https://scholars.lib.ntu.edu.tw/handle/123456789/487344
標題: | Comparison of the phosphorylation of 4′-ethynyl 2′,3′- dihydro3′-deoxythymidine with that of other anti-human immunodeficiency virus thymidine analogs | 作者: | CHIH-HUNG HSU Hu R. Dutschman G.E. Yang G. Krishnan P. Tanaka H. Baba M. Cheng Y.-C. |
公開日期: | 2007 | 卷: | 51 | 期: | 5 | 起(迄)頁: | 1687-1693 | 來源出版物: | Antimicrobial Agents and Chemotherapy | 摘要: | Thymidine analogs, including 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxy-3′-deoxythymidine (D4T), are important antiretroviral agents. To exert antiretroviral activity, these analogs undergo a stepwise phosphorylation intracellularly to the active triphosphate metabolites. We previously reported that 4′-substituted D4T with an ethynyl group (i.e., 4′-ethynyl D4T) increased the anti-human immunodeficiency virus (HIV) activity and was active against multidrug-resistant HIV strains. 4′-Ethynyl D4T is a better substrate for phosphorylation by human thymidine kinase 1 than D4T is. In this report, we first studied the enzymes involved in the phosphorylation of 4′-ethynyl D4T from monophosphate to triphosphate metabolites. The 4′-ethynyl D4TMP is phosphorylated by recombinant human TMP kinase with a Km of 19 ± 4 μM and a kcat of 0.007 ± 0.001 s-1 the relative efficiency is about 9 and 15% of those of D4TMP and AZTMP, respectively. Several enzymes from crude cellular extracts, including nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, and 3-phosphoglycerate kinase, could phosphorylate 4′-ethynyl D4T-diphosphate. The relative phosphorylation efficiencies of 4′-ethynyl D4TDP were about 3 to 25% of those of D4TDP and were generally similar to those of AZTDP. In T-lymphoid cell lines, there was a preponderant accumulation of 4′-ethynyl D4TMP, suggesting that TMP kinase could be the rate-limiting enzyme in the metabolism of 4′-ethynyl D4T. Although the same enzymes are involved in the stepwise phosphorylation of thymidine analogs, their behaviors in phosphorylating metabolites of 4′-ethynyl D4T are different from those of D4T and AZT. Qualitatively, the metabolism of 4′-ethynyl D4T is more similar to that of AZT than to that of its progenitor, D4T. Copyright ? 2007, American Society for Microbiology. All Rights Reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-34248344120&doi=10.1128%2fAAC.01432-06&partnerID=40&md5=03e151009fea1d65021a0b945d20c1c6 https://scholars.lib.ntu.edu.tw/handle/123456789/487344 |
ISSN: | 0066-4804 | DOI: | 10.1128/AAC.01432-06 | SDG/關鍵字: | 4' ethynyl 2',3' dihydro 3' deoxythymidine; anti human immunodeficiency virus agent; cell extract; creatine kinase; nucleoside diphosphate kinase; phosphoglycerate kinase; pyruvate kinase; stavudine; thymidine derivative; thymidine kinase 1; unclassified drug; zidovudine; article; controlled study; drug metabolism; drug synthesis; enzyme phosphorylation; human; human cell; lymphoid cell; priority journal; Anti-HIV Agents; Humans; Nucleoside-Phosphate Kinase; Phosphorylation; Stavudine; Structure-Activity Relationship; Zidovudine |
顯示於: | 腫瘤醫學研究所 |
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