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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
PFD0830w
Database Links Click here for help
Alphafold
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
P218 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pf Parasite liver stage assay - - >7.9 pEC50 4
pEC50 >7.9 (EC50 <1.2x10-8 M) Primary human hepatocyte assay to assess inhibition of hepatic schizonts (prophylactic activity) [4]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
P218 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Pv Parasite liver stage assay - - 7.3 pEC50 4
pEC50 7.3 (EC50 4.5x10-8 M) Primary human hepatocyte assay to assess inhibition of hepatic schizonts (prophylactic activity) [4]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
cycloguanil Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand 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)
P218 Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfNF54 Parasite exflagellation assay - - 8.4 pIC50 3
pIC50 8.4 (IC50 4x10-9 M) Induction of male gamete activation (exflagellation) following 48 hour exposure of mature gametocytes to P218 [3]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
cycloguanil Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand PfTM4 Parasite growth inhibition assay - - 8.3 pIC50 6
pIC50 8.3 (IC50 4.6x10-9 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand PfV1/S Parasite growth inhibition assay - - 7.3 pIC50 6
pIC50 7.3 (IC50 5.6x10-8 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pyrimethamine Small molecule or natural product Approved drug Ligand has a PDB structure Guide to Malaria Pharmacology Ligand PfTM4 Parasite growth inhibition assay - - 7.2 pIC50 6
pIC50 7.2 (IC50 5.8x10-8 M) [3H]-hypoxanthine incorporation assay using wild-type P. falciparum (TM4) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cycloguanil Small molecule or natural product Ligand has a PDB structure Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand 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 Guide to Malaria Pharmacology Ligand PfV1/S Parasite growth inhibition assay - - <4.0 – 5.0 pIC50 1,6
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) [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Malaria Pharmacology Comments
The P. falciparum enzyme, bifunctional 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 antifolates such as pyrimethamine emerged soon after their clinical introduction and arises from mutations in the DHFR domain, leading to reduced binding affinity [2,5,7-8].

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. Peterson DS, Milhous WK, Wellems TE. (1990) Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci U S A, 87 (8): 3018-22. [PMID:2183222]

3. Posayapisit N, Pengon J, Prommana P, Shoram M, Yuthavong Y, Uthaipibull C, Kamchonwongpaisan S, Jupatanakul N. (2021) Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug. Int J Parasitol, 51 (8): 635-642. [PMID:33713651]

4. Roth A, Maher SP, Conway AJ, Ubalee R, Chaumeau V, Andolina C, Kaba SA, Vantaux A, Bakowski MA, Thomson-Luque R et al.. (2018) A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat Commun, 9 (1): 1837. [PMID:29743474]

5. 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]

6. 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]

7. Yuthavong Y, Yuvaniyama J, Chitnumsub P, Vanichtanankul J, Chusacultanachai S, Tarnchompoo B, Vilaivan T, Kamchonwongpaisan S. (2005) Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors. Parasitology, 130 (Pt 3): 249-59. [PMID:15796007]

8. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y. (2003) Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol, 10 (5): 357-65. [PMID:12704428]

How to cite this page

Folate biosynthesis enzymes: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase. Last modified on 31/10/2021. Accessed on 16/08/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2981.