Disease relevance of CTPS

• The MOMP DNA vaccine but not the CTP synthetase DNA vaccine generated significant delayed-type hypersensitivity and serum antibodies to MoPn elementary bodies and reduced the peak growth of MoPn by >100-fold following lung challenge infection [1].
• Thiourea dioxide was used in chemical modification studies to identify functionally important amino acids in Escherichia coli CTP synthetase [2].
• Retinoic acid likely confers resistance of neuroblastoma cells to CPEC in part by slowing down proliferation, and in part by shifting the synthesis of CTP towards the salvage of cytidine, thereby bypassing CTP synthetase [3].
• Therefore, the high activity of CTP synthetase in acute non-lymphocytic leukaemic cells can be inhibited by CPEC, which provides a key to a new approach for the treatment of ANLL [4].
• (1) Acivicin competitively inhibited the activities of amidophosphoribosyl-transferase, CTP synthetase and carbamoyl-phosphate synthetase II from extracts of liver and hepatoma 3924A [5].

High impact information on CTPS

• Clustered base substitutions in CTP synthetase conferring drug resistance in Chinese hamster ovary cells [6].
• Dominantly acting mutations that eliminate the allosteric regulation of CTP synthetase confer a form of multidrug resistance and a mutator phenotype to cultured Chinese hamster ovary cells [6].
• Successive rounds of chromosome-mediated gene transfer were used to complement a hamster cytidine auxotroph deficient in CTP synthetase activity and eventually to clone human genomic and cDNA fragments coding for the structural gene [7].
• As regulatory mutations of CTP synthetase confer both multi-drug resistance to agents widely used in cancer chemotherapy and a mutator phenotype, the cloning of the structural gene will be important in assessing the relevance of such phenotypes to the development of cellular drug resistance [7].
• Molecular cloning of the human CTP synthetase gene by functional complementation with purified human metaphase chromosomes [7].

Chemical compound and disease context of CTPS

• The effect of the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC) on the metabolism and cytotoxicity of 2',2'-difluorodeoxycytidine (dFdC, gemcitabine) and the expression and activity of deoxycytidine kinase (dCK) was studied in human neuroblastoma cell lines [8].
• CTP synthetase (UTP: ammonia ligase (ADP-forming), EC 6.3.4.2) was purified 200-fold from Ehrlich ascites tumor cells with about 50% purity as judged by polyacrylamide gel electrophoresis [9].

Biological context of CTPS

• Chromosome mapping of the human cytidine-5'-triphosphate synthetase (CTPS) gene to band 1p34.1-p34.3 by fluorescence in situ hybridization [10].
• A panel of human-rodent somatic cell hybrids and the CTPS cDNA were used to assign the structural gene to the short arm of human chromosome 1 [11].
• The human cytidine-5'-triphosphate synthetase (CTPS) gene was mapped by a direct mapping system combined with fluorescence in situ hybridization and replicated prometaphase R-bands [10].
• Expression of Human CTP synthetase in Saccharomyces cerevisiae reveals phosphorylation by protein kinase A [12].
• The activity of CTP synthetase in situ, measured in pulse-chase experiments, was similar in the G1-phase and S-phase MOLT-3 cells [13].

Anatomical context of CTPS

• We also investigated the mRNA expression of CTP synthase in lymphocytes and monocytes [14].
• The highest activity of CTP synthase was found in thrombocytes (6.48 nmol CTP x mg(-1) x h(-1)), followed by that of monocytes (2.23), lymphocytes (1.69), granulocytes (0.52) and erythrocytes (0.42) [14].
• In this study we investigated the activity of CTP synthase in various human blood cells isolated from healthy volunteers by density centrifugation and elutriation centrifugation [14].
• The presence of CTP synthetase monomer, dimer and tetramer has been demonstrated in the ammonium sulfate fraction of rat liver cytosol [15].
• The pattern of incorporation of [14C]uridine showed that in MOLT-3 cells an increased proportion of CTP was synthesized via CTP synthetase, compared to proliferating normal human T lymphocytes at a physiological concentration of cytidine (< 0.5 microM) [16].

Associations of CTPS with chemical compounds

• Cotransfection of the DNAs into CTPS-deficient, cytidine-requiring CHO mutants can transform them to cytidine-independent growth, indicating that the complete structural gene has been isolated [11].
• Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5'-triphosphate (UTP), and adenosine-5'-triphosphate [17].
• The CTP synthetase inhibitors 6-diazo-5-oxo-l-norleucine (DON) and alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even further and inhibited trypanosome proliferation in vitro and in T. brucei-infected mice [18].
• 3-Deazauridine, a competitive inhibitor of CTP synthetase, depleted CTP pools and curtailed surface membrane resialylation with little or no effect on synthesis of de novo sialic acid from precursor sugars [19].
• Its mode of action as an antitumor agent appears to be inhibition by its triphosphate (CPEC-TP) of CTP synthase, the enzyme which converts UTP to CTP [20].

Other interactions of CTPS

• Xanthine oxidase, CTP synthetase, cytidine deaminase and several kinases for the salvage of pyrimidine nucleosides were not detected in the parasites [21].
• CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases [22].
• The roles of uridine-cytidine kinase and CTP synthetase in the synthesis of CTP in malignant human T-lymphocytic cells [16].
• In contrast, in S-phase T lymphocytes, an increased activity of CTP synthetase was observed compared with G1-phase T lymphocytes [13].
• Mycophenolic acid, an inhibitor of the enzyme IMP dehydrogenase, antagonizes the CTP synthetase inhibitor 3-deazauridine in its anti-proliferative effects on MOLT-3 human T leukemia cells [23].

Analytical, diagnostic and therapeutic context of CTPS

• With the increasing complexity of radiotherapy computer treatment planning systems (CTPS), verification of the treatments is an important component of a quality assurance program [24].
• Northern blot analyses of polyadenylated RNA from the resistant and sensitive cells indicated a 3-fold increase in transcripts of the CTP synthase gene in the resistant line [20].
• Cyclopentenyl cytosine (CPEC) is a carbocyclic cytidine analog inhibitor of CTP synthetase and experimental drug for combination chemotherapy [25].
• The coding region of G. intestinalis CTP synthetase was generated by PCR and subsequently cloned into the pQE30 vector for expression in E. coli [26].
• The degree of CTP depletion of ALL cells after treatment with CPEC was positively correlated with the activity of CTP synthetase [27].

References