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Evidence that a Point Mutation in Dihydrofolate Reductase-Thymidylate Synthase Confers Resistance to Pyrimethamine in Falciparum Malaria
David S. Peterson, David Walliker and Thomas E. Wellems
Proceedings of the National Academy of Sciences of the United States of America
Vol. 85, No. 23 (Dec. 1, 1988), pp. 9114-9118
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/32898
Page Count: 5
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Analysis of a genetic cross of Plasmodium falciparum and of independent parasite isolates from Southeast Asia, Africa, and South America indicates that resistance to pyrimethamine, an antifolate used in the treatment of malaria, results from point mutations in the gene encoding dihydrofolate reductase-thymidylate synthase (EC 22.214.171.124 and EC 126.96.36.199, respectively). Parasites having a mutation from Thr-108/Ser-108 to Asn-108 in DHFR-TS are resistant to the drug. The Asn-108 mutation occurs in a region analogous to the C α -helix bordering the active site cavity of bacterial, avian, and mammalian enzymes. Additional point mutations (Asn-51 to Ile-51 and Cys-59 to Arg-59) are associated with increased pyrimethamine resistance and also occur at sites expected to border the active site cavity. Analogies with known inhibitor/enzyme structures from other organisms suggest that the point mutations occur where pyrimethamine contacts the enzyme and may act by inhibiting binding of the drug.
Proceedings of the National Academy of Sciences of the United States of America © 1988 National Academy of Sciences