Broad specificity of human phosphoglycerate kinase for antiviral nucleoside analogs

被引:28
|
作者
Gallois-Montbrun, S
Faraj, A
Seclaman, E
Sommadossi, JP
Deville-Bonne, D [1 ]
Véron, M
机构
[1] Inst Pasteur, CNRS, URA 2185, Unite Regulat Enzymat Activ Cellulaires, F-75724 Paris 15, France
[2] Univ Montpellier 2, CNRS, IDENIX, Lab Cooperatif, Montpellier, France
[3] Idenix Pharmaceut, Cambridge, MA USA
[4] Inst Pasteur, Lab Chim Struct Macromol, F-75724 Paris 15, France
关键词
phosphoglycerate kinase; NDP kinase; antiviral analog; acyclovir; L-dC; L-dT;
D O I
10.1016/j.bcp.2004.06.012
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nucleoside analogs used in antiviral therapies need to be phosphorylated to their tri-phospho counterparts in order to be active on their cellular target. Human phosphoglycerate kinase (hPGK) was recently reported to participate in the last step of phosphorylation of cytidine L-nucleotide derivatives [Krishnan PGE, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation Of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003;278:36726-32]. In the present work, we extended the enzymatic study of human PGK specificity to purine and pyrimidine nucleotide derivatives in both D- and L-configuration. Human PGK demonstrated catalytic efficiencies in the 10(4)-10(5) M-1 s(-1) range for purine ribo-, deoxyribo- and dideoxyribonucleotide derivatives, either in D- or L-Configuration. In contrast, it was poorly active with natural pyrimidine D-nucleotides (less than 10(3) M-1 s(-1)). Pyrimidine L-enantiomers, which are promising therapeutic analogs against B hepatitis, were 2-25 times better substrates than their D-counterparts. The broad specificity of substrate of human PGK suggests that this enzyme may be involved in the cellular activation of several antiviral nucleoside analogs including dideoxyinosine, acyclovir, L-2'-deoxycytosine and L-2'-deoxythymidine. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:1749 / 1756
页数:8
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