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118  structures 4626  species 6  interactions 6787  sequences 50  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
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
1f76.gif
Dihydroorotate dehydrogenase from E. coli
Identifiers
Symbol DHO_dh
Pfam PF01180
InterPro IPR001295
PROSITE PDOC00708
SCOP 1dor
SUPERFAMILY 1dor
OPM superfamily 59
OPM protein 1uum
Human dihydroorotate dehydrogenase
Identifiers
Symbol DHODH
Entrez 1723
HUGO 2867
OMIM 126064
PDB 1D3G (RCSB PDB PDBe PDBj)
RefSeq NM_001361
UniProt Q02127
Other data
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

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. 
  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. 

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.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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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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Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(12)
Full
(6787)
Representative proteomes NCBI
(6540)
Meta
(4232)
RP15
(544)
RP35
(1054)
RP55
(1421)
RP75
(1697)
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Format an alignment

  Seed
(12)
Full
(6787)
Representative proteomes NCBI
(6540)
Meta
(4232)
RP15
(544)
RP35
(1054)
RP55
(1421)
RP75
(1697)
Alignment:
Format:
Order:
Sequence:
Gaps:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(12)
Full
(6787)
Representative proteomes NCBI
(6540)
Meta
(4232)
RP15
(544)
RP35
(1054)
RP55
(1421)
RP75
(1697)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: DHOdehase;
Type: Domain
Author: Finn RD, Bateman A, Griffiths-Jones SR
Number in seed: 12
Number in full: 6787
Average length of the domain: 282.50 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 80.42 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -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: 16
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 6 interactions for this family. More...

Fer4 DHODB_Fe-S_bind Pyr_redox Pyr_redox_2 FAD_binding_6 DHO_dh

Structures

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 118 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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