Q93099 (HGD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Homogentisate 1,2-dioxygenase
EC=1.13.11.5

Alternative name(s):
Homogentisate oxygenase
Homogentisic acid oxidase
Homogentisicase

Gene names

Name:	HGD
Synonyms:	HGO

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	445 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	Homogentisate + O2 = 4-maleylacetoacetate.
Cofactor	Iron.
Pathway	Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 4/6.
Tissue specificity	Highest expression in the prostate, small intestine, colon, kidney and liver.
Involvement in disease	Alkaptonuria (AKU) [MIM:203500]: An autosomal recessive error of metabolism characterized by an increase in the level of homogentisic acid. The clinical manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and spine arthritis. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17
Sequence similarities	Belongs to the homogentisate dioxygenase family.

Ontologies

Keywords
Biological process	Phenylalanine catabolism Tyrosine catabolism
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	Iron Metal-binding
Molecular function	Dioxygenase Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	L-phenylalanine catabolic process Traceable author statement. Source: Reactome cellular nitrogen compound metabolic process Traceable author statement. Source: Reactome tyrosine catabolic process Traceable author statement Ref.1. Source: ProtInc
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	homogentisate 1,2-dioxygenase activity Inferred from experiment. Source: Reactome metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 445

445

Homogentisate 1,2-dioxygenase

PRO_0000220240

Sites

Metal binding

335

1

Iron

Metal binding

341

1

Iron

Metal binding

371

1

Iron

Amino acid modifications

Modified residue

98

1

N6-acetyllysine Ref.8

Natural variations

Natural variant

25

1

L → P in AKU. Ref.15 Ref.16

VAR_009618

Natural variant

42

1

E → A in AKU. Ref.12

VAR_005272

Natural variant

60

1

W → G in AKU. Ref.14

VAR_005273

Natural variant

62

1

Y → C in AKU. Ref.14

VAR_005274

Natural variant

80

1

Q → H. Ref.1 Ref.2 Ref.3 Ref.4 Ref.6 Ref.7
Corresponds to variant rs2255543 [ dbSNP | Ensembl ].

VAR_049353

Natural variant

97

1

W → G in AKU. Ref.12

VAR_005275

Natural variant

122

1

A → D in AKU. Ref.14

VAR_005276

Natural variant

153

1

D → G in AKU. Ref.12

VAR_005277

Natural variant

161

1

G → R in AKU; loss of activity; most prevalent mutation in Slovak and Czech patients. Ref.11 Ref.16
Corresponds to variant rs28941783 [ dbSNP | Ensembl ].

VAR_005278

Natural variant

168

1

E → K in AKU; loss of activity. Ref.13

VAR_009619

Natural variant

189

1

S → I in AKU. Ref.12

VAR_005279

Natural variant

216

1

I → T in AKU. Ref.12

VAR_005280

Natural variant

225

1

R → H in AKU. Ref.12

VAR_005281

Natural variant

227

1

F → S in AKU. Ref.12

VAR_005282

Natural variant

230

1

P → S in AKU; complete loss of activity. Ref.1 Ref.16
Corresponds to variant rs28942100 [ dbSNP | Ensembl ].

VAR_005283

Natural variant

230

1

P → T in AKU. Ref.14

VAR_005284

Natural variant

270

1

G → R in AKU. Ref.16

VAR_009620

Natural variant

291

1

D → E in AKU. Ref.14

VAR_005285

Natural variant

300

1

V → G in AKU. Ref.1 Ref.16

VAR_005286

Natural variant

330

1

R → S in AKU. Ref.17

VAR_008744

Natural variant

368

1

M → V in AKU; loss of activity. Ref.12 Ref.15 Ref.16 Ref.17

VAR_005287

Natural variant

371

1

H → R in AKU. Ref.17

VAR_008745

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

445

Helix Strand Turn

Details...

Beta strand

6 – 8

3

Beta strand

14 – 17

4

Helix

36 – 38

3

Beta strand

40 – 47

8

Helix

53 – 55

3

Beta strand

58 – 65

8

Helix

85 – 87

3

Beta strand

95 – 97

3

Turn

105 – 107

3

Turn

112 – 115

4

Beta strand

116 – 123

8

Helix

125 – 127

3

Beta strand

131 – 138

8

Beta strand

144 – 161

18

Beta strand

163 – 167

5

Beta strand

170 – 174

5

Beta strand

178 – 182

5

Beta strand

188 – 191

4

Beta strand

193 – 205

13

Helix

214 – 216

3

Helix

224 – 226

3

Beta strand

227 – 230

4

Beta strand

238 – 249

12

Beta strand

252 – 260

9

Beta strand

265 – 271

7

Beta strand

275 – 278

4

Helix

279 – 281

3

Beta strand

288 – 291

4

Helix

295 – 298

4

Beta strand

299 – 304

6

Beta strand

311 – 318

8

Beta strand

320 – 323

4

Beta strand

326 – 328

3

Beta strand

340 – 347

8

Beta strand

362 – 365

4

Helix

375 – 383

9

Beta strand

389 – 392

4

Beta strand

396 – 404

9

Helix

410 – 415

6

Sequences

	Sequence		Length	Mass (Da)
	Q93099 [UniParc]. Last modified May 18, 2010. Version 2. Checksum: F99B51C134FFF965	FASTA	445	49,964
	10 20 30 40 50 60 MAELKYISGF GNECSSEDPR CPGSLPEGQN NPQVCPYNLY AEQLSGSAFT CPRSTNKRSW 70 80 90 100 110 120 LYRILPSVSH KPFESIDEGQ VTHNWDEVDP DPNQLRWKPF EIPKASQKKV DFVSGLHTLC 130 140 150 160 170 180 GAGDIKSNNG LAIHIFLCNT SMENRCFYNS DGDFLIVPQK GNLLIYTEFG KMLVQPNEIC 190 200 210 220 230 240 VIQRGMRFSI DVFEETRGYI LEVYGVHFEL PDLGPIGANG LANPRDFLIP IAWYEDRQVP 250 260 270 280 290 300 GGYTVINKYQ GKLFAAKQDV SPFNVVAWHG NYTPYKYNLK NFMVINSVAF DHADPSIFTV 310 320 330 340 350 360 LTAKSVRPGV AIADFVIFPP RWGVADKTFR PPYYHRNCMS EFMGLIRGHY EAKQGGFLPG 370 380 390 400 410 420 GGSLHSTMTP HGPDADCFEK ASKVKLAPER IADGTMAFMF ESSLSLAVTK WGLKASRCLD 430 440 ENYHKCWEPL KSHFTPNSRN PAEPN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The molecular basis of alkaptonuria." Fernandez-Canon J.M., Granadino B., Beltran-Valero de Bernabe D., Renedo M., Fernandez-Ruiz E., Penalva M.A., Rodriguez de Cordoba S. Nat. Genet. 14:19-24(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS HIS-80; AKU SER-230 AND GLY-300.
[2]	"Homogentisate 1,2-dioxygenase human cDNA sequence." Ramos S., Hernandez M., Rozes A., Larruga J., Gonzalez P., Cabrera V.M. Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-80. Tissue: Liver.
[3]	"The human homogentisate 1,2-dioxygenase (HGO) gene." Granadino B., Beltran-Valero de Bernabe D., Fernandez-Canon J.M., Penalva M.A., Rodriguez de Cordoba S. Genomics 43:115-122(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HIS-80.
[4]	"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 HIS-80. Tissue: Prostate.
[5]	"The DNA sequence, annotation and analysis of human chromosome 3." Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J. , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A. Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT HIS-80.
[7]	"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], VARIANT HIS-80.
[8]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-98, MASS SPECTROMETRY.
[9]	"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].
[10]	"Crystal structure of human homogentisate dioxygenase." Titus G.P., Mueller H.A., Burgner J., Rodriguez de Cordoba S., Penalva M.A., Timm D.E. Nat. Struct. Biol. 7:542-546(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[11]	"Molecular defects in alkaptonuria." Gehrig A., Schmidt S.R., Mueller C.R., Srsen S., Srsnova K., Kress W. Cytogenet. Cell Genet. 76:14-16(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT AKU ARG-161.
[12]	"Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients." Beltran-Valero de Bernabe D., Granadino B., Chiarelli I., Porfirio B., Mayatepek E., Aquaron R., Moore M.M., Festen J.J.M., Sanmarti R., Penalva M.A., de Cordoba S.R. Am. J. Hum. Genet. 62:776-784(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AKU ALA-42; GLY-97; GLY-153; ILE-189; THR-216; HIS-225; SER-227 AND VAL-368.
[13]	"A novel point mutation associated with alkaptonuria." Higashino K., Liu W., Ohkawa T., Yamamoto T., Fukui K., Ohno M., Imanishi H., Iwasaki A., Amuro Y., Hada T. Clin. Genet. 53:228-229(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT AKU LYS-168.
[14]	"Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO)." Beltran-Valero de Bernabe D., Jimenez F.J., Aquaron R., Rodriguez de Cordoba S. Am. J. Hum. Genet. 64:1316-1322(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AKU GLY-60; CYS-62; ASP-122; THR-230 AND GLU-291.
[15]	"Ocular ochronosis in alkaptonuria patients carrying mutations in the homogentisate 1,2-dioxygenase gene." Felbor U., Mutsch Y., Grehn F., Mueller C.R., Kress W. Br. J. Ophthalmol. 83:680-683(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AKU PRO-25 AND VAL-368. Tissue: Leukocyte.
[16]	"Allelic heterogeneity of alkaptonuria in Central Europe." Mueller C.R., Fregin A., Srsen S., Srsnova K., Halliger-Keller B., Felbor U., Seemanova E., Kress W. Eur. J. Hum. Genet. 7:645-651(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AKU PRO-25; ARG-161; SER-230; ARG-270; GLY-300 AND VAL-368. Tissue: Lymphocyte.
[17]	"Mutational analysis of the HGO gene in Finnish alkaptonuria patients." Beltran-Valero de Bernabe D., Peterson P., Luopajarvi K., Matintalo P., Alho A., Konttinen Y., Krohn K., Rodriguez de Cordoba S., Ranki A. J. Med. Genet. 36:922-923(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AKU SER-330; VAL-368 AND ARG-371.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U63008 mRNA. Translation: AAB16836.1.
Z75048 mRNA. Translation: CAA99340.1.
AF000573 Genomic DNA. Translation: AAC51650.1.
AF045167 mRNA. Translation: AAC02698.1.
AK313563 mRNA. Translation: BAG36337.1.
AC126182 Genomic DNA. No translation available.
AC133474 Genomic DNA. No translation available.
CH471052 Genomic DNA. Translation: EAW79524.1.
BC071757 mRNA. Translation: AAH71757.1.

IPI

IPI00303174.

RefSeq

NP_000178.2. NM_000187.3.

UniGene

Hs.368254.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1EY2	X-ray	2.30	A	1-445	[»]
1EYB	X-ray	1.90	A	1-445	[»]

ProteinModelPortal

Q93099.

SMR

Q93099. Positions 2-440.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q93099. 3 interactions.

STRING

9606.ENSP00000283871.

PTM databases

PhosphoSite

Q93099.

Polymorphism databases

DMDM

296434531.

Proteomic databases

PaxDb

Q93099.

PRIDE

Q93099.

Protocols and materials databases

DNASU

3081.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000283871; ENSP00000283871; ENSG00000113924.

GeneID

3081.

KEGG

hsa:3081.

UCSC

uc003edv.3. human.

Organism-specific databases

CTD

3081.

GeneCards

GC03M120347.

H-InvDB

HIX0003593.

HGNC

HGNC:4892. HGD.

MIM

203500. phenotype.
607474. gene.

neXtProt

NX_Q93099.

Orphanet

56. Alkaptonuria.

PharmGKB

PA29268.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG3508.

HOGENOM

HOG000139824.

HOVERGEN

HBG005965.

InParanoid

Q93099.

KO

K00451.

OMA

AVTKWGL.

OrthoDB

EOG4255SQ.

PhylomeDB

Q93099.

Enzyme and pathway databases

BioCyc

MetaCyc:HS03728-MONOMER.

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00139; UER00339.

Gene expression databases

ArrayExpress

Q93099.

Bgee

Q93099.

CleanEx

HS_HGD.

Genevestigator

Q93099.

GermOnline

ENSG00000113924. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.10. 2 hits.

InterPro

IPR005708. Homogentis_dOase.
IPR014710. RmlC-like_jellyroll.
IPR011051. RmlC_Cupin.
[Graphical view]

PANTHER

PTHR11056. PTHR11056. 1 hit.

Pfam

PF04209. HgmA. 1 hit.
[Graphical view]

SUPFAM

SSF51182. RmlC_like_cupin. 1 hit.

TIGRFAMs

TIGR01015. hmgA. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

Q93099.

GenomeRNAi

3081.

NextBio

12197.

SOURCE

Search...

Entry information

Entry name

HGD_HUMAN

Accession

Primary (citable) accession number: Q93099
Secondary accession number(s): B2R8Z0

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	May 18, 2010
Last modified:	May 1, 2013
This is version 129 of the entry and version 2 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.