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J Biol Chem, Vol. 273, Issue 51, 34098-34104, December 18, 1998
From the Department of Medical Biochemistry and Biophysics, Umeå
University, S-901 87 Umeå, Sweden
Trypanosoma brucei is the causative
agent for African sleeping sickness. We have made in vitro
and in vivo studies on the allosteric regulation of the
trypanosome ribonucleotide reductase, a key enzyme in the production of
dNTPs needed for DNA synthesis. Results with the isolated recombinant
trypanosome ribonucleotide reductase showed that dATP specifically
directs pyrimidine ribonucleotide reduction instead of being a general
negative effector as in other related ribonucleotide reductases,
whereas dTTP and dGTP directed GDP and ADP reduction, respectively.
Pool measurements of NDPs, NTPs, and dNTPs in the cultivated
bloodstream form of trypanosomes exposed to deoxyribonucleosides or
inhibited by hydroxyurea confirmed our in vitro allosteric
regulation model of ribonucleotide reductase. Interestingly, the
trypanosomes had extremely low CDP and CTP pools, whereas the dCTP pool
was comparable with that of other dNTPs. The trypanosome ribonucleotide
reductase seems adapted to this situation by having a high affinity for
the CDP/UDP-specific effector dATP and a high catalytic efficiency,
Kcat/Km, for CDP reduction.
Thymidine and deoxyadenosine were readily taken up and phosphorylated
to dTTP and dATP, respectively, the latter in a nonsaturating manner.
This uncontrolled uptake of deoxyadenosine strongly inhibited
trypanosome proliferation, a valuable observation in the search
for new trypanocidal nucleoside analogues.
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