Indispensable residue for uridine binding in the uridine-cytidine kinase family

Tomoike, Fumiaki; Nakagawa, Noriko; Fukui, Kenji; Yano, Takayuki; Kuramitsu, Seiki; Masui, Ryoji

doi:10.1016/j.bbrep.2017.07.002

Cited by 12 publications

(15 citation statements)

References 30 publications

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“…Uridine‐cytidine kinase 2 is an enzyme encoded by the UCK2 gene located on chromosome 1q22‐23.2 and 1 of 2 human UCKs . The other UCK protein, UCK1, has 70% sequence homology with UCK2 . Both of them can catalyze the phosphorylation of uridine and cytidine to the monophosphate form, which plays a key role in the biosynthesis of the pyrimidine nucleotides that constitute DNA and RNA .…”

Section: Introductionmentioning

confidence: 99%

“…The other UCK protein, UCK1, has 70% sequence homology with UCK2 . Both of them can catalyze the phosphorylation of uridine and cytidine to the monophosphate form, which plays a key role in the biosynthesis of the pyrimidine nucleotides that constitute DNA and RNA . The catalyzing efficiency of UCK2 for uridine and cytidine substrates is 15‐20 times higher than UCK1 .…”

Section: Introductionmentioning

confidence: 99%

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Uridine‐cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer

Jamal

Xie

et al. 2019

Cancer Science

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Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine‐cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor‐associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uridine‐cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer

Jamal

Xie

et al. 2019

Cancer Science

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“…UCK is involved in the conversion of both cytidine and uridine to nucleoside monophosphate. STE7 is associated with the MAPK pathway, and DPCK is involved with the final steps of the pathway for CoA biosynthesis ( Wadler and Cronan, 2007 ; Tomoike et al, 2017 ; Mendes et al, 2018 ). One gene was down-regulated (nucleoside diphosphate kinase) in the early response to UDA (3 h).…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

et al. 2018

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Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.

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“…In order to guide our SAR studies, we developed an enzymatic assay to evaluate the inhibitory effect of each CPU analog against recombinant human UCK2, which was expressed and purified in E. coli. A continuous assay system was optimized by coupling UCK2 activity to the pyruvate kinase (PK) reaction, which in turn was coupled to lactate dehydrogenase (LDH) (Tomoike et al, 2017). Overall reaction progress was continuously monitored by detecting the UV absorption change at 340 nm, which was correlated with the ATP consumption by UCK2.…”

Section: Enzymatic Analysis Of Cpu Analogs Against Uck2 and Cmpk1mentioning

confidence: 99%

“…To continuously monitor reaction progress spectrophotometrically, ATP hydrolysis was coupled to NADH oxidation via pyruvate kinase (PK) and lactate dehydrogenase (LDH) (Tomoike et al, 2017). Reactions were conducted at room temperature in 100 µL in 96-well plates (Greiner Bio-One, UV-Star, Half Area).…”

Section: In Vitro Enzyme Activity Assays With Recombinant Human Uck2mentioning

confidence: 99%

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

Liu

Gupta

Okesli-Armlovich

et al. 2020

Preprint

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Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase (DHODH) as its target, along with the discovery that knockdown of genes in pyrimidine salvage pathways sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was efficiently converted into its triphosphates in cells. When combined with GSK983, it led to large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral genome infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activities of RdRp inhibitors.

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Indispensable residue for uridine binding in the uridine-cytidine kinase family

Cited by 12 publications

References 30 publications

Uridine‐cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer

Uridine‐cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

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