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J. Biol. Chem., Vol. 276, Issue 13, 10498-10504, March 30, 2001

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Human Cytosolic 5'-Nucleotidase I
CHARACTERIZATION AND ROLE IN NUCLEOSIDE ANALOG RESISTANCE^*

Sally Anne Hunsucker, Jozef Spychala^§, and Beverly S. Mitchell^¶

From the Lineberger Comprehensive Cancer Center, Departments of  Pharmacology and ^¶ Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295

Nucleoside analogs are important in the treatment of hematologic malignancies, solid tumors, and viral infections. Their metabolism to the triphosphate form is central to their chemotherapeutic efficacy. Although the nucleoside kinases responsible for the phosphorylation of these compounds have been well described, the nucleotidases that may mediate drug resistance through dephosphorylation remain obscure. We have cloned and characterized a novel human cytosolic 5'-nucleotidase (cN-I) that potentially may have an important role in nucleoside analog metabolism. It is expressed at a high level in skeletal and heart muscle, at an intermediate level in pancreas and brain, and at a low level in kidney, testis, and uterus. The recombinant cN-I showed high affinity toward dCMP and lower affinity toward AMP and IMP. ADP was necessary for maximal catalytic activity. Expression of cN-I in Jurkat and HEK 293 cells conferred resistance to 2-chloro-2'-deoxyadenosine, with a 49-fold increase in the IC₅₀ in HEK 293 and a greater than 400-fold increase in the IC₅₀ in Jurkat cells. Expression of cN-I also conferred a 22-fold increase in the IC₅₀ to 2',3'-difluorodeoxycytidine in HEK 293 cells and an 82-fold increase in the IC₅₀ to 2',3'-dideoxycytidine in Jurkat cells. These data indicate that cN-I may play an important role in the regulation of physiological pyrimidine nucleotide pools and may also alter the therapeutic efficacy of certain nucleoside analogs.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF331801.

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