Dihydroorotate dehydrogenase
Dihydroorotate oxidase | |||||||||
---|---|---|---|---|---|---|---|---|---|
ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
|
OPM superfamily | 56 | ||||||||
---|---|---|---|---|---|---|---|---|---|
OPM protein | 1uum | ||||||||
CDD | cd02810 | ||||||||
Membranome | 250 | ||||||||
|
Human dihydroorotate dehydrogenase | |||||||
---|---|---|---|---|---|---|---|
Identifiers | |||||||
Symbol | DHODH | ||||||
Chr. 16 q22 | |||||||
|
Dihydroorotate dehydrogenase (DHODH) is an
Structure
DHODH can vary in
In higher
Function
Human DHODH is a ubiquitous FMN flavoprotein. In bacteria (gene pyrD), it is located on the inner side of the cytosolic membrane. In some yeasts, such as in Saccharomyces cerevisiae (gene URA1), it is a cytosolic protein, whereas, in other eukaryotes, it is found in the mitochondria.[5] It is also the only enzyme in the pyrimidine biosynthesis pathway located in the mitochondria rather than the cytosol.[4]
As an enzyme associated with the
Mechanism
In mammalian species, DHODH catalyzes the fourth step in de novo pyrimidine biosynthesis, which involves the ubiquinone-mediated oxidation of dihydroorotate to orotate and the reduction of FMN to dihydroflavin mononucleotide (FMNH2):
- (S)-dihydroorotate + O2 orotate + H2O2
-
Orotic acid. Note the double bond in the ring.
The particular mechanism for the dehydrogenation of dihydroorotic acid by DHODH differs between the two classes of DHODH. Class 1 DHODHs follow a concerted mechanism, in which the two C–H bonds of dihydroorotic acid break in concert. Class 2 DHODHs follow a stepwise mechanism, in which the breaking of the C–H bonds precedes the equilibration of iminium into orotic acid.[2]
Inhibitors
Clinical significance
The immunomodulatory drugs teriflunomide and leflunomide have been shown to inhibit DHODH. Human DHODH has two domains: an alpha/beta-barrel domain containing the active site and an alpha-helical domain that forms the opening of a tunnel leading to the active site. Leflunomide has been shown to bind in this tunnel.[7] Leflunomide is being used for treatment of rheumatoid and psoriatic arthritis, as well as multiple sclerosis.[2][7] Its immunosuppressive effects have been attributed to the depletion of the pyrimidine supply for T cells or to more complex interferon or interleukin-mediated pathways, but nonetheless require further research.[2]
Additionally, DHODH may play a role in retinoid N-(4-hydroxyphenyl)retinamide (
Mutations in this gene have been shown to cause Miller syndrome, also known as Genee-Wiedemann syndrome, Wildervanck-Smith syndrome or post-axial acrofacial dystosis.[9][10]
Interactions
DHODH binds to its FMN cofactor in conjunction with ubiquinone to catalyze the oxidation of dihydroorotate to orotate.[2]
References
Further reading
- Rowland P, Björnberg O, Nielsen FS, Jensen KF, Larsen S (Jun 1998). "The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function". Protein Science. 7 (6): 1269–79. PMID 9655329. Archived from the originalon 2008-12-01.
External links
- dihydroorotate+dehydrogenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)