dihydroorotate dehydrogenase (quinone)

Target id: 2604

Nomenclature: dihydroorotate dehydrogenase (quinone)

Family: Nucleoside synthesis and metabolism, 1.-.-.- Oxidoreductases

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 :     dihydroorotate dehydrogenase (quinone) has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 395 16q22.2 DHODH dihydroorotate dehydrogenase (quinone)
Mouse - 395 8 D3 Dhodh dihydroorotate dehydrogenase
Rat - 395 19q12 Dhodh dihydroorotate dehydrogenase (quinone)
Gene and Protein Information Comments
More information about P. falciparum DHODH (gene symbol PF3D7_0603300 for P. falciparum strain 3D7) as an antimalarial drug target is contained in the Antimalarial targets family.
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog
PDB Id:  4IGH
Resolution:  1.3Å
Species:  Human
References:  1
Enzyme Reaction
EC Number: 1.3.5.2

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
teriflunomide Hs Inhibition 7.5 pKi 2
pKi 7.5 (Ki 3x10-8 M) [2]
leflunomide Hs Inhibition 4.9 pKi 5
pKi 4.9 (Ki 1.3x10-5 M) [5]
vidofludimus Hs Inhibition 7.3 pIC50 3
pIC50 7.3 (IC50 4.8x10-8 M) [3]
Description: Determined in an indirect in vitro enzyme assay which measures the reduced co-substrate ubiquinone.
vidofludimus Rn Inhibition 6.3 pIC50 3
pIC50 6.3 (IC50 4.6x10-7 M) [3]
vidofludimus Mm Inhibition 5.4 pIC50 3
pIC50 5.4 (IC50 3.8x10-6 M) [3]
View species-specific inhibitor tables
Immunopharmacology Comments
Dihydroorotate dehydrogenase (DHODH) is the fourth, and rate-limiting enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway, but the enzyme's expression is selectively upregulated in proliferating and activated lymphocytes, making it a target susceptible to pharmacological inhibition in activated immune cells. Inhibition of DHODH causes a reduction in the available pyrimidine pool, which leads to metabolic stress and apoptosis in highly activated cells.

DHODH inhibitors are used clinically to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide respectively) [4]. Vidofludimus was a Phase 2 clinical candidate for IBD and RA, but has been superceded by IMU-838 which is an orally active polymorph of vidofludimus calcium that will be evaluated for clinical efficacy in a Phase 2 ulcerative colitis trial (NCT03341962).
Clinically-Relevant Mutations and Pathophysiology
Disease:  Postaxial acrofacial dysostosis
Synonyms: Miller syndrome
OMIM: 263750
Orphanet: ORPHA246
General Comments
Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. DHODH inhibitors are used clinically to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide respectively) and have been investigated in oncology, virology, and parasitology (e.g. malaria) [4]. More information about P. falciparum DHODH (gene symbol PF3D7_0603300 for P. falciparum strain 3D7) as an antimalarial drug target is contained in our evolving Antimalarial targets family.

References

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1. Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK. (2013) SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity. ACS Med Chem Lett, 4 (6): 517-521. [PMID:23930152]

2. Heikkilä T, Ramsey C, Davies M, Galtier C, Stead AM, Johnson AP, Fishwick CW, Boa AN, McConkey GA. (2007) Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J. Med. Chem., 50 (2): 186-91. [PMID:17228860]

3. Kulkarni OP, Sayyed SG, Kantner C, Ryu M, Schnurr M, Sárdy M, Leban J, Jankowsky R, Ammendola A, Doblhofer R et al.. (2010) 4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice. Am. J. Pathol., 176 (6): 2840-7. [PMID:20413687]

4. Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL. (2013) On dihydroorotate dehydrogenases and their inhibitors and uses. J. Med. Chem., 56 (8): 3148-67. [PMID:23452331]

5. Papageorgiou C, Albert R, Floersheim P, Lemaire M, Bitch F, Weber HP, Andersen E, Hungerford V, Schreier MH. (1998) Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations. J. Med. Chem., 41 (18): 3530-8. [PMID:9719606]

How to cite this page

1.-.-.- Oxidoreductases: dihydroorotate dehydrogenase (quinone). Last modified on 25/04/2018. Accessed on 21/06/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2604.