Target type: molecularfunction
Catalysis of the reaction: (S)-dihydroorotate + A = AH(2) + orotate. [RHEA:18073]
Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo biosynthesis of pyrimidine nucleotides. It catalyzes the oxidation of dihydroorotate to orotate, the penultimate step in the pathway. This reaction involves the transfer of two electrons from dihydroorotate to the flavin adenine dinucleotide (FAD) cofactor of DHODH. The reduced FAD is then reoxidized by the electron transport chain, generating a proton gradient that drives ATP synthesis.
DHODH is a transmembrane protein that resides in the inner mitochondrial membrane. It has two domains: a catalytic domain that binds dihydroorotate and FAD, and a transmembrane domain that anchors the enzyme to the membrane.
The catalytic mechanism of DHODH involves a series of steps:
1. Dihydroorotate binds to the enzyme.
2. FAD accepts two electrons from dihydroorotate, forming FADH2.
3. The electrons are transferred from FADH2 to the electron transport chain.
4. Orotate is released from the enzyme.
DHODH is a crucial enzyme for cell viability, as it provides the essential pyrimidine nucleotide precursors for DNA and RNA synthesis. It is also a target for several drugs, including leflunomide, a drug used to treat rheumatoid arthritis.
In summary, DHODH is a vital enzyme in the de novo biosynthesis of pyrimidine nucleotides. It catalyzes the oxidation of dihydroorotate to orotate, a key step in the pathway. This reaction involves electron transfer from dihydroorotate to FAD, followed by reoxidation of FAD by the electron transport chain. DHODH is a transmembrane protein with a catalytic domain and a transmembrane domain. Its activity is essential for cell viability and it is a target for therapeutic intervention.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Dihydroorotate dehydrogenase (quinone), mitochondrial | A dihydroorotate dehydrogenase (quinone), mitochondrial that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q02127] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone | 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone: ubiquinol analog 6-decylubiquinone : A member of the class of 1,4-benzoquinones that is 2,3-dimethoxybenzoquinone which has been substituted at positions 5 and 6 by decyl and methyl groups. | 1,4-benzoquinones | cofactor |
| lapachol | lapachol : A hydroxy-1,4-naphthoquinone that is 1,4-naphthoquinone substituted by hydroxy and 3-methylbut-2-en-1-yl groups at positions 2 and 3, respectively. It is a natural compound that exhibits antibacterial and anticancer properties, first isolated in 1882 from the bark of Tabebuia avellanedae. | ||
| leflunomide | leflunomide : A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-methyl-1,2-oxazole-4-carboxylic acid with the anilino group of 4-(trifluoromethyl)aniline. The prodrug of teriflunomide. Leflunomide: An isoxazole derivative that inhibits dihydroorotate dehydrogenase, the fourth enzyme in the pyrimidine biosynthetic pathway. It is used an immunosuppressive agent in the treatment of RHEUMATOID ARTHRITIS and PSORIATIC ARTHRITIS. | (trifluoromethyl)benzenes; isoxazoles; monocarboxylic acid amide | antineoplastic agent; antiparasitic agent; EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor; EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor; hepatotoxic agent; immunosuppressive agent; non-steroidal anti-inflammatory drug; prodrug; pyrimidine synthesis inhibitor; tyrosine kinase inhibitor |
| niflumic acid | Niflumic Acid: An analgesic and anti-inflammatory agent used in the treatment of rheumatoid arthritis. | aromatic carboxylic acid; pyridines | |
| quinone | 1,4-benzoquinone : The simplest member of the class of 1,4-benzoquinones, obtained by the formal oxidation of hydroquinone to the corresponding diketone. It is a metabolite of benzene. benzoquinone : The simplest members of the class of benzoquinones, consisting of cyclohexadiene which is substituted by two oxo groups. quinone : Compounds having a fully conjugated cyclic dione structure, such as that of benzoquinones, derived from aromatic compounds by conversion of an even number of -CH= groups into -C(=O)- groups with any necessary rearrangement of double bonds (polycyclic and heterocyclic analogues are included). | 1,4-benzoquinones | cofactor; human xenobiotic metabolite; mouse metabolite |
| cinchophen | cinchophen: was heading 1963-94; ACIPHENOCHINOLIUM was see CHINOPHEN 1978-94; use QUINOLINES to search CINCHOPHEN 1966-94 | quinolines | |
| oxycinchophen | quinolines | ||
| clonixin | clonixin : A pyridinemonocarboxylic acid that is nicotinic acid substituted at position 2 by a (2-methyl-3-chlorophenyl)amino group. Used (as its lysine salt) for treatment of renal colic, muscular pain and moderately severe migraine attacks. Clonixin: Anti-inflammatory analgesic. | aminopyridine; organochlorine compound; pyridinemonocarboxylic acid | antipyretic; EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; lipoxygenase inhibitor; non-narcotic analgesic; non-steroidal anti-inflammatory drug; platelet aggregation inhibitor; vasodilator agent |
| flunixin | flunixin : A pyridinemonocarboxylic acid that is nicotinic acid substituted at position 2 by a 2-methyl-3-(trifluoromethyl)phenylamino group. A relatively potent non-narcotic, nonsteroidal analgesic with anti-inflammatory, anti-endotoxic and anti-pyretic properties; used in veterinary medicine (usually as the meglumine salt) for treatment of horses, cattle and pigs. | aminopyridine; organofluorine compound; pyridinemonocarboxylic acid | antipyretic; EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; non-narcotic analgesic; non-steroidal anti-inflammatory drug |
| brequinar | brequinar : A quinolinemonocarboxylic acid that is quinoline substituted by 2'-fluoro[1,1'-biphenyl]-4-yl, methyl, carboxy and fluoro groups at positions 2, 3, 4, and 6, respectively. It is an inhibitor of dihydroorotate dehydrogenase, an enzyme that is required for de novo pyrimidine biosynthesis. The compound exhibits antineoplastic and antiviral properties. | biphenyls; monocarboxylic acid; monofluorobenzenes; quinolinemonocarboxylic acid | anticoronaviral agent; antimetabolite; antineoplastic agent; antiviral agent; EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor; immunosuppressive agent; pyrimidine synthesis inhibitor |
| atovaquone | atovaquone : A naphthoquinone compound having a 4-(4-chlorophenyl)cyclohexyl group at the 2-position and a hydroxy substituent at the 3-position. Atovaquone: A hydroxynaphthoquinone that has antimicrobial activity and is being used in antimalarial protocols. | hydroxy-1,2-naphthoquinone | |
| hydrolapachol | hydrolapachol: inhibits mitochondrial respiratory chain | ||
| 3',4'-dihydroxyflavone | 3',4'-dihydroxyflavone: inhibitors of arachidonic acid peroxidation | ||
| nsc-126771 | dichloroallyl lawsone: structure | ||
| cyclo(l-phe-l-pro) | organic molecular entity | metabolite | |
| piperine | piperine : A N-acylpiperidine that is piperidine substituted by a (1E,3E)-1-(1,3-benzodioxol-5-yl)-5-oxopenta-1,3-dien-5-yl group at the nitrogen atom. It is an alkaloid isolated from the plant Piper nigrum. | benzodioxoles; N-acylpiperidine; piperidine alkaloid; tertiary carboxamide | food component; human blood serum metabolite; NF-kappaB inhibitor; plant metabolite |
| 2-phenylamino-4-methyl-5-acetylthiazole | 2-phenylamino-4-methyl-5-acetylthiazole: structure in first source | ||
| pd 156252 | |||
| n-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide | N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide: inhibits dihydroorotate dehydrogenase from P. falciparum; structure in first source | ||
| isobavachalcone | isobavachalcone : A member of the class of chalcones that is trans-chalcone substituted by hydroxy groups at positions 4, 2' and 4' and a prenyl group at position 3'. isobavachalcone: RN given for (E)-isomer; structure in first source | chalcones; polyphenol | antibacterial agent; metabolite; platelet aggregation inhibitor |
| cyclosporine | ramihyphin A: one of the metabolites produced by Fusarium sp. S-435; RN given refers to cpd with unknown MF | homodetic cyclic peptide | anti-asthmatic drug; anticoronaviral agent; antifungal agent; antirheumatic drug; carcinogenic agent; dermatologic drug; EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor; geroprotector; immunosuppressive agent; metabolite |
| ascofuranone | ascofuranone : A dihydroxybenzaldehyde that is 2,4-dihydroxybenzaldehyde which is substituted by a (2E,6E)-7-[(2S)-5,5-dimethyl-4-oxotetrahydrofuran-2-yl]-3-methylocta-2,6-dien-1-yl group at position 3, chlorine at position 5, and a methyl group at position 6. A meroterpenoid produced by the soil fungus, Acremonium sclerotigenum. It is a promising drug candidate against the tropical disease, African trypanosomiasis. ascofuranone: structure | dihydroxybenzaldehyde; meroterpenoid; monochlorobenzenes; olefinic compound; resorcinols; sesquiterpenoid; tetrahydrofuranone | angiogenesis inhibitor; antilipemic drug; antineoplastic agent; antiprotozoal drug; fungal metabolite |
| cyclo(prolyl-valyl) | piperazinone | metabolite | |
| cyclo(leucyl-prolyl) | cyclo(L-Leu-L-Pro) : A homodetic cyclic peptide composed from leucyl and prolyl residues. cyclo(leucyl-prolyl): structure in first source | dipeptide; homodetic cyclic peptide; pyrrolopyrazine | bacterial metabolite; marine metabolite |
| vidofludimus | vidofludimus: a dihydroorotate dehydrogenase inhibitor; structure in first source | ||
| ascochlorin | ascochlorin : A dihydroxybenzaldehyde that is 2,4-dihydroxybenzaldehyde which is substituted by a (1E,3E)-3-methyl-1-[(1R,2R,6R)-1,2,6-trimethyl-3-oxocyclohexyl]penta-1,3-dien-5-yl group at position 3, chlorine at position 5, and a methyl group at position 6. A meroterpenoid produced by several fungi including Ascochyta viciae . It exhibits anticancer, antifungal and antiprotozoal activities. ascochlorin: structure in first source | cyclohexanones; dihydroxybenzaldehyde; meroterpenoid; monochlorobenzenes; olefinic compound; resorcinols; sesquiterpenoid | angiogenesis inhibitor; antifungal agent; antineoplastic agent; antiprotozoal drug; fungal metabolite |
| brequinar sodium | brequinar sodium : An organic sodium salt of brequinar. | organic sodium salt | anticoronaviral agent; antimetabolite; antineoplastic agent; antiviral agent; EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor; immunosuppressive agent; pyrimidine synthesis inhibitor |
| dsm 74 | |||
| teriflunomide | (trifluoromethyl)benzenes; aromatic amide; enamide; enol; nitrile; secondary carboxamide | drug metabolite; EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor; hepatotoxic agent; non-steroidal anti-inflammatory drug; tyrosine kinase inhibitor | |
| 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate | 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate: has antineoplastic activity; structure in first source |