BIOMAT Database Logo BIOMAT Database Logo

Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. 1988

D S Peterson, and D Walliker, and T E Wellems
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.

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 1.5.1.3 and EC 2.1.1.45, 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 alpha-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.

UI MeSH Term Description Entries
D009097 Multienzyme Complexes Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES. Complexes, Multienzyme
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D010963 Plasmodium falciparum A species of protozoa that is the causal agent of falciparum malaria (MALARIA, FALCIPARUM). It is most prevalent in the tropics and subtropics. Plasmodium falciparums,falciparums, Plasmodium
D011739 Pyrimethamine One of the FOLIC ACID ANTAGONISTS that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis. Chloridin,Daraprim,Malocide,Tindurine
D012150 Polymorphism, Restriction Fragment Length Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment. RFLP,Restriction Fragment Length Polymorphism,RFLPs,Restriction Fragment Length Polymorphisms
D003433 Crosses, Genetic Deliberate breeding of two different individuals that results in offspring that carry part of the genetic material of each parent. The parent organisms must be genetically compatible and may be from different varieties or closely related species. Cross, Genetic,Genetic Cross,Genetic Crosses
D004351 Drug Resistance Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. Resistance, Drug
D005796 Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Cistron,Gene,Genetic Materials,Cistrons,Genetic Material,Material, Genetic,Materials, Genetic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

D S Peterson, and D Walliker, and T E Wellems
Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum.
January 1995, Molecular and biochemical parasitology,
D S Peterson, and D Walliker, and T E Wellems
[Gene point mutation in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum].
January 2001, Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases,
D S Peterson, and D Walliker, and T E Wellems
Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum.
October 1989, Molecular and biochemical parasitology,
D S Peterson, and D Walliker, and T E Wellems
Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.
December 1988, Proceedings of the National Academy of Sciences of the United States of America,
D S Peterson, and D Walliker, and T E Wellems
Mutant dihydrofolate reductase-thymidylate synthase genes in pyrimethamine-resistant Plasmodium falciparum with polymorphic chromosome duplications.
August 1990, Molecular and biochemical parasitology,
D S Peterson, and D Walliker, and T E Wellems
Subunit complementation of thymidylate synthase in Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase.
January 2005, Molecular and biochemical parasitology,
D S Peterson, and D Walliker, and T E Wellems
Study of dihydrofolate reductase-thymidylate synthase in Plasmodium falciparum.
October 1988, The American journal of tropical medicine and hygiene,
D S Peterson, and D Walliker, and T E Wellems
Retroviral coexpression of thymidylate synthase and dihydrofolate reductase confers fluoropyrimidine and antifolate resistance.
February 1998, Biochemical and biophysical research communications,
D S Peterson, and D Walliker, and T E Wellems
Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil.
February 2000, The American journal of tropical medicine and hygiene,
D S Peterson, and D Walliker, and T E Wellems
Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance.
April 1990, Proceedings of the National Academy of Sciences of the United States of America,
Copied contents to your clipboard!