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