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Q02127 (PYRD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 148. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dihydroorotate dehydrogenase (quinone), mitochondrial

Short name=DHOdehase
EC=1.3.5.2
Alternative name(s):
Dihydroorotate oxidase
Gene names
Name:DHODH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length395 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.

Catalytic activity

(S)-dihydroorotate + a quinone = orotate + a quinol. Ref.5

Cofactor

Binds 1 FMN per subunit. Ref.8

Pathway

Pyrimidine metabolism; UMP biosynthesis via de novo pathway; orotate from (S)-dihydroorotate (quinone route): step 1/1.

Subunit structure

Monomer.

Subcellular location

Mitochondrion inner membrane; Single-pass membrane protein Ref.6.

Post-translational modification

The uncleaved transit peptide is required for mitochondrial targeting and proper membrane integration.

Involvement in disease

Postaxial acrofacial dysostosis (POADS) [MIM:263750]: POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10

Miscellaneous

The identification of DHODH defects as the cause of postaxial acrofacial dysostosis (POADS) was obtained via exome sequencing (Ref.10), demonstrating that this method is a powerful tool for identifying genes underlying rare Mendelian disorders. Exome sequencing consists of targeted resequencing of all protein-coding subsequences, which requires around 5% as much sequencing as a whole human genome.

Sequence similarities

Belongs to the dihydroorotate dehydrogenase family. Type 2 subfamily.

Ontologies

Keywords
   Biological processPyrimidine biosynthesis
   Cellular componentMembrane
Mitochondrion
Mitochondrion inner membrane
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainTransit peptide
Transmembrane
Transmembrane helix
   LigandFlavoprotein
FMN
   Molecular functionOxidoreductase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_process'de novo' UMP biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

'de novo' pyrimidine nucleobase biosynthetic process

Inferred from electronic annotation. Source: Ensembl

female pregnancy

Inferred from electronic annotation. Source: Ensembl

lactation

Inferred from electronic annotation. Source: Ensembl

nucleobase-containing small molecule metabolic process

Traceable author statement. Source: Reactome

positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

pyrimidine nucleobase metabolic process

Traceable author statement. Source: Reactome

pyrimidine nucleoside biosynthetic process

Traceable author statement. Source: Reactome

regulation of mitochondrial fission

Inferred from electronic annotation. Source: Ensembl

response to caffeine

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to starvation

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentintegral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

mitochondrial inner membrane

Traceable author statement. Source: Reactome

neuronal cell body

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionFMN binding

Inferred from electronic annotation. Source: Ensembl

dihydroorotate dehydrogenase activity

Traceable author statement. Source: Reactome

dihydroorotate oxidase activity

Inferred from electronic annotation. Source: Ensembl

drug binding

Inferred from electronic annotation. Source: Ensembl

ubiquinone binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 395395Dihydroorotate dehydrogenase (quinone), mitochondrial
PRO_0000029884
Transit peptide1 – 1010Mitochondrion; not cleaved By similarity

Regions

Topological domain1 – 1010Mitochondrial matrix By similarity
Transmembrane11 – 3020Helical; By similarity
Topological domain31 – 395365Mitochondrial intermembrane By similarity
Nucleotide binding95 – 995FMN
Nucleotide binding355 – 3562FMN
Region144 – 1485Substrate binding
Region211 – 2166Substrate binding
Region283 – 2842Substrate binding

Sites

Active site2141Nucleophile
Binding site991Substrate
Binding site1191FMN
Binding site1801FMN
Binding site2111FMN
Binding site2541FMN
Binding site2821FMN; via carbonyl oxygen
Binding site3051FMN; via amide nitrogen
Binding site3341FMN; via amide nitrogen

Natural variations

Natural variant71K → Q. Ref.1 Ref.3
Corresponds to variant rs3213422 [ dbSNP | Ensembl ].
VAR_022094
Natural variant191G → E in POADS. Ref.10
VAR_062412
Natural variant1351R → C in POADS. Ref.10
VAR_062413
Natural variant1521G → R in POADS. Ref.10
VAR_062414
Natural variant1991R → C in POADS. Ref.10
VAR_062415
Natural variant2021G → A in POADS. Ref.10
VAR_062416
Natural variant2021G → D in POADS. Ref.10
VAR_062417
Natural variant2441R → W in POADS. Ref.10
VAR_062418
Natural variant2841T → I in POADS. Ref.10
VAR_062419
Natural variant3461R → W in POADS. Ref.10
VAR_062420
Natural variant3921D → G in POADS. Ref.10
VAR_062421

Experimental info

Sequence conflict1 – 22MA → KLP in AAA50163. Ref.1

Secondary structure

.................................................................. 395
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q02127 [UniParc].

Last modified December 7, 2004. Version 3.
Checksum: 072C3169E78C6440

FASTA39542,867
        10         20         30         40         50         60 
MAWRHLKKRA QDAVIILGGG GLLFASYLMA TGDERFYAEH LMPTLQGLLD PESAHRLAVR 

        70         80         90        100        110        120 
FTSLGLLPRA RFQDSDMLEV RVLGHKFRNP VGIAAGFDKH GEAVDGLYKM GFGFVEIGSV 

       130        140        150        160        170        180 
TPKPQEGNPR PRVFRLPEDQ AVINRYGFNS HGLSVVEHRL RARQQKQAKL TEDGLPLGVN 

       190        200        210        220        230        240 
LGKNKTSVDA AEDYAEGVRV LGPLADYLVV NVSSPNTAGL RSLQGKAELR RLLTKVLQER 

       250        260        270        280        290        300 
DGLRRVHRPA VLVKIAPDLT SQDKEDIASV VKELGIDGLI VTNTTVSRPA GLQGALRSET 

       310        320        330        340        350        360 
GGLSGKPLRD LSTQTIREMY ALTQGRVPII GVGGVSSGQD ALEKIRAGAS LVQLYTALTF 

       370        380        390 
WGPPVVGKVK RELEALLKEQ GFGGVTDAIG ADHRR 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and sequencing of a human cDNA coding for dihydroorotate dehydrogenase by complementation of the corresponding yeast mutant."
Minet M., Dufour M.E., Lacroute F.
Gene 121:393-396(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLN-7.
[2]"Recombinant human dihydroorotate dehydrogenase: expression, purification, and characterization of a catalytically functional truncated enzyme."
Copeland R.A., Davis J.P., Dowling R.L., Lombardo D., Murphy K.B., Patterson T.A.
Arch. Biochem. Biophys. 323:79-86(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLN-7.
Tissue: Testis.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Skin.
[5]"Functional expression of a fragment of human dihydroorotate dehydrogenase by means of the baculovirus expression vector system, and kinetic investigation of the purified recombinant enzyme."
Knecht W., Bergjohann U., Gonski S., Kirschbaum B., Loeffler M.
Eur. J. Biochem. 240:292-301(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME ACTIVITY.
[6]"Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase."
Rawls J., Knecht W., Diekert K., Lill R., Loeffler M.
Eur. J. Biochem. 267:2079-2087(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[7]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]"Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents."
Liu S., Neidhardt E.A., Grossman T.H., Ocain T., Clardy J.
Structure 8:25-33(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 29-395 IN COMPLEX WITH FMN; DIHYDROOROTATE AND INHIBITORS, COFACTOR.
[9]"Dual binding mode of a novel series of DHODH inhibitors."
Baumgartner R., Walloschek M., Kralik M., Gotschlich A., Tasler S., Mies J., Leban J.
J. Med. Chem. 49:1239-1247(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 29-395 IN COMPLEX WITH FMN AND INHIBITORS.
[10]"Exome sequencing identifies the cause of a Mendelian disorder."
Ng S.B., Buckingham K.J., Lee C., Bigham A.W., Tabor H.K., Dent K.M., Huff C.D., Shannon P.T., Jabs E.W., Nickerson D.A., Shendure J., Bamshad M.J.
Nat. Genet. 42:30-35(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS POADS GLU-19; CYS-135; ARG-152; CYS-199; ALA-202; ASP-202; TRP-244; ILE-284; TRP-346 AND GLY-392.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M94065 mRNA. Translation: AAA50163.1.
AK292293 mRNA. Translation: BAF84982.1.
BC065245 mRNA. Translation: AAH65245.1.
PIRPC1219.
RefSeqNP_001352.2. NM_001361.4.
UniGeneHs.654427.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1D3GX-ray1.60A29-395[»]
1D3HX-ray1.80A29-395[»]
2B0MX-ray2.00A29-395[»]
2BXVX-ray2.15A29-395[»]
2FPTX-ray2.40A29-395[»]
2FPVX-ray1.80A29-395[»]
2FPYX-ray2.00A29-395[»]
2FQIX-ray1.95A29-395[»]
2PRHX-ray2.40A29-395[»]
2PRLX-ray2.10A29-395[»]
2PRMX-ray3.00A29-395[»]
2WV8X-ray1.90A31-395[»]
3F1QX-ray2.00A29-395[»]
3FJ6X-ray1.80A29-395[»]
3FJLX-ray1.90A29-395[»]
3G0UX-ray2.00A29-395[»]
3G0XX-ray1.80A29-395[»]
3KVJX-ray1.94A29-395[»]
3KVKX-ray2.05A29-395[»]
3KVLX-ray1.85A29-395[»]
3KVMX-ray2.00A29-395[»]
3U2OX-ray2.18A1-395[»]
3ZWSX-ray1.60A29-395[»]
3ZWTX-ray1.55A29-395[»]
4IGHX-ray1.30A32-395[»]
4JGDX-ray2.05A29-395[»]
ProteinModelPortalQ02127.
SMRQ02127. Positions 32-395.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108068. 13 interactions.
IntActQ02127. 2 interactions.
STRING9606.ENSP00000219240.

Chemistry

BindingDBQ02127.
ChEMBLCHEMBL1966.
DrugBankDB01117. Atovaquone.
DB01097. Leflunomide.
GuidetoPHARMACOLOGY2604.

PTM databases

PhosphoSiteQ02127.

Polymorphism databases

DMDM56405372.

Proteomic databases

PaxDbQ02127.
PRIDEQ02127.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000219240; ENSP00000219240; ENSG00000102967.
GeneID1723.
KEGGhsa:1723.
UCSCuc002fbp.3. human.

Organism-specific databases

CTD1723.
GeneCardsGC16P072042.
HGNCHGNC:2867. DHODH.
HPAHPA010123.
HPA011942.
MIM126064. gene.
263750. phenotype.
neXtProtNX_Q02127.
Orphanet246. Postaxial acrofacial dysostosis.
PharmGKBPA27327.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0167.
HOGENOMHOG000225103.
HOVERGENHBG006898.
InParanoidQ02127.
KOK00254.
OMAVYEGPGL.
PhylomeDBQ02127.
TreeFamTF105973.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
SABIO-RKQ02127.
UniPathwayUPA00070; UER00946.

Gene expression databases

ArrayExpressQ02127.
BgeeQ02127.
CleanExHS_DHODH.
GenevestigatorQ02127.

Family and domain databases

Gene3D3.20.20.70. 1 hit.
InterProIPR013785. Aldolase_TIM.
IPR012135. Dihydroorotate_DH_1_2.
IPR005719. Dihydroorotate_DH_2.
IPR001295. Dihydroorotate_DH_CS.
[Graphical view]
PfamPF01180. DHO_dh. 1 hit.
[Graphical view]
PIRSFPIRSF000164. DHO_oxidase. 1 hit.
TIGRFAMsTIGR01036. pyrD_sub2. 1 hit.
PROSITEPS00911. DHODEHASE_1. 1 hit.
PS00912. DHODEHASE_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ02127.
GenomeRNAi1723.
NextBio6971.
PROQ02127.
SOURCESearch...

Entry information

Entry namePYRD_HUMAN
AccessionPrimary (citable) accession number: Q02127
Secondary accession number(s): A8K8C8, Q6P176
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: December 7, 2004
Last modified: April 16, 2014
This is version 148 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM