Reviewed, UniProtKB/Swiss-Prot Q93099 (HGD_HUMAN)

Names and origin

Protein names

Recommended name:
    Homogentisate 1,2-dioxygenase
    EC=1.13.11.5
Alternative name(s):
    Homogentisic acid oxidase
    Homogentisate oxygenase
    Homogentisicase

Gene names

Name:	HGD
Synonyms:	HGO

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	445 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	Homogentisate + O2 = 4-maleylacetoacetate.
Cofactor	Iron.
Pathway	Amino-acid degradation; L-phenylalanine degradation; acetoacetic acid and fumarate from L-phenylalanine: step 4/6.
Tissue specificity	Highest expression in the prostate, small intestine, colon, kidney and liver.
Involvement in disease	Defects in HGD are the cause of alkaptonuria (AKU) [MIM:203500]. AKU is an autosomal recessive error of metabolism characterized by an increase in the level of homogentisic acid. The clinical manifestations of AKU are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and spine arthritis. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12
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
Technical term	3D-structure
Gene Ontology (GO)
Biological process	L-phenylalanine catabolic process Ref.1 Traceable author statement. Source: ProtInc oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW tyrosine catabolic process Ref.1 Traceable author statement. Source: ProtInc
Molecular function	homogentisate 1,2-dioxygenase activity Ref.1 Traceable author statement. Source: ProtInc iron 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

Natural variations

Natural variant

25

1

L → P in AKU. Ref.10 Ref.11

VAR_009618

Natural variant

42

1

E → A in AKU. Ref.7

VAR_005272

Natural variant

60

1

W → G in AKU. Ref.9

VAR_005273

Natural variant

62

1

Y → C in AKU. Ref.9

VAR_005274

Natural variant

80

1

H → Q: dbSNP rs2255543.

VAR_049353

Natural variant

97

1

W → G in AKU. Ref.7

VAR_005275

Natural variant

122

1

A → D in AKU. Ref.9

VAR_005276

Natural variant

153

1

D → G in AKU. Ref.7

VAR_005277

Natural variant

161

1

G → R in AKU; loss of activity; most prevalent mutation in Slovak and Czech patients. Ref.6 Ref.11

VAR_005278

Natural variant

168

1

E → K in AKU; loss of activity. Ref.8

VAR_009619

Natural variant

189

1

S → I in AKU. Ref.7

VAR_005279

Natural variant

216

1

I → T in AKU. Ref.7

VAR_005280

Natural variant

225

1

R → H in AKU. Ref.7

VAR_005281

Natural variant

227

1

F → S in AKU. Ref.7

VAR_005282

Natural variant

230

1

P → S in AKU; complete loss of activity. Ref.1 Ref.9 Ref.11

VAR_005283

Natural variant

230

1

P → T in AKU. Ref.1 Ref.9 Ref.11

VAR_005284

Natural variant

270

1

G → R in AKU. Ref.11

VAR_009620

Natural variant

291

1

D → E in AKU. Ref.9

VAR_005285

Natural variant

300

1

V → G in AKU. Ref.1 Ref.11

VAR_005286

Natural variant

330

1

R → S in AKU. Ref.12

VAR_008744

Natural variant

368

1

M → V in AKU; loss of activity. Ref.7 Ref.10 Ref.11 Ref.12

VAR_005287

Natural variant

371

1

H → R in AKU. Ref.12

VAR_008745

Secondary structure

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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

Beta strand

95 – 97

3

Turn

105 – 107

3

Turn

112 – 115

4

Beta strand

116 – 124

9

Turn

125 – 128

4

Beta strand

129 – 138

10

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

285 – 291

7

Helix

295 – 298

4

Beta strand

299 – 304

6

Beta strand

311 – 318

8

Beta strand

320 – 323

4

Beta strand

334 – 347

14

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)
	Q93099-1 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: 6429349A51A9C3E8	FASTA	445	49,973
	10 20 30 40 50 60 MAELKYISGF GNECSSEDPR CPGSLPEGQN NPQVCPYNLY AEQLSGSAFT CPRSTNKRSW 70 80 90 100 110 120 LYRILPSVSH KPFESIDEGH 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: 8782815] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS 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]. 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: 9244427] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"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: 10876237] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[6]	"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: 9154114] [Abstract] Cited for: VARIANT AKU ARG-161.
[7]	"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: 9529363] [Abstract] Cited for: VARIANTS AKU ALA-42; GLY-97; GLY-153; ILE-189; THR-216; HIS-225; SER-227 AND VAL-368.
[8]	"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: 9630082] [Abstract] Cited for: VARIANT AKU LYS-168.
[9]	"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: 10205262] [Abstract] Cited for: VARIANTS AKU GLY-60; CYS-62; ASP-122; THR-230 AND GLU-291.
[10]	"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: 10340975] [Abstract] Cited for: VARIANTS AKU PRO-25 AND VAL-368. Tissue: Leukocyte.
[11]	"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: 10482952] [Abstract] Cited for: VARIANTS AKU PRO-25; ARG-161; SER-230; ARG-270; GLY-300 AND VAL-368. Tissue: Lymphocyte.
[12]	"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: 10594001] [Abstract] Cited for: VARIANTS AKU SER-330; VAL-368 AND ARG-371.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

U63008 mRNA. Translation: AAB16836.1.
Z75048 mRNA. Translation: CAA99340.1.
AF000573 Genomic DNA. Translation: AAC51650.1.
AF045167 mRNA. Translation: AAC02698.1.
BC071757 mRNA. Translation: AAH71757.1.

IPI

IPI00303174.

RefSeq

NP_000178.2.
XP_001713658.1.

UniGene

Hs.368254
Hs.616526

3D structure databases

PDBPDBe

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

ModBase

Search...

Proteomic databases

PRIDE

Q93099.

Genome annotation databases

Ensembl

ENSG00000113924. Homo sapiens. [Contig view]
ENSG00000215729. Homo sapiens. [Contig view]

GeneID

3081.

KEGG

hsa:3081.
hsa:727722.

Organism-specific databases

GeneCards

GC03M121829.
GC03M121830.
GC03P9I0014.

H-InvDB

HIX0023018.
HIX0057359.

HGNC

HGNC:4892. HGD.

MIM

203500. phenotype.
607474. gene.

Orphanet

56. Alkaptonuria.

PharmGKB

PA29268.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q93099.

HOVERGEN

Q93099.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-12038.

BRENDA

1.13.11.5. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

CleanEx

HS_HGD.

GermOnline

ENSG00000113924. Homo sapiens.

Family and domain databases

InterPro

IPR005708. Homogentis_dOase.
[Graphical view]

PANTHER

PTHR11056. Homogentis_dOase. 1 hit.

Pfam

PF04209. HgmA. 1 hit.
[Graphical view]

TIGRFAMs

TIGR01015. hmgA. 1 hit.

ProtoNet

Search...

Other Resources

NextBio

12197.

SOURCE

Search...

Entry information

Entry name

HGD_HUMAN

Accession

Primary (citable) accession number: Q93099

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	February 1, 1997
Last modified:	May 26, 2009
This is version 89 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)