Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents
Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents
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DOI：
10.1074/jbc.m307052200
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发表时间：
2003-09-19
影响因子：
4.8
通讯作者：
Cheng, YC
中科院分区：
文献类型：
--
作者：
Krishnan, P;Gullen, EA;Cheng, YC
L-核苷类似物是一类新型的具有临床活性的抗病毒和抗癌药物。这些类似物从二磷酸到三磷酸代谢物的磷酸化对于它们的生物学作用是至关重要的。我们研究了3-磷酸甘油酸激酶（一种糖酵解酶）在L-核苷类似物代谢中的作用，使用小干扰RNA下调HelaS 3和2.2.15细胞中该酶的量，选择该细胞作为研究该酶对这些类似物的抗癌和抗B型肝炎病毒活性的影响的模型。3-磷酸甘油酸激酶表达的减少导致L-核苷类似物（但不是D-核苷类似物）的三磷酸代谢物形成的相应减少，从而对其活性产生不利影响。该酶对于产生以及维持细胞中L-核苷酸的稳态水平是重要的，从而在L-核苷类似物抗人免疫缺陷病毒、B型肝炎病毒和癌症的活性中起关键作用。这项研究还表明，在L-和D-核苷类似物的代谢的结构为基础的区别，争议的经典概念，即核苷二磷酸激酶是负责所有类别的核苷类似物二磷酸的磷酸化。
L-Nucleoside analogs are a new class of clinically active antiviral and anticancer agents. The phosphorylation of these analogs from diphosphate to triphosphate metabolites is crucial for their biological action. We studied the role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the metabolism of L-nucleoside analogs, using small interfering RNAs to down-regulate the amount of this enzyme in HelaS3 and 2.2.15 cells, chosen as models for studying the impact of the enzyme on the anticancer and antihepatitis B virus activities of these analogs. Decrease in the expression of 3-phosphoglycerate kinase led to a corresponding decrease in the formation of the triphosphate metabolites of L-nucleoside analogs (but not D-nucleoside analogs), resulting in detrimental effects on their activity. The enzyme is important for generating as well as maintaining the steady state levels of L-nucleotides in the cells, thereby playing a key role in the activity of L-nucleoside analogs against human immunodeficiency virus, hepatitis B virus, and cancer. This study also indicates a structure-based distinction in the metabolism of L- and D-nucleoside analogs, disputing the classic notion that nucleoside diphosphate kinases are responsible for the phosphorylation of all classes of nucleoside analog diphosphates.