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dihydroorotate dehydrogenase (quinone)

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Target id: 2604

Nomenclature: dihydroorotate dehydrogenase (quinone)

Abbreviated Name: DHODH

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

Gene and Protein Information Click here for help
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
The Antimalarial targets family provides information about P. falciparum DHODH.
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
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 Click here for help
EC Number: 1.3.5.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
S416 Small molecule or natural product Hs Binding 8.8 pKd 9
pKd 8.8 (Kd 1.69x10-9 M) [9]
S312 Small molecule or natural product Ligand has a PDB structure Hs Binding 7.7 pKd 9
pKd 7.7 (Kd 2.03x10-8 M) [9]
teriflunomide Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pKi 2
pKi 7.5 (Ki 3x10-8 M) [2]
brequinar Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.0 pKi 7
pKi 7.0 (Ki 1x10-7 M) [7]
leflunomide Small molecule or natural product Approved drug Primary target of this compound Immunopharmacology Ligand Hs Inhibition 4.9 pKi 6
pKi 4.9 (Ki 1.3x10-5 M) [6]
S416 Small molecule or natural product Hs Inhibition 8.1 pIC50 9
pIC50 8.1 (IC50 7.5x10-9 M) [9]
S312 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.5 pIC50 9
pIC50 7.5 (IC50 2.92x10-8 M) [9]
vidofludimus Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand 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.
teriflunomide Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 9
pIC50 6.5 (IC50 3.071x10-7 M) [9]
vidofludimus Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Rn Inhibition 6.3 pIC50 3
pIC50 6.3 (IC50 4.6x10-7 M) [3]
vidofludimus Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Mm Inhibition 5.4 pIC50 3
pIC50 5.4 (IC50 3.8x10-6 M) [3]
DSM421 Small molecule or natural product Ligand has a PDB structure Hs Inhibition <4.0 pIC50 8
pIC50 <4.0 (IC50 >1x10-4 M) [8]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
DSM421 Small molecule or natural product Ligand has a PDB structure Mm Inhibition <4.0 pIC50 8
pIC50 <4.0 (IC50 >1x10-4 M) [8]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
DSM421 Small molecule or natural product Ligand has a PDB structure Rn Inhibition <4.0 pIC50 8
pIC50 <4.0 (IC50 >1x10-4 M) [8]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
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) [5]. 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 (PubChem CID: 56944639) that is under evaluation for clinical efficacy in ulcerative colitis (NCT03341962), primary sclerosing cholangitis (NCT03722576) and multiple sclerosis (NCT03846219) [4].
Clinically-Relevant Mutations and Pathophysiology Click here for help
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) [5]. 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.

DHODH has also been proposed as a host enzyme whose inhibition could have antiviral effects [9], based on evidence which confirms that viruses are highly dependent on host pyrimidine synthesis for the supply of RNA precursors that they rely on for replication. Several DHODH inhibitors have reported anti-SARS-CoV-2 activity.

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. Muehler A, Peelen E, Kohlhof H, Gröppel M, Vitt D. (2020) Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord, 43: 102129. [PMID:32428844]

5. 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]

6. 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]

7. Peters GJ, Sharma SL, Laurensse E, Pinedo HM. (1987) Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). Invest New Drugs, 5 (3): 235-44. [PMID:2822596]

8. 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]

9. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang Y, Zhao Y, Wu Y, Shang W, Jiang X et al.. (2020) Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell, [Epub ahead of print]. DOI: 10.1007/s13238-020-00768-w [PMID:32754890]

How to cite this page

Nucleoside synthesis and metabolism: dihydroorotate dehydrogenase (quinone). Last modified on 24/09/2020. Accessed on 29/10/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2604.