Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase | Antimalarial targets | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

Target id: 2981

Nomenclature: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

Abbreviated Name: PfDHFR-TS

Family: Antimalarial targets

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 608 DHFR-TS bifunctional dihydrofolate reductase-thymidylate synthase
Database Links
UniProtKB
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
cycloguanil PfD6 Parasite growth inhibition assay - - 8.8 pIC50 1
pIC50 8.8 (IC50 1.7x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil PfNF54 Parasite growth inhibition assay - - 8.4 pIC50 1
pIC50 8.4 (IC50 4.5x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
P218 PfTM4 Parasite growth inhibition assay - - 8.3 pIC50 3
pIC50 8.3 (IC50 4.6x10-9 M) [3H]-hypoxanthine incorporation [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
P218 PfV1/S Parasite growth inhibition assay - - 7.3 pIC50 3
pIC50 7.3 (IC50 5.6x10-8 M) [3H]-hypoxanthine incorporation [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pyrimethamine PfTM4 Parasite growth inhibition assay - - 7.2 pIC50 3
pIC50 7.2 (IC50 5.8x10-8 M) [3H]-hypoxanthine incorporation assay wild-type P. falciparum (TM4) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil Pf7G8 Parasite growth inhibition assay - - 6.4 pIC50 1
pIC50 6.4 (IC50 3.657x10-7 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil PfK1 Parasite growth inhibition assay - - 6.3 pIC50 1
pIC50 6.3 (IC50 4.45x10-7 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil PfW2 Parasite growth inhibition assay - - 6.0 pIC50 1
pIC50 6.0 (IC50 1.002x10-6 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil PfTM90C2A Parasite growth inhibition assay - - 5.4 pIC50 1
pIC50 5.4 (IC50 4.262x10-6 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil PfV1/S Parasite growth inhibition assay - - <5.0 pIC50 1
pIC50 <5.0 (IC50 >1x10-5 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Malaria Pharmacology Comments
The P. falciparum enzyme, dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), catalyzes sequential reactions in the thymidylate cycle and is an important target of the antifolate class of antimalarial drugs. In contrast to the bifunctional protein of protozoan species, DHFR and TS are separate enzymes in higher eukaryotes and in bacteria. Resistance to the antifolate class of antimalarial drugs emerged soon after their clinical introduction and arisies from mutations in PfDHFR-TS [2].

References

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1. Delves M, Plouffe D, Scheurer C, Meister S, Wittlin S, Winzeler EA, Sinden RE, Leroy D. (2012) The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Med., 9 (2): e1001169. [PMID:22363211]

2. Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV. (1997) Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. U.S.A., 94 (4): 1124-9. [PMID:9037017]

3. Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E et al.. (2012) Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl. Acad. Sci. U.S.A., 109 (42): 16823-8. [PMID:23035243]

How to cite this page

Antimalarial targets: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase. Last modified on 08/04/2019. Accessed on 18/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2981.