Q02127 (PYRD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dihydroorotate dehydrogenase (quinone), mitochondrial
Short name=DHOdehase
EC=1.3.5.2

Alternative name(s):
Dihydroorotate oxidase

Gene names

Name:

DHODH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	395 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Pyrimidine biosynthesis
Cellular component	Membrane Mitochondrion Mitochondrion inner membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide Transmembrane Transmembrane helix
Ligand	FMN Flavoprotein
Molecular function	Oxidoreductase
Technical term	3D-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 Non-traceable author statement. Source: UniProtKB female pregnancy Inferred from electronic annotation. Source: Compara lactation Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara pyrimidine nucleoside biosynthetic process Traceable author statement. Source: Reactome regulation of mitochondrial fission Inferred from electronic annotation. Source: Compara response to caffeine Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to starvation Inferred from electronic annotation. Source: Compara
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial inner membrane Non-traceable author statement. Source: UniProtKB neuronal cell body Inferred from electronic annotation. Source: Compara
Molecular_function	FMN binding Inferred from electronic annotation. Source: Compara dihydroorotate dehydrogenase activity Non-traceable author statement. Source: UniProtKB dihydroorotate oxidase activity Inferred from electronic annotation. Source: Compara drug binding Inferred from electronic annotation. Source: Compara ubiquinone binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 395

395

Dihydroorotate dehydrogenase (quinone), mitochondrial

PRO_0000029884

Transit peptide

1 – 10

10

Mitochondrion; not cleaved By similarity

Regions

Topological domain

1 – 10

10

Mitochondrial matrix By similarity

Transmembrane

11 – 30

20

Helical; By similarity

Topological domain

31 – 395

365

Mitochondrial intermembrane By similarity

Nucleotide binding

95 – 99

5

FMN

Nucleotide binding

355 – 356

2

FMN

Region

144 – 148

5

Substrate binding

Region

211 – 216

6

Substrate binding

Region

283 – 284

2

Substrate binding

Sites

Active site

214

1

Nucleophile

Binding site

99

1

Substrate

Binding site

119

1

FMN

Binding site

180

1

FMN

Binding site

211

1

FMN

Binding site

254

1

FMN

Binding site

282

1

FMN; via carbonyl oxygen

Binding site

305

1

FMN; via amide nitrogen

Binding site

334

1

FMN; via amide nitrogen

Natural variations

Natural variant

7

1

K → Q. Ref.1 Ref.3
Corresponds to variant rs3213422 [ dbSNP | Ensembl ].

VAR_022094

Natural variant

19

1

G → E in POADS. Ref.10

VAR_062412

Natural variant

135

1

R → C in POADS. Ref.10

VAR_062413

Natural variant

152

1

G → R in POADS. Ref.10

VAR_062414

Natural variant

199

1

R → C in POADS. Ref.10

VAR_062415

Natural variant

202

1

G → A in POADS. Ref.10

VAR_062416

Natural variant

202

1

G → D in POADS. Ref.10

VAR_062417

Natural variant

244

1

R → W in POADS. Ref.10

VAR_062418

Natural variant

284

1

T → I in POADS. Ref.10

VAR_062419

Natural variant

346

1

R → W in POADS. Ref.10

VAR_062420

Natural variant

392

1

D → G in POADS. Ref.10

VAR_062421

Experimental info

Sequence conflict

1 – 2

2

MA → KLP in AAA50163. Ref.1

Secondary structure

1

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395

Helix Strand Turn

Details...

Helix

34 – 39

6

Helix

41 – 48

8

Helix

51 – 63

13

Helix

76 – 78

3

Beta strand

80 – 82

3

Beta strand

85 – 93

9

Turn

95 – 100

6

Beta strand

101 – 103

3

Helix

104 – 109

6

Beta strand

113 – 120

8

Beta strand

133 – 136

4

Helix

137 – 139

3

Beta strand

141 – 144

4

Helix

153 – 161

9

Helix

164 – 172

9

Beta strand

177 – 181

5

Helix

190 – 201

12

Helix

202 – 204

3

Beta strand

206 – 211

6

Helix

220 – 224

5

Helix

226 – 241

16

Helix

245 – 247

3

Beta strand

250 – 255

6

Helix

261 – 274

14

Beta strand

278 – 281

4

Turn

295 – 298

4

Beta strand

299 – 305

7

Helix

306 – 308

3

Helix

309 – 322

14

Turn

323 – 325

3

Beta strand

329 – 334

6

Helix

338 – 347

10

Beta strand

350 – 355

6

Helix

356 – 361

6

Helix

364 – 379

16

Helix

385 – 388

4

Helix

391 – 393

3

Sequences

	Sequence		Length	Mass (Da)
	Q02127 [UniParc]. Last modified December 7, 2004. Version 3. Checksum: 072C3169E78C6440	FASTA	395	42,867
	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

References

	« Hide 'large scale' referencesShow '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. , 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.

IPI

IPI00024462.

PIR

PC1219.

RefSeq

NP_001352.2. NM_001361.4.

UniGene

Hs.654427.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1D3G	X-ray	1.60	A	29-395	[»]
1D3H	X-ray	1.80	A	29-395	[»]
2B0M	X-ray	2.00	A	29-395	[»]
2BXV	X-ray	2.15	A	29-395	[»]
2FPT	X-ray	2.40	A	29-395	[»]
2FPV	X-ray	1.80	A	29-395	[»]
2FPY	X-ray	2.00	A	29-395	[»]
2FQI	X-ray	1.95	A	29-395	[»]
2PRH	X-ray	2.40	A	29-395	[»]
2PRL	X-ray	2.10	A	29-395	[»]
2PRM	X-ray	3.00	A	29-395	[»]
2WV8	X-ray	1.90	A	31-395	[»]
3F1Q	X-ray	2.00	A	29-395	[»]
3FJ6	X-ray	1.80	A	29-395	[»]
3FJL	X-ray	1.90	A	29-395	[»]
3G0U	X-ray	2.00	A	29-395	[»]
3G0X	X-ray	1.80	A	29-395	[»]
3KVJ	X-ray	1.94	A	29-395	[»]
3KVK	X-ray	2.05	A	29-395	[»]
3KVL	X-ray	1.85	A	29-395	[»]
3KVM	X-ray	2.00	A	29-395	[»]
3U2O	X-ray	2.18	A	1-395	[»]
3ZWS	X-ray	1.60	A	29-395	[»]
3ZWT	X-ray	1.55	A	29-395	[»]

ProteinModelPortal

Q02127.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q02127. 2 interactions.

STRING

9606.ENSP00000219240.

PTM databases

PhosphoSite

Q02127.

Polymorphism databases

DMDM

56405372.

Proteomic databases

PaxDb

Q02127.

PRIDE

Q02127.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000219240; ENSP00000219240; ENSG00000102967.

GeneID

1723.

KEGG

hsa:1723.

UCSC

uc002fbp.3. human.

Organism-specific databases

CTD

1723.

GeneCards

GC16P072042.

HGNC

HGNC:2867. DHODH.

HPA

HPA010123.
HPA011942.

MIM

126064. gene.
263750. phenotype.

neXtProt

NX_Q02127.

Orphanet

246. Postaxial acrofacial dysostosis.

PharmGKB

PA27327.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0167.

HOGENOM

HOG000225103.

HOVERGEN

HBG006898.

InParanoid

Q02127.

KO

K00254.

OMA

ALNRMGF.

OrthoDB

EOG47WNNW.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

Q02127.

UniPathway

UPA00070; UER00946.

Gene expression databases

ArrayExpress

Q02127.

Bgee

Q02127.

CleanEx

HS_DHODH.

Genevestigator

Q02127.

GermOnline

ENSG00000102967. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.70. 1 hit.

InterPro

IPR013785. Aldolase_TIM.
IPR012135. Dihydroorotate_DH_1_2.
IPR005719. Dihydroorotate_DH_2.
IPR001295. Dihydroorotate_DH_CS.
[Graphical view]

Pfam

PF01180. DHO_dh. 1 hit.
[Graphical view]

PIRSF

PIRSF000164. DHO_oxidase. 1 hit.

TIGRFAMs

TIGR01036. pyrD_sub2. 1 hit.

PROSITE

PS00911. DHODEHASE_1. 1 hit.
PS00912. DHODEHASE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q02127.

ChEMBL

CHEMBL1966.

DrugBank

DB01117. Atovaquone.
DB01097. Leflunomide.

EvolutionaryTrace

Q02127.

GenomeRNAi

1723.

NextBio

6971.

SOURCE

Search...

Entry information

Entry name

PYRD_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 140 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.