Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

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Folate biosynthesis enzymes
Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

Target id: 2981

Nomenclature: Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase

Abbreviated Name: PfDHFR-TS

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

Previous and Unofficial Names
DHFR-TS \| Pf3D7_04_v3:747,897..750,065(+) \| PFD0830w

Database Links
Alphafold	Q8I1R6 (Pf3D7)
ChEMBL Target	CHEMBL4296323 (Pf3D7)
PlasmoDB	PF3D7_0417200 (Pf3D7)
UniProtKB	Q8I1R6 (Pf3D7)

Ligand		Sp.	Assay description	Type	Action	Value	Parameter	Reference
P218		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	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		Pv Plasmodium vivax P. vivax (Pv) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pv is the second most common cause of malaria in humans, after P. falciparum, and is prevalent in Southeast Asia and Latin America. Pv has a dormant liver stage that can reactivate and lead to clinical symptoms. ✖	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		PfD6 Plasmodium falciparum D6 P. falciparum strain D6 (PfD6) was collected in Sierra Leone. PfD6 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is generally considered drug sensitive with minor mefloquine resistance. ✖	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		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	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		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	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		PfD6 Plasmodium falciparum D6 P. falciparum strain D6 (PfD6) was collected in Sierra Leone. PfD6 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is generally considered drug sensitive with minor mefloquine resistance. ✖	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		PfTM4 Plasmodium falciparum TM4 P. falciparum strain TM4 (PfTM4) was isolated from a patient at the Tropical Medical Hospital, Bangkok, Thailand in 1985. ✖	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		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	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		PfV1/S Plasmodium falciparum V1/S P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam. PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine. ✖	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		PfTM4 Plasmodium falciparum TM4 P. falciparum strain TM4 (PfTM4) was isolated from a patient at the Tropical Medical Hospital, Bangkok, Thailand in 1985. ✖	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		Pf7G8 Plasmodium falciparum 7G8 P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980. Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant. ✖	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 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖	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 Plasmodium falciparum W2 P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine. ✖	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 Plasmodium falciparum TM90C2A P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone. ✖	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		Pf7G8 Plasmodium falciparum 7G8 P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980. Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant. ✖	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		PfTM90C2A Plasmodium falciparum TM90C2A P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone. ✖	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		PfK1 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖	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		PfW2 Plasmodium falciparum W2 P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine. ✖	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		PfV1/S Plasmodium falciparum V1/S P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam. PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine. ✖	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		PfV1/S Plasmodium falciparum V1/S P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam. PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine. ✖	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].

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 13/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2981.