Dihydroorotate dehydrogenase

Dihydroorotate oxidase
Identifiers
EC number	1.3.3.1
CAS number	9029-03-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles

Dihydroorotate dehydrogenase from E. coli
Identifiers
Symbol	DHO_dh
Pfam	PF01180
InterPro	IPR001295
PROSITE	PDOC00708
SCOP	1dor
OPM family	59
OPM protein	1uum
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Human dihydroorotate dehydrogenase
Identifiers
Symbol	DHODH
Entrez	1723
HUGO	2867
OMIM	126064
PDB	1D3G
RefSeq	NM_001361
UniProt	Q02127
Other data
EC number	1.3.3.1
Locus	Chr. 16 q22

Dihydroorotate dehydrogenase (EC 1.3.3.1) is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine. It converts dihydroorotate to orotate:

(S)-dihydroorotate + O₂ $\rightleftharpoons$ orotate + H₂O₂

• 

  4,5-Dihydroorotic acid

• 

  Orotic acid. Note the double bond in the ring.

Human dihydroorotate dehydrogenase 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.^[1]

Human proteins containing this domain

DHODH; DPYD;

Clinical significance

The anti-inflammatory drug leflunomide has 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.^[2] Leflunomide is being used for treatment of rheumatoid and psoriatic arthritis.

Mutations in this gene have been shown to cause Miller syndrome ^[3] also known as Genee-Wiedemann syndrome, Wildervanck-Smith syndrome or post axial acrofacial dystosis (POADS).

References

1. ^ Lacroute F, Thomas D, Nagy M (1992). "Divergent evolution of pyrimidine biosynthesis between anaerobic and aerobic yeasts". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 8966–70. doi:10.1073/pnas.89.19.8966. PMC 50045. PMID 1409592. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=50045. 
2. ^ Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J (January 2000). "Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents". Structure 8 (1): 25–33. doi:10.1016/S0969-2126(00)00077-0. PMID 10673429. 
3. ^ Ng SB, Buckingham KJ,Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (December 2009). "Exome Sequencing identifies the cause of a mendelian disorder". Nature Genetics 42 (1): 30–5. doi:10.1038/ng.499. PMC 2847889. PMID 19915526. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2847889. 

Further reading

• Rowland P, Björnberg O, Nielsen FS, Jensen KF, Larsen S (June 1998). "The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function". Protein Sci. 7 (6): 1269–79. doi:10.1002/pro.5560070601. PMC 2144028. PMID 9655329. http://www.proteinscience.org/cgi/content/abstract/7/6/1269. 

External links

• MeSH dihydroorotate+dehydrogenase

This article includes text from the public domain Pfam and InterPro IPR001295

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