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Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

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Target id: 2981

Nomenclature: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

Abbreviated Name: PfDHFR-TS

Family: Folate biosynthesis enzymes

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 608 DHFR-TS bifunctional dihydrofolate reductase-thymidylate synthase
Previous and Unofficial Names Click here for help
DHFR-TS | bifunctional dihydrofolate reductase-thymidylate synthase
Database Links Click here for help
ChEMBL Target
PlasmoDB
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 Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Ligand has a PDB structure 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)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfD6 Parasite growth inhibition assay - - 8.3 pIC50 1
pIC50 8.3 (IC50 4.6x10-9 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
P218 Small molecule or natural product Ligand has a PDB structure 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)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfNF54 Parasite growth inhibition assay - - 7.8 pIC50 1
pIC50 7.8 (IC50 1.7x10-8 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
P218 Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Approved drug Ligand has a PDB structure PfTM4 Parasite growth inhibition assay - - 7.2 pIC50 3
pIC50 7.2 (IC50 5.8x10-8 M) [3H]-hypoxanthine incorporation assay using wild-type P. falciparum (TM4) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Ligand has a PDB structure 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)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure Pf7G8 Parasite growth inhibition assay - - 5.2 pIC50 1
pIC50 5.2 (IC50 6.689x10-6 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfTM90C2A Parasite growth inhibition assay - - 5.1 pIC50 1
pIC50 5.1 (IC50 8.231x10-6 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfK1 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)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfW2 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)
cycloguanil Small molecule or natural product Ligand has a PDB structure 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)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure PfV1/S Parasite growth inhibition assay - - <4.0 – 5.0 pIC50 1,3
pIC50 <5.0 (IC50 >1x10-5 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pIC50 <4.0 (IC50 >1x10-4 M) [3H]-hypoxanthine incorporation assay using quadruple mutant P. falciparum (V1/S) [3]
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 USA, 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 USA, 109 (42): 16823-8. [PMID:23035243]

How to cite this page

Folate biosynthesis enzymes: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase. Last modified on 01/02/2021. Accessed on 18/09/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2981.