國家衛生研究院 NHRI:Item 3990099045/2915
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    题名: Phosphorylation of cytidine, deoxycytidine, and their analog monophosphates by human UMP/CMP kinase is differentially regulated by ATP and magnesium
    作者: Hsu, CH;Liou, JY;Dutschman, GE;Cheng, YC
    贡献者: National Institute of Cancer Research
    摘要: Human UMP/CMP kinase (cytidylate kinase; EC 2.7.4.14) is responsible for phosphorylation of CMP, UMP, and deoxycytidine monophosphate (dCMP) and also plays an important role in the activation of pyrimidine analogs, some of which are clinically useful anticancer or antiviral drugs. Previous kinetic data using recombinant or highly purified human UMP/CMP kinase showed that dCMP, as well as pyrimidine analog monophosphates, were much poorer substrates than CMP or UMP for this enzyme. This implies that other unidentified mechanisms must be involved to make phosphorylation of dCMP or pyrimidine analog monophosphates inside cells by this enzyme possible. Here, we reevaluated the optimal reaction conditions for human recombinant human UMP/CMP kinase to phosphorylate dCMP and CMP (referred as dCMPK and CMPK activities). We found that ATP and magnesium were important regulators of the kinase activities of this enzyme. Free magnesium enhanced dCMPK activity but inhibited CMPK activity. Free ATP or excess ATP/magnesium, on the other hand, inhibited dCMPK but not CMPK reactions. The differential regulation of dCMPK versus CMPK activities by ATP or magnesium was also seen in other 2'-deoxypyrimidine analog monophosphates (deoxyuridine monophosphate, 5-fluorodeoxyuridine monophosphate, 1-beta-D-arabinofuranosylcytosine monophosphate, and gemcitabine monophosphate) versus their ribose-counterparts (UMP and 5-fluorouridine monophosphate), in a similar manner. The data suggest that the active sites of human UMP/CMP kinase for dCMP and for CMP cannot be identical. Furthermore, enzyme inhibition studies demonstrated that CMP could inhibit dCMP phosphorylation in a noncompetitive manner, with K-i values much higher than its own K-m values. We thus propose novel models for the phosphorylation action of human UMP/CMP kinase.
    关键词: Pharmacology & Pharmacy
    日期: 2005-03
    關聯: Molecular Pharmacology. 2005 Mar;67(3):806-814.
    Link to: http://dx.doi.org/10.1124/mol.104.006098
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0026-895X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000227071900027
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=14944366413
    显示于类别:[劉界元(2003-2010)] 期刊論文

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