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Vol. 53, Issue 2, 270-273, February 1998
Department of Veterinary Medical Chemistry, Swedish University of
Agricultural Sciences, Biomedical Center, Uppsala, Sweden
Deoxyguanosine kinase (dGK) is an enzyme responsible for the
phosphorylation of purine deoxynucleosides in mitochondria of mammalian
cells. Its role in activation of pharmacologically used nucleoside
analogs is not well understood, because of the low levels of dGK found
in tissue extracts and its inactivation during purification. The cDNA
for dGK was recently cloned and expressed in Escherichia
coli. Here we present an improved procedure for expression and
purification of a highly active form of human recombinant dGK. The
enzyme showed a broad substrate specificity toward natural purine and
pyrimidine deoxynucleosides as well as toward important nucleoside
analogs. The Km and
Vmax values for deoxyguanosine, deoxyinosine, deoxyadenosine, and deoxycytidine were 4, 13, 460, 330 µM and 43, 330, 430 and 60 nmol/min/mg of protein,
respectively. Antileukemic purine analogs such as arabinosyl guanine,
2-chloro-2
-deoxyadenosine, 2-chloro-2-arabino-fluoro-2-deoxyadenosine, and
2-fluoro-arabinosyl-adenine were phosphorylated as efficiently by dGK
as the natural nucleoside substrates. This is the first report in which
2-fluoro-arabinosyl-adenine and
2-chloro-2-arabino-fluoro-2-deoxyadenosine were shown
to be good substrates for dGK. The antiviral analogs dideoxyinosine and
arabinosyl adenine also showed significant activity with dGK, as did
several pyrimidine analogs (e.g., the cytostatic drugs 5-fluoro-2-deoxycytidine and difluorodeoxycytidine). The broad specificity of dGK described here may change our understanding of the
mechanisms responsible for the efficacy and mitochondrial toxicity of
several nucleoside analogs.
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