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245  structures 19081  species 8  interactions 26772  sequences 61  architectures

Family: DHO_dh (PF01180)

Summary: Dihydroorotate dehydrogenase

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This is the Wikipedia entry entitled "Dihydroorotate dehydrogenase". More...

Dihydroorotate dehydrogenase Edit Wikipedia article

Dihydroorotate oxidase
EC number
CAS number 9029-03-2
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Dihydroorotate dehydrogenase from E. coli
Symbol DHO_dh
Pfam PF01180
InterPro IPR001295
SCOP 1dor
OPM superfamily 59
OPM protein 1uum
CDD cd02810
Human dihydroorotate dehydrogenase
Symbol DHODH
Entrez 1723
HUGO 2867
OMIM 126064
RefSeq NM_001361
UniProt Q02127
Other data
EC number
Locus Chr. 16 q22

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

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

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]

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.[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).

Model organisms

Model organisms have been used in the study of DHODH function. A conditional knockout mouse line called Dhodhtm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10]



  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. 
  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. 
  4. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley. 
  5. ^ a b "International Mouse Phenotyping Consortium". 
  6. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V et al. (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750. 
  7. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  8. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  9. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN et al. (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  10. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 

Further reading

External links

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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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Literature references

  1. Rowland P, Bjornberg O, Nielsen FS, Jensen KF, Larsen S; , Protein Sci 1998;7:1269-1279.: The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function. PUBMED:9655329 EPMC:9655329

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR012135

Dihydroorotate dehydrogenase (DHOD), also known as dihydroorotate oxidase, catalyses the fourth step in de novo pyrimidine biosynthesis, the stereospecific oxidation of (S)-dihydroorotate to orotate, which is the only redox reaction in this pathway. DHODs can be divided into two mains classes: class 1 cytosolic enzymes found primarily in Gram-positive bacteria, and class 2 membrane-associated enzymes found primarily in eukaryotic mitochondria and Gram-negative bacteria [PUBMED:9405053].

The class 1 DHODs can be further divided into subclasses 1A and 1B, which differ in their structural organisation and use of electron acceptors. The 1A enzyme is a homodimer of two PyrD subunits where each subunit forms a TIM barrel fold with a bound FMN cofactor located near the top of the barrel [PUBMED:9655329]. Fumarate is the natural electron acceptor for this enzyme. The 1B enzyme, in contrast is a heterotetramer composed of a central, FMN-containing, PyrD homodimer resembling the 1A homodimer, and two additional PyrK subunits which contain FAD and a 2Fe-2S cluster [PUBMED:11188687]. These additional groups allow the enzyme to use NAD(+) as its natural electron acceptor.

The class 2 membrane-associated enzymes are monomers which have the FMN-containing TIM barrel domain found in the class 1 PyrD subunit, and an additional N-terminal alpha helical domain [PUBMED:10673429, PUBMED:12220493]. These enzymes use respiratory quinones as the physiological electron acceptor.

Gene Ontology

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Domain organisation

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Seed source: Prosite
Previous IDs: DHOdehase;
Type: Domain
Author: Finn RD, Bateman A, Griffiths-Jones SR
Number in seed: 11
Number in full: 26772
Average length of the domain: 285.20 aa
Average identity of full alignment: 33 %
Average coverage of the sequence by the domain: 81.48 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.3 20.3
Trusted cut-off 20.3 20.3
Noise cut-off 20.2 20.2
Model length: 295
Family (HMM) version: 17
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Species distribution

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There are 8 interactions for this family. More...

DHO_dh DHODB_Fe-S_bind NAD_binding_8 Fer4_21 Fer4_20 Fer4_20 FAD_binding_6 Fer4_21


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DHO_dh domain has been found. There are 245 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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