P32754 (HPPD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
4-hydroxyphenylpyruvate dioxygenase
EC=1.13.11.27

Alternative name(s):
4-hydroxyphenylpyruvic acid oxidase
Short name=4HPPD
Short name=HPD
Short name=HPPDase

Gene names

Name:	HPD
Synonyms:	PPD

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	393 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	Key enzyme in the degradation of tyrosine.
Catalytic activity	4-hydroxyphenylpyruvate + O2 = homogentisate + CO2.
Cofactor	Binds 1 iron ion per subunit By similarity.
Pathway	Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 3/6.
Subunit structure	Homodimer.
Involvement in disease	Defects in HPD are the cause of tyrosinemia type 3 (TYRO3) [MIM:276710]. TYRO3 is an inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation. Ref.8 Ref.9 Defects in HPD are a cause of hawkinsinuria (HAWK) [MIM:140350]. HAWK is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine. Ref.9
Sequence similarities	Belongs to the 4HPPD family.

Ontologies

Keywords
Biological process	Phenylalanine catabolism Tyrosine catabolism
Coding sequence diversity	Polymorphism
Disease	Disease mutation Mental retardation
Ligand	Iron Metal-binding
Molecular function	Dioxygenase Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	L-phenylalanine catabolic process Traceable author statement. Source: Reactome tyrosine catabolic process Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	4-hydroxyphenylpyruvate dioxygenase activity Inferred from sequence or structural similarity. Source: UniProtKB 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

Initiator methionine

1

1

Removed By similarity

Chain

2 – 393

392

4-hydroxyphenylpyruvate dioxygenase

PRO_0000088388

Sites

Metal binding

183

1

Iron Probable

Metal binding

266

1

Iron Probable

Metal binding

349

1

Iron Probable

Amino acid modifications

Modified residue

2

1

N-acetylthreonine By similarity

Modified residue

250

1

Phosphoserine By similarity

Natural variations

Natural variant

33

1

A → T in two patients with hawkinsinuria. Ref.8 Ref.9
Corresponds to variant rs1154510 [ dbSNP | Ensembl ].

VAR_015444

Natural variant

113

1

R → Q.
Corresponds to variant rs11833399 [ dbSNP | Ensembl ].

VAR_048101

Natural variant

160

1

Y → C in TYRO3. Ref.8
Corresponds to variant rs28934278 [ dbSNP | Ensembl ].

VAR_015445

Natural variant

267

1

I → F. Ref.8

VAR_015446

Natural variant

268

1

A → V in TYRO3. Ref.9

VAR_015447

Natural variant

335

1

I → M in TYRO3. Ref.8

VAR_015448

Natural variant

340

1

V → L. Ref.8
Corresponds to variant rs36023382 [ dbSNP | Ensembl ].

VAR_015449

Experimental info

Sequence conflict

162

1

A → P in AAC73008. Ref.3

Secondary structure

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393

Helix Strand Turn

Details...

Beta strand

16 – 25

10

Helix

29 – 39

11

Beta strand

43 – 48

6

Beta strand

56 – 63

8

Beta strand

68 – 76

9

Helix

85 – 88

4

Beta strand

95 – 101

7

Helix

103 – 112

10

Beta strand

117 – 124

8

Beta strand

131 – 137

7

Beta strand

143 – 151

9

Helix

170 – 172

3

Beta strand

178 – 185

8

Helix

193 – 204

12

Beta strand

207 – 212

6

Turn

214 – 216

3

Beta strand

223 – 230

8

Beta strand

237 – 244

8

Helix

251 – 258

8

Beta strand

266 – 272

7

Helix

274 – 283

10

Helix

293 – 303

11

Helix

314 – 320

7

Beta strand

323 – 325

3

Beta strand

332 – 337

6

Beta strand

340 – 344

5

Beta strand

347 – 355

9

Helix

364 – 377

14

Sequences

	Sequence		Length	Mass (Da)
	P32754 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 4314A16532C33A2F	FASTA	393	44,934
	10 20 30 40 50 60 MTTYSDKGAK PERGRFLHFH SVTFWVGNAK QAASFYCSKM GFEPLAYRGL ETGSREVVSH 70 80 90 100 110 120 VIKQGKIVFV LSSALNPWNK EMGDHLVKHG DGVKDIAFEV EDCDYIVQKA RERGAKIMRE 130 140 150 160 170 180 PWVEQDKFGK VKFAVLQTYG DTTHTLVEKM NYIGQFLPGY EAPAFMDPLL PKLPKCSLEM 190 200 210 220 230 240 IDHIVGNQPD QEMVSASEWY LKNLQFHRFW SVDDTQVHTE YSSLRSIVVA NYEESIKMPI 250 260 270 280 290 300 NEPAPGKKKS QIQEYVDYNG GAGVQHIALK TEDIITAIRH LRERGLEFLS VPSTYYKQLR 310 320 330 340 350 360 EKLKTAKIKV KENIDALEEL KILVDYDEKG YLLQIFTKPV QDRPTLFLEV IQRHNHQGFG 370 380 390 AGNFNSLFKA FEEEQNLRGN LTNMETNGVV PGM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD)." Awata H., Endo F., Matsuda I. Genomics 23:534-539(1994) [PubMed: 7851880] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Regional assignment of the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) to 12q24-->qter by fluorescence in situ hybridization." Stenman G., Roijer E., Rueetschi U., Dellsen A., Rymo L., Lindstedt S. Cytogenet. Cell Genet. 71:374-376(1995) [PubMed: 8521727] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Human 4-hydroxyphenylpyruvate dioxygenase gene (HPD)." Ruetschi U., Rymo L., Lindstedt S. Genomics 44:292-299(1997) [PubMed: 9325050] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[5]	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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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]. Tissue: Liver.
[7]	"Crystal structure of human 4-hydroxyphenylpyruvate dioxygenase." Structural genomics consortium (SGC) Submitted (SEP-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 8-393 IN COMPLEX WITH COBALT IONS.
[8]	"Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III." Rueetschi U., Cerone R., Perez-Cerda C., Schiaffino M.C., Standing S., Ugarte M., Holme E. Hum. Genet. 106:654-662(2000) [PubMed: 10942115] [Abstract] Cited for: VARIANTS TYRO3 CYS-160 AND MET-335, VARIANTS THR-33; PHE-267 AND LEU-340.
[9]	"Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria." Tomoeda K., Awata H., Matsuura T., Matsuda I., Ploechl E., Milovac T., Boneh A., Scott C.R., Danks D.M., Endo F. Mol. Genet. Metab. 71:506-510(2000) [PubMed: 11073718] [Abstract] Cited for: VARIANT TYRO3 VAL-268, VARIANT HAWK THR-33.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D31628 Genomic DNA. Translation: BAA06498.1.
X72389 mRNA. Translation: CAA51082.1.
U29895 Genomic DNA. Translation: AAC73008.1.
AK290826 mRNA. Translation: BAF83515.1.
CH471054 Genomic DNA. Translation: EAW98292.1.
BC024287 mRNA. Translation: AAH24287.1.

IPI

IPI00218297.

PIR

S32458.

RefSeq

NP_001165464.1. NM_001171993.1.
NP_002141.1. NM_002150.2.

UniGene

Hs.2899.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3ISQ	X-ray	1.75	A	8-393	[»]

ProteinModelPortal

P32754.

SMR

P32754. Positions 9-384.

ModBase

Search...

Protein-protein interaction databases

IntAct

P32754. 4 interactions.

STRING

P32754.

PTM databases

PhosphoSite

P32754.

Polymorphism databases

DMDM

417144.

Proteomic databases

PRIDE

P32754.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000289004; ENSP00000289004; ENSG00000158104.

GeneID

3242.

KEGG

hsa:3242.

UCSC

uc001ubj.1. human.

Organism-specific databases

CTD

3242.

GeneCards

GC12M122277.

H-InvDB

HIX0011091.

HGNC

HGNC:5147. HPD.

HPA

HPA038322.

MIM

140350. phenotype.
276710. phenotype.
609695. gene.

neXtProt

NX_P32754.

Orphanet

2118. Hawkinsinuria.
69723. Tyrosinemia type 3.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG17767.

GeneTree

ENSGT00530000063474.

HOGENOM

HBG680392.

HOVERGEN

HBG005987.

InParanoid

P32754.

OrthoDB

EOG4Q58PF.

PhylomeDB

P32754.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-12030.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P32754.

Bgee

P32754.

CleanEx

HS_HPD.

Genevestigator

P32754.

GermOnline

ENSG00000158104. Homo sapiens.

Family and domain databases

InterPro

IPR005956. 4OHPhenylPyrv_dOase.
IPR004360. Glyas_Fos-R_dOase.
[Graphical view]

KO

K00457.

PANTHER

PTHR11959. HPP_dOase. 1 hit.

Pfam

PF00903. Glyoxalase. 2 hits.
[Graphical view]

PIRSF

PIRSF009283. HPP_dOase. 1 hit.

TIGRFAMs

TIGR01263. 4HPPD. 1 hit.

ProtoNet

Search...

Other

DrugBank

DB00348. Nitisinone.

NextBio

12905.

SOURCE

Search...

Entry information

Entry name

HPPD_HUMAN

Accession

Primary (citable) accession number: P32754
Secondary accession number(s): A8K461, Q13234

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1993
Last sequence update:	January 23, 2007
Last modified:	January 25, 2012
This is version 124 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.