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Originally published In Press as doi:10.1074/jbc.M205115200 on June 21, 2002

J. Biol. Chem., Vol. 277, Issue 35, 31593-31600, August 30, 2002
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Phosphorylation of Pyrimidine L-Deoxynucleoside Analog Diphosphates
KINETICS OF PHOSPHORYLATION AND DEPHOSPHORYLATION OF NUCLEOSIDE ANALOG DIPHOSPHATES AND TRIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE*

Preethi Krishnan, Jieh-Yuan Liou, and Yung-Chi ChengDagger

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

Anticancer and antiviral D- and L-nucleoside analogs are phosphorylated stepwise in the cells to the pharmacologically active triphosphate metabolites. We recently reported that in the last step, L-deoxynucleoside analog diphosphates are phosphorylated by 3-phosphoglycerate kinase (PGK). To explain the preference of PGK for L- over D-deoxynucleoside analog diphosphates, the kinetics of their phosphorylation were compared with the dephosphorylation of the respective triphosphates using recombinant human PGK. The results attributed favorable phosphorylation of L-deoxynucleoside analog diphosphates by PGK to differences in kcat, which were consequences of varied orientations of the sugar and diphosphates in the catalytic site of PGK. The amino acids involved in the catalytic reaction of PGK (including Glu344, Lys220, and Asn337) were therefore mutated. The impact of mutations on the phosphorylation of L- and D-deoxynucleoside analog diphosphates was different from those on dephosphorylation of the respective triphosphates. This suggested that the interactions of the nucleoside analogs with amino acids during the transition state are different in the phosphorylation and dephosphorylation reactions. Thus, reversible action of the enzyme may not involve the same configuration of the active site. Furthermore, the amino acid determinants of the action of PGK for L-deoxynucleotides were not the same as for the D-deoxynucleotides. This study also suggests the potential impact of nucleoside analog diphosphates and triphosphates on the multiple cellular functions of PGK, which may contribute to the action of the analogs.

* This work was supported by Grant AI-38204 from NFAID, National Institutes of Health and Grant CA-63477 from NCI, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Fellow of the National Foundation for Cancer Research. To whom correspondence should be addressed: 333 Cedar St., SHM B313, Dept. of Pharmacology, Yale University School of Medicine, New Haven, CT 06520. Tel.: 203-785-7119; Fax: 203-785-7129; E-mail: Cheng. lab{at}yale.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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