13191-15-6Relevant articles and documents
4-Substituted uridine 5′-triphosphates as agonists of the P2y2 purinergic receptor
Shaver, Sammy R.,Pendergast, William,Siddiqi, Suhaib M.,Yerxa, Benjamin R.,Croom, Dallas K.,Dougherty, Robert W.,James, Michael K.,Neil Jones,Rideout, Janet L.
, p. 1099 - 1102 (1997)
Undine 5′-O-triphosphate (UTP) is a potent agonist of the purinergic receptor designated P2Y2. UTP is rapidly metabolized in human tissue. To find a compound with similar activity that may be more slowly metabolized, a series of 4-substituted uridine 5′-triphosphates were prepared and evaluated in a P2Y2 receptor second messenger assay. Copyright
“Pinching” the ammonia tunnel of CTP synthase unveils coordinated catalytic and allosteric-dependent control of ammonia passage
McCluskey, Gregory D.,Bearne, Stephen L.
, p. 2714 - 2727 (2018)
Molecular gates within enzymes often play important roles in synchronizing catalytic events. We explored the role of a gate in cytidine-5′-triphosphate synthase (CTPS) from Escherichia coli. This glutamine amidotransferase catalyzes the biosynthesis of CTP from UTP using either L-glutamine or exogenous NH3 as a substrate. Glutamine is hydrolyzed in the glutaminase domain, with GTP acting as a positive allosteric effector, and the nascent NH3 passes through a gate located at the end of a ~25-? tunnel before entering the synthase domain where CTP is generated. Substitution of the gate residue Val 60 by Ala, Cys, Asp, Trp, or Phe using site-directed mutagenesis and subsequent kinetic analyses revealed that V60-substitution impacts glutaminase activity, nucleotide binding, salt-dependent inhibition, and inter-domain NH3 transport. Surprisingly, the increase in steric bulk present in V60F perturbed the local structure consistent with “pinching” the tunnel, thereby revealing processes that synchronize the transfer of NH3 from the glutaminase domain to the synthase domain. V60F had a slightly reduced coupling efficiency at maximal glutaminase activity that was ameliorated by slowing down the glutamine hydrolysis reaction, consistent with a “bottleneck” effect. The inability of V60F to use exogenous NH3 was overcome in the presence of GTP, and more so if CTPS was covalently modified by 6-diazo-5-oxo-L-norleucine. Use of NH2OH by V60F as an alternative bulkier substrate occurred most efficiently when it was concomitant with the glutaminase reaction. Thus, the glutaminase activity and GTP-dependent activation act in concert to open the NH3 gate of CTPS to mediate inter-domain NH3 transport.
Synthesis of CMP-NeuAc from N-acetylglucosamine: generation of CTP from CMP using adenylate kinase.
Simon, Ethan S.,Bednarski, Mark D.,Whitesides, George M.
, p. 7159 - 7163 (1988)
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Preparation of a mixture of nucleoside triphosphates from yeast RNA: use in enzymic synthesis requiring nucleoside triphosphate regeneration and conversion to nucleoside diphosphate sugars.
Wong, Chi-Huey,Haynie, Sharon L.,Whitesides, George M.
, p. 115 - 117 (1983)
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Inhibition of CTP synthase from Escherichia coli by xanthines and uric acids
Roy, Alexander C.,Lunn, Faylene A.,Bearne, Stephen L.
, p. 141 - 144 (2010)
CTP synthase (CTPS) catalyzes the conversion of UTP to CTP and is a recognized target for the development of anticancer, antiviral, and antiprotozoal agents. Xanthine and related compounds inhibit CTPS activity (IC50 = 0.16-0.58 mM). The presence of an 8-oxo function (i.e., uric acids) enhances inhibition (IC50 = 0.060-0.121 mM). An intact purine ring with anionic character favors inhibition. In general, methylation of the purine does not significantly affect inhibition.
Cytidine-5'-triphosphate Synthetase Catalyzes the Phosphorylation of Uridine 5'-Triphosphate by Adenosine 5'-Triphosphate
Saal, Wolfgang von der,Villafranca, Joseph J.,Anderson, Paul M.
, p. 703 - 704 (1985)
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Nucleotide promiscuity of 3-phosphoglycerate kinase is in focus: Implications for the design of better anti-HIV analogues
Varga, Andrea,Chaloin, Laurent,Sagi, Gyula,Sendula, Robert,Graczer, Eva,Liliom, Karoly,Zavodszky, Peter,Lionne, Corinne,Vas, Maria
experimental part, p. 1863 - 1873 (2012/04/17)
The wide specificity of 3-phosphoglycerate kinase (PGK) towards its nucleotide substrate is a property that allows contribution of this enzyme to the effective phosphorylation (i.e. activation) of nucleotide-based pro-drugs against HIV. Here, the structural basis of the nucleotide-PGK interaction is characterised in comparison to other kinases, namely pyruvate kinase (PK) and creatine kinase (CK), by enzyme kinetic analysis and structural modelling (docking) studies. The results provided evidence for favouring the purine vs. pyrimidine base containing nucleotides for PGK rather than for PK or CK. This is due to the exceptional ability of PGK in forming the hydrophobic contacts of the nucleotide rings that assures the appropriate positioning of the connected phosphate-chain for catalysis. As for the d-/l-configurations of the nucleotides, the l-forms (both purine and pyrimidine) are well accepted by PGK rather than either by PK or CK. Here again the dominance of the hydrophobic interactions of the l-form of pyrimidines with PGK is underlined in comparison with those of PK or CK. Furthermore, for the l-forms, the absence of the ribose OH-groups with PGK is better tolerated for the purine than for the pyrimidine containing compounds. On the other hand, the positioning of the phosphate-chain is an even more important term for PGK in the case of both purines and pyrimidines with an l-configuration, as deduced from the present kinetic studies with various nucleotide-site mutants of PGK. These characteristics of the kinase-nucleotide interactions can provide a guideline for designing new drugs.
