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Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.
Open accessAbstract
We describe the isolation and the sequence of the gene for the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS; EC 1.5.1.3 and EC 2.1.1.45, respectively) from two pyrimethamine-resistant clones of Plasmodium falciparum, HB3 and 7G8. We have also derived the sequence of the DHFR portion of the gene, by amplification using polymerase chain reaction, for the pyrimethamine-sensitive clone 3D7 and the pyrimethamine-resistant strains V-1, K-1, Csl-2, and Palo-alto. The deduced protein sequence of the resistant DHFR portion of the enzyme from HB3 contained a single amino acid difference from the pyrimethamine-sensitive clone 3D7. It is highly likely that this difference is involved in the mechanism of drug resistance in HB3. The sequence of the DHFR gene from other pyrimethamine-resistant strains contains the same amino acid difference from the sensitive clone 3D7. However, they all differ at one other site that may influence pyrimethamine resistance. The DHFR-TS gene is present as a single copy on chromosome 4 in all pyrimethamine-sensitive and pyrimethamine-resistant isolates tested. Therefore, the molecular basis of pyrimethamine resistance in the parasites tested is not amplification of the DHFR-TS gene.
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Cites
Primer-Directed Enzymatic Amplification of DNA with a Thermostable DNA Polymerase
Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullis, K. B., & Erlich, H. A. (1988) · Science · doi:10.1126/science.2448875 · Cited by 17,719
Cited by
Foote, S. J., Thompson, J. K., Cowman, A. F., & Kemp, D. J. (1989) · Cell · doi:10.1016/0092-8674(89)90330-9 · Cited by 573
Self-citationMechanisms of Resistance of Malaria Parasites to Antifolates
Gregson, A., & Plowe, C. V. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.1.4 · Cited by 499
Peterson, D. S., Milhous, W. K., & Wellems, T. E. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.8.3018 · Cited by 419
Plasmodium—a brief introduction to the parasites causing human malaria and their basic biology
Sato, S. (2021) · Journal of Physiological Anthropology · doi:10.1186/s40101-020-00251-9 · Cited by 404
Brooks, D. R., Wang, P., Read, M., Watkins, W. M., Sims, P. F. G., & Hyde, J. E. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.00397.x · Cited by 369
Metadata
- Authors
- Cowman, A. F., Morry, M. J., Biggs, B. A., Cross, G. A., & Foote, S. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1988-12
- Volume
- 85
- Issue
- 23
- Pages
- 9109-9113
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2079451231
- Cited by
- 526
- References
- 1
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- green
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- Cowman, A. F., Morry, M. J., Biggs, B. A., Cross, G. A., & Foote, S. J. (1988). Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.85.23.9109
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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