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J. Biol. Chem., Vol. 278, Issue 38, 36726-36732, September 19, 2003

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Novel Role of 3-Phosphoglycerate Kinase, a Glycolytic Enzyme, in the Activation of L-Nucleoside Analogs, a New Class of Anticancer and Antiviral Agents^*

Preethi Krishnan, Elizabeth A. Gullen, Wing Lam, Ginger E. Dutschman, Susan P. Grill and Yung-chi Cheng 

From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

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.

Received for publication, July 2, 2003 , and in revised form, July 16, 2003.

^* This work was supported by R01 Grants CA36477 and AI38204 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A fellow of the National Foundation for Cancer Research. To whom correspondence should be addressed: Dept. of Pharmacology, Yale University School of Medicine, 333 Cedar St., SHM B254, New Haven, CT 06520. Tel.: 203-785-7119; Fax: 203-785-7129; E-mail: cheng.lab{at}yale.edu.

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