Plasmodium falciparum dihydroorotate dehydrogenase

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Nucleoside synthesis and metabolism (Plasmodium spp.)
Plasmodium falciparum dihydroorotate dehydrogenase

Target id: 2949

Nomenclature: Plasmodium falciparum dihydroorotate dehydrogenase

Abbreviated Name: PfDHODH

Family: Nucleoside synthesis and metabolism (Plasmodium spp.)

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Plasmodium falciparum 3D7	-	569		DHODH	dihydroorotate dehydrogenase
Gene and Protein Information Comments
Our dihydroorotate dehydrogenase (quinone) summary page provides information about the homologous human target.

Previous and Unofficial Names
DHODH \| Pf3D7_06_v3:130,191..132,792(-) \| DHOD \| PFF0160c

Previous and Unofficial Names

DHODH | Pf3D7_06_v3:130,191..132,792(-) | DHOD | PFF0160c

Database Links
Alphafold	Q08210 (Pf3D7)
ChEMBL Target	CHEMBL3588732 (Pf3D7)
PlasmoDB	PF3D7_0603300 (Pf3D7)
SynPHARM	85411 (in complex with DSM421) 85410 (in complex with DSM421) 85405 (in complex with DSM421)
UniProtKB	Q08210 (Pf3D7)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421
PDB Id:	5TBO
Ligand:	DSM421
Resolution:	2.151Å
Species:	Plasmodium falciparum 3D7
References:	9

Description:	Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM705
PDB Id:	7KZ4
Ligand:	DSM705
Resolution:	1.75Å
Species:	Plasmodium falciparum 3D7
References:	6

Description:	Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM265
PDB Id:	4RX0
Ligand:	DSM265
Resolution:	2.25Å
Species:	Plasmodium falciparum 3D7
References:	7

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Inhibitors

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
BRD9185		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. ✖	Inhibition	7.9	pIC₅₀	5
⤷	pIC₅₀ 7.9 (IC₅₀ 1.2x10^-8 M) [5]
DSM502		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. ✖	Inhibition	7.8	pIC₅₀	3
⤷	pIC₅₀ 7.8 (IC₅₀ 1.4x10^-8 M) [3] Description: Steady-state kinetic analysis.
DSM502		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. ✖	Inhibition	7.7	pIC₅₀	3
⤷	pIC₅₀ 7.7 (IC₅₀ 2x10^-8 M) [3] Description: Steady-state kinetic analysis.
DSM265		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. ✖	Inhibition	7.5	pIC₅₀	3
⤷	pIC₅₀ 7.5 (IC₅₀ 3x10^-8 M) [3] Description: Steady-state kinetic analysis.
DSM421		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. ✖	Inhibition	7.3	pIC₅₀	9
⤷	pIC₅₀ 7.3 (IC₅₀ 5.3x10^-8 M) [9] Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM705		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. ✖	Inhibition	7.3	pIC₅₀	6
⤷	pIC₅₀ 7.3 (IC₅₀ 5.2x10^-8 M) [6] Description: Steady-state kinetic analysis.
DSM265		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. ✖	Inhibition	7.1	pIC₅₀	3
⤷	pIC₅₀ 7.1 (IC₅₀ 7.2x10^-8 M) [3] Description: Steady-state kinetic analysis.
DSM421		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. ✖	Inhibition	7.0	pIC₅₀	9
⤷	pIC₅₀ 7.0 (IC₅₀ 9.4x10^-8 M) [9] Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM705		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. ✖	Inhibition	7.0	pIC₅₀	6
⤷	pIC₅₀ 7.0 (IC₅₀ 9.5x10^-8 M) [6] Description: Steady-state kinetic analysis.

View species-specific inhibitor tables

Whole Organism Assay Data Linked to This Target

Key to terms and symbols

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Ligand		Sp.	Assay description	Type	Action	Value	Parameter	Reference
DSM705		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 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	-	-	7.9	pEC₅₀	6
⤷	pEC₅₀ 7.9 (EC₅₀ 1.2x10^-8 M) SYBR Green I assay (72h) [6] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM705		Pb Plasmodium berghei P. berghei (Pb) is a malaria parasite that infects mammals other than humans with the natural mammalian host being the thicket rat (G. surdaster) from Central Africa. Pb is used in rodent model studies of malaria. ✖	Parasite liver stage assay	-	-	7.9	pEC₅₀	6
⤷	pEC₅₀ 7.9 (EC₅₀ 1.3x10^-8 M) Luciferase bioluminescence (Pbluc) assay to measure sporozoite invasion into HepG2 liver cells (prophylactic activity) [6] Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
DSM502		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 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	pEC₅₀	3
⤷	pEC₅₀ 7.8 (EC₅₀ 1.4x10^-8 M) SYBR Green I [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM502		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	7.8	pEC₅₀	3
⤷	pEC₅₀ 7.8 (EC₅₀ 1.6x10^-8 M) SYBR Green I [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
BRD9185		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	7.8	pEC₅₀	5
⤷	pEC₅₀ 7.8 (EC₅₀ 1.6x10^-8 M) SYBR Green I assay [5] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 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	-	-	7.4 – 7.8	pEC₅₀	9
⤷	pEC₅₀ 7.8 (EC₅₀ 1.4x10^-8 M) SYBR Green incorporation (72h assay) [9] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) pEC₅₀ 7.4 (EC₅₀ 4.3x10^-8 M) SYBR Green incorporation (48h assay) [9] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421		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. ✖	Blood-stage: schizont maturation assay using P. vivax field isolates.	-	-	6.7	pEC₅₀	9
⤷	pEC₅₀ 6.7 (EC₅₀ 1.8x10^-7 M) [9] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM265		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	-	-	7.5	pIC₅₀	7
⤷	pIC₅₀ 7.5 (IC₅₀ 3x10^-8 M) [³H]-hypoxanthine incorporation [7] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)

Malaria Pharmacology Comments
P. falciparum dihydroorotate dehydrogenase (PfDHODH) is the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway [4]. In contrast to its human host, the malaria parasite lacks pyrimidine salvage enzymes and the de novo pathway is an essential source of pyrimidines for cell growth and has facilitated the validation of PfDHODH as a potential target for antimalarial therapy [8]. A number of chemical series have been identified that are potent and selective inhibitors of PfDHODH, these include: the triazolopyrimidines [2], thiophene-2-carboxamides [1], azetidine-2-carbonitriles [5] and more recently a pyrrole-based series [6].

Malaria Pharmacology Comments

P. falciparum dihydroorotate dehydrogenase (PfDHODH) is the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway [4]. In contrast to its human host, the malaria parasite lacks pyrimidine salvage enzymes and the de novo pathway is an essential source of pyrimidines for cell growth and has facilitated the validation of PfDHODH as a potential target for antimalarial therapy [8].
A number of chemical series have been identified that are potent and selective inhibitors of PfDHODH, these include: the triazolopyrimidines [2], thiophene-2-carboxamides [1], azetidine-2-carbonitriles [5] and more recently a pyrrole-based series [6].

References

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1. Booker ML, Bastos CM, Kramer ML, Barker Jr RH, Skerlj R, Sidhu AB, Deng X, Celatka C, Cortese JF, Guerrero Bravo JE et al.. (2010) Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem, 285 (43): 33054-33064. [PMID:20702404]

2. Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, Koltun M, El Mazouni F, Kokkonda S, Katneni K et al.. (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem, 54 (15): 5540-61. [PMID:21696174]

3. Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J et al.. (2020) Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria. J Med Chem, 63 (9): 4929-4956. [PMID:32248693]

4. LeBlanc SB, Wilson CM. (1993) The dihydroorotate dehydrogenase gene homologue of Plasmodium falciparum. Mol Biochem Parasitol, 60 (2): 349-51. [PMID:8232427]

5. Maetani M, Kato N, Jabor VAP, Calil FA, Nonato MC, Scherer CA, Schreiber SL. (2017) Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparum Dihydroorotate Dehydrogenase. ACS Med Chem Lett, 8 (4): 438-442. [PMID:28435533]

6. Palmer MJ, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White KL, Striepen J et al.. (2021) Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series. J Med Chem, 64 (9): 6085-6136. [PMID:33876936]

7. Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, Njoroge JW, El Mazouni F, Lao Y, Kokkonda S et al.. (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med, 7 (296): 296ra111. [PMID:26180101]

8. Phillips MA, Rathod PK. (2010) Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets, 10 (3): 226-39. [PMID:20334617]

9. Phillips MA, White KL, Kokkonda S, Deng X, White J, El Mazouni F, Marsh K, Tomchick DR, Manjalanagara K, Rudra KR et al.. (2016) A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. ACS Infect Dis, 2 (12): 945-957. [PMID:27641613]

How to cite this page

Nucleoside synthesis and metabolism (Plasmodium spp.): Plasmodium falciparum dihydroorotate dehydrogenase. Last modified on 20/10/2021. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2949.