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J Biol Chem, Vol. 273, Issue 6, 3461-3469, February 6, 1998
From the Department of Biology, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6018
We have exploited the experimental accessibility
of the protozoan parasite Toxoplasma gondii and its
similarity to Plasmodium falciparum to investigate the
influence of specific dihydrofolate reductase polymorphisms known from
field isolates of drug-resistant malaria. By engineering appropriate
recombinant shuttle vectors, it is feasible to examine mutations by
transient or stable transformation of T. gondii parasites,
in bacterial and yeast complementation assays, and through biochemical
analysis of purified enzyme. A series of mutant alleles that mirror
P. falciparum variants reveals that the key mutation
Asn-108 (Asn-83 in T. gondii) probably confers resistance
to pyrimethamine by affecting critical interactions in the ternary
complex. Mutations such as Arg-59 (T. gondii 36) have
limited effect in isolation, but in combination with other mutations
they enhance the competitive ability of folate by increasing the speed
of product turnover. Val-16 (T. gondii 10) confers low level resistance to cycloguanil but hypersensitivity to pyrimethamine. This mutation precludes Asn-108, probably because compression of the
folate binding pocket introduced by this combination is incompatible
with enzyme function. These studies permit detailed biochemical,
kinetic, and structural analysis of drug resistance mutations and
reconstruction of the probable phylogeny of antifolate resistance in
malaria.
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