You are not currently logged in.
Access your personal account or get JSTOR access through your library or other institution:
If You Use a Screen ReaderThis content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
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
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Preview not available
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 126.96.36.199 and EC 188.8.131.52, 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