4.2 pyrrole-2-carboxylate weak competitive inhibition of the reaction with ammonia as substrate, no significant inhibition with glutamine as substrate 4860 6.3.4.2 S-nitroso-L-cysteine specific irreversible inhibitor,inhibits the activity by 94% 22674 6.3.4.2 S-nitroso-L-homocysteine specific irreversible inhibitor, inhibits the activity by 90% 9907 6.3.4.2 s4UTP - 22364 6.3.4.2 SO42- - 245 6.3.4.2 Theobromine - 2761 6.3.4.2 theophylline pH-dependent inhibition, overview 1221 6.3.4.2 Uracil - 334 6.3.4.2 uracil-4-acetic acid - 39971 6.3.4.2 uric acid pH-dependent inhibition, overview 1421 6.3.4.2 uric acid - 1421 6.3.4.2 uridine - 261 6.3.4.2 UTP competitive with ATP 65 6.3.4.2 xanthine pH-dependent inhibition, overview 234 6.3.4.2 Xanthosine - 1222 6.3.4.2 Zn2+ inhibition is reversed by EDTA, in presence of dithiothreitol inhibition at concentrations below 0.2 mM 14