Plasmodium falciparum dihydroorotate dehydrogenase | Antimalarial targets | IUPHAR/BPS Guide to PHARMACOLOGY

Plasmodium falciparum dihydroorotate dehydrogenase

Target id: 2949

Nomenclature: Plasmodium falciparum dihydroorotate dehydrogenase

Abbreviated Name: PfDHODH

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

   GtoImmuPdb view: OFF :     Currently no data for Plasmodium falciparum dihydroorotate dehydrogenase in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 569 DHODH dihydroorotate dehydrogenase
Previous and Unofficial Names
Pfal DHODH
Database Links
UniProtKB
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
References:  3

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
DSM421 Pf Inhibition 7.3 pIC50 3
pIC50 7.3 (IC50 5.3x10-8 M) [3]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
DSM421 Pv Inhibition 7.0 pIC50 3
pIC50 7.0 (IC50 9.4x10-8 M) [3]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
View species-specific inhibitor tables
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Affinity Units Reference
DSM421 Pf3D7 Parasite growth inhibition assay using SYBR Green incorporation (72h assay). - - 7.8 pEC50 3
pEC50 7.8 (EC50 1.4x10-8 M) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Pf3D7 Parasite growth inhibition assay using SYBR Green incorporation (48h assay). - - 7.4 pEC50 3
pEC50 7.4 (EC50 4.3x10-8 M) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM421 Pv Blood-stage: schizont maturation assay using P. vivax field isolates. - - 6.7 pEC50 3
pEC50 6.7 (EC50 1.8x10-7 M) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
DSM265 PfNF54 Parasite growth inhibition assay - - 7.5 pIC50 1
pIC50 7.5 (IC50 3x10-8 M) [3H]-hypoxanthine incorporation [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
General Comments
The pyrimidine biosynthetic pathway has facilitated the successful identification of antimalarial drug targets. These include the fourth enzyme in the pathway as P. falciparum dihydroorotate dehydrogenase (PfDHODH) [2]. In this publication they established that the cross reactivity with human DHODH was orders of magnitude lower.

References

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1. 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]

2. 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]

3. 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

Antimalarial targets: Plasmodium falciparum dihydroorotate dehydrogenase. Last modified on 05/07/2018. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2949.