Target Information

Target General Infomation
Target ID
T01318
Former ID
TTDS00059
Target Name
Dihydroorotate dehydrogenase, mitochondrial
Gene Name
PFF0160c
Synonyms
DHOD; DHODH; DHODase; DHOdehase; Dihydroorotate dehydrogenase ; Dihydroorotate oxidase; Mitochondrially bound dihydroorotate-ubiqui oxidoreductase; PFF0160c
Target Type
Successful
Disease Fungal infections [ICD9: 110-118; ICD10: B35-B49]
Malaria [ICD10: B54]
Multiple scierosis; Active rheumatoid arthritis [ICD9:340, 714; ICD10: G35, M05, M06]
Function
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
BioChemical Class
Oxidoreductases acting on CH-CH group of donors
Target Validation
T01318
UniProt ID
Q08210
EC Number
EC 1.3.5.2
Sequence
MISKLKPQFMFLPKKHILSYCRKDVLNLFEQKFYYTSKRKESNNMKNESLLRLINYNRYY
NKIDSNNYYNGGKILSNDRQYIYSPLCEYKKKINDISSYVSVPFKINIRNLGTSNFVNNK
KDVLDNDYIYENIKKEKSKHKKIIFLLFVSLFGLYGFFESYNPEFFLYDIFLKFCLKYID
GEICHDLFLLLGKYNILPYDTSNDSIYACTNIKHLDFINPFGVAAGFDKNGVCIDSILKL
GFSFIEIGTITPRGQTGNAKPRIFRDVESRSIINSCGFNNMGCDKVTENLILFRKRQEED
KLLSKHIVGVSIGKNKDTVNIVDDLKYCINKIGRYADYIAINVSSPNTPGLRDNQEAGKL
KNIILSVKEEIDNLEKNNIMNDESTYNEDNKIVEKKNNFNKNNSHMMKDAKDNFLWFNTT
KKKPLVFVKLAPDLNQEQKKEIADVLLETNIDGMIISNTTTQINDIKSFENKKGGVSGAK
LKDISTKFICEMYNYTNKQIPIIASGGIFSGLDALEKIEAGASVCQLYSCLVFNGMKSAV
QIKRELNHLLYQRGYYNLKEAIGRKHSKS
Structure
1D3G; 1D3H; 2B0M; 2BXV; 2FPT; 2FPV; 2FPY; 2FQI; 2PRH; 2PRL; 2PRM; 2WV8; 3F1Q; 3FJ6; 3FJL; 3G0U; 3G0X; 3KVJ; 3KVK; 3KVL; 3KVM; 3U2O; 3W7R; 3ZWS; 3ZWT; 4IGH; 4JGD; 4JS3; 4JTS; 4JTT; 4JTU; 4LS0; 4LS1; 4LS2; 4OQV
Drugs and Mode of Action
Drug(s) Artemisinin Drug Info Approved Malaria [536602]
Atovaquone Drug Info Approved Fungal infections [536602]
Leflunomide Drug Info Approved Multiple scierosis; Active rheumatoid arthritis [532210], [536772], [541907]
Inhibitor 1,4-Naphthoquinone Drug Info [534955]
1-hydroxy-2-dodecyl-4(1H)quinolone Drug Info [529879]
2-(2-bromo-2-naphthamido)benzoic acid Drug Info [527807]
2-(2-naphthamido)benzoic acid Drug Info [527807]
2-(3-(3,5-dichlorophenyl)ureido)benzoic acid Drug Info [530724]
2-[(biphenyl-4-carbonyl)-amino]-benzoic acid Drug Info [527807]
3,6,9,12,15-PENTAOXATRICOSAN-1-OL Drug Info [551374]
3-hydroxy-2-phenylquinoline-4-carboxylic acid Drug Info [528605]
5,8-hydroxy-naphthoquinone Drug Info [534955]
5-Fluoro orotate Drug Info [535811]
8-aminoquinolines Drug Info [537905]
A77-1726 (monosodium salt) Drug Info [535028], [538136]
Acetate Ion Drug Info [551393]
Antimycin A Drug Info [537862]
Antiproliferative Agent A771726 Drug Info [551393]
Artemisinin Drug Info [536602]
Atovaquone Drug Info [534955], [534960], [535931], [537905]
B-Octylglucoside Drug Info [551393]
Cinchoninic acid Drug Info [534955]
Cyanide Drug Info [537862]
Decylamine-N,N-Dimethyl-N-Oxide Drug Info [551393]
Dichloroally-lawsone Drug Info [534955]
Dichloroallyl lawsone Drug Info [535540]
Diethyl 2-((biphenyl-3-ylamino)methylene)malonate Drug Info [528617]
Dihydroorotate Drug Info [537699]
DSM1 Drug Info [530805]
DSM2 Drug Info [530805]
Ethyl 3-(biphenyl-3-ylamino)-2-cyanoacrylate Drug Info [528617]
GNF-PF-85 Drug Info [529511]
Isoxazol Drug Info [534955]
Juglon Drug Info [534955]
Lauryl Dimethylamine-N-Oxide Drug Info [551393]
Leflunomide Drug Info [534936], [537837], [538007], [538113]
LY214352 Drug Info [537964]
N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide Drug Info [528617]
N-(4-bromo-2-methylphenyl)-2-naphthamide Drug Info [528617]
N-(Biphenyl-4-yl)-2-cyano-3-hydroxybut-2-enamide Drug Info [530060]
NSC 665564 Drug Info [537969]
Orotate Drug Info [535811]
Orotic acid Drug Info [537699]
Plumbagin Drug Info [534955]
Polyporic acid Drug Info [534955]
Redoxal Drug Info [534956], [535540]
RS-61980 Drug Info [537837]
Salicylhydroxamic acid Drug Info [537862]
Triazine Drug Info [534955]
UNDECYLAMINE-N,N-DIMETHYL-N-OXIDE Drug Info [551374]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Pyrimidine metabolism
Metabolic pathways
PathWhiz Pathway Pyrimidine Metabolism
Reactome Pyrimidine biosynthesis
WikiPathways Metabolism of nucleotides
References
Ref 532210Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
Ref 536602The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
Ref 536772New drugs in development for the treatment of endometriosis. Expert Opin Investig Drugs. 2008 Aug;17(8):1187-202.
Ref 541907(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6825).
Ref 527807Bioorg Med Chem Lett. 2006 Jan 1;16(1):88-92. Epub 2005 Oct 19.The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.
Ref 528605J Med Chem. 2007 Jan 11;50(1):21-39.Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists.
Ref 528617J Med Chem. 2007 Jan 25;50(2):186-91.Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.
Ref 529511J Med Chem. 2008 Jun 26;51(12):3649-53. Epub 2008 Jun 4.Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum.
Ref 529879Bioorg Med Chem Lett. 2009 Feb 1;19(3):972-5. Epub 2008 Nov 24.Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors.
Ref 530060J Med Chem. 2009 May 14;52(9):2683-93.Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases.
Ref 530724Bioorg Med Chem Lett. 2010 Mar 15;20(6):1981-4. Epub 2010 Jan 25.Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures.
Ref 530805Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets. 2010 Jun;10(3):226-39.
Ref 534936Identification and characterization of potential new therapeutic targets in inflammatory and autoimmune diseases. Eur J Biochem. 1999 Dec;266(3):1184-91.
Ref 534955Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact. 2000 Jan 3;124(1):61-76.
Ref 534956Redoxal as a new lead structure for dihydroorotate dehydrogenase inhibitors: a kinetic study of the inhibition mechanism. FEBS Lett. 2000 Feb 4;467(1):27-30.
Ref 534960Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob Agents Chemother. 2000 Mar;44(3):713-9.
Ref 535028Expression and characterization of E. coli-produced soluble, functional human dihydroorotate dehydrogenase: a potential target for immunosuppression. J Mol Microbiol Biotechnol. 1999 Aug;1(1):183-8.
Ref 535540Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J Biol Chem. 2002 Nov 1;277(44):41827-34. Epub 2002 Aug 19.
Ref 535811Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase. Biochem Pharmacol. 1992 Mar 17;43(6):1295-301.
Ref 535931Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 2004 Apr;13(4):1031-42.
Ref 536602The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
Ref 537699Structure-activity relationships of pyrimidines as dihydroorotate dehydrogenase inhibitors. Biochem Pharmacol. 1988 Oct 15;37(20):3807-16.
Ref 537837Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol. 1995 Sep 7;50(6):861-7.
Ref 537862Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother. 1995 Feb;39(2):325-8.
Ref 537905The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase. Exp Parasitol. 1994 Aug;79(1):50-6.
Ref 537964Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach. Curr Genet. 1996 Jul 31;30(2):159-65.
Ref 537969Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar. Biochem Biophys Res Commun. 1996 Jun 25;223(3):654-9.
Ref 538007Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplant Proc. 1996 Dec;28(6):3088-91.
Ref 538113Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase. Protein Expr Purif. 1998 Aug;13(3):414-22.
Ref 538136Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol. 1998 Nov 1;56(9):1259-64.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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