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Protein

4-hydroxyphenylpyruvate dioxygenase

Gene

HPD

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Key enzyme in the degradation of tyrosine.

Catalytic activityi

4-hydroxyphenylpyruvate + O2 = homogentisate + CO2.

Cofactori

Fe cationBy similarityNote: Binds 1 Fe cation per subunit.By similarity

Pathwayi: L-phenylalanine degradation

This protein is involved in step 3 of the subpathway that synthesizes acetoacetate and fumarate from L-phenylalanine.
Proteins known to be involved in the 6 steps of the subpathway in this organism are:
  1. Phenylalanine-4-hydroxylase (PAH)
  2. Tyrosine aminotransferase (TAT)
  3. 4-hydroxyphenylpyruvate dioxygenase (HPD)
  4. Homogentisate 1,2-dioxygenase (HGD)
  5. Maleylacetoacetate isomerase (GSTZ1)
  6. Fumarylacetoacetase (FAH)
This subpathway is part of the pathway L-phenylalanine degradation, which is itself part of Amino-acid degradation.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes acetoacetate and fumarate from L-phenylalanine, the pathway L-phenylalanine degradation and in Amino-acid degradation.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi183IronCurated1
Metal bindingi266IronCurated1
Metal bindingi349IronCurated1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDioxygenase, Oxidoreductase
Biological processPhenylalanine catabolism, Tyrosine catabolism
LigandIron, Metal-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS08267-MONOMER.
BRENDAi1.13.11.27. 2681.
ReactomeiR-HSA-71182. Phenylalanine and tyrosine catabolism.
UniPathwayiUPA00139; UER00362.

Names & Taxonomyi

Protein namesi
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 namesi
Name:HPD
Synonyms:PPD
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000158104.11.
HGNCiHGNC:5147. HPD.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Pathology & Biotechi

Involvement in diseasei

Tyrosinemia 3 (TYRSN3)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation.
See also OMIM:276710
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_015445160Y → C in TYRSN3. 1 PublicationCorresponds to variant dbSNP:rs28934278Ensembl.1
Natural variantiVAR_015447268A → V in TYRSN3. 1 Publication1
Natural variantiVAR_015448335I → M in TYRSN3. 1 Publication1
Hawkinsinuria (HAWK)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn 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.
See also OMIM:140350

Keywords - Diseasei

Disease mutation, Mental retardation

Organism-specific databases

DisGeNETi3242.
MalaCardsiHPD.
MIMi140350. phenotype.
276710. phenotype.
OpenTargetsiENSG00000158104.
Orphaneti2118. Hawkinsinuria.
69723. Tyrosinemia type 3.
PharmGKBiPA29420.

Chemistry databases

ChEMBLiCHEMBL1861.
DrugBankiDB02850. (1-Tert-Butyl-5-Hydroxy-1h-Pyrazol-4-Yl)-(6-Methanesulfonyl-4'-Methoxy-2-Methyl-Biphenyl-3-Yl)-Methanone.
DB00348. Nitisinone.

Polymorphism and mutation databases

BioMutaiHPD.
DMDMi417144.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000883882 – 3934-hydroxyphenylpyruvate dioxygenaseAdd BLAST392

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylthreonineCombined sources1
Modified residuei132N6-succinyllysineBy similarity1
Modified residuei211PhosphoserineCombined sources1
Modified residuei226PhosphoserineBy similarity1
Modified residuei250PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiP32754.
PaxDbiP32754.
PeptideAtlasiP32754.
PRIDEiP32754.

PTM databases

iPTMnetiP32754.
PhosphoSitePlusiP32754.

Expressioni

Gene expression databases

BgeeiENSG00000158104.
CleanExiHS_HPD.
ExpressionAtlasiP32754. baseline and differential.
GenevisibleiP32754. HS.

Organism-specific databases

HPAiHPA038321.
HPA038322.

Interactioni

Subunit structurei

Homodimer.1 Publication

Protein-protein interaction databases

BioGridi109482. 6 interactors.
IntActiP32754. 4 interactors.
STRINGi9606.ENSP00000289004.

Chemistry databases

BindingDBiP32754.

Structurei

Secondary structure

1393
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi15 – 25Combined sources11
Helixi29 – 40Combined sources12
Beta strandi43 – 49Combined sources7
Helixi50 – 52Combined sources3
Beta strandi56 – 64Combined sources9
Beta strandi67 – 76Combined sources10
Helixi80 – 89Combined sources10
Beta strandi91 – 101Combined sources11
Helixi103 – 113Combined sources11
Beta strandi117 – 126Combined sources10
Beta strandi129 – 137Combined sources9
Beta strandi143 – 151Combined sources9
Beta strandi154 – 156Combined sources3
Helixi170 – 172Combined sources3
Beta strandi178 – 187Combined sources10
Helixi193 – 204Combined sources12
Beta strandi207 – 212Combined sources6
Turni214 – 216Combined sources3
Beta strandi223 – 230Combined sources8
Beta strandi237 – 244Combined sources8
Helixi251 – 259Combined sources9
Beta strandi261 – 272Combined sources12
Helixi274 – 283Combined sources10
Helixi293 – 303Combined sources11
Helixi314 – 320Combined sources7
Beta strandi323 – 326Combined sources4
Beta strandi331 – 337Combined sources7
Beta strandi340 – 344Combined sources5
Beta strandi347 – 355Combined sources9
Helixi361 – 377Combined sources17

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3ISQX-ray1.75A8-393[»]
5EC3X-ray2.10A1-393[»]
ProteinModelPortaliP32754.
SMRiP32754.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP32754.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 149VOC 1PROSITE-ProRule annotationAdd BLAST132
Domaini180 – 338VOC 2PROSITE-ProRule annotationAdd BLAST159

Sequence similaritiesi

Belongs to the 4HPPD family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0638. Eukaryota.
COG3185. LUCA.
GeneTreeiENSGT00530000063474.
HOGENOMiHOG000188687.
HOVERGENiHBG005987.
InParanoidiP32754.
KOiK00457.
PhylomeDBiP32754.

Family and domain databases

Gene3Di3.10.180.10. 2 hits.
InterProiView protein in InterPro
IPR005956. 4OHPhenylPyrv_dOase.
IPR029068. Glyas_Bleomycin-R_OHBP_Dase.
IPR004360. Glyas_Fos-R_dOase_dom.
PANTHERiPTHR11959. PTHR11959. 1 hit.
PfamiView protein in Pfam
PF00903. Glyoxalase. 1 hit.
PIRSFiPIRSF009283. HPP_dOase. 1 hit.
SUPFAMiSSF54593. SSF54593. 1 hit.
TIGRFAMsiTIGR01263. 4HPPD. 1 hit.
PROSITEiView protein in PROSITE
PS51819. VOC. 2 hits.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P32754-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MTTYSDKGAK PERGRFLHFH SVTFWVGNAK QAASFYCSKM GFEPLAYRGL
60 70 80 90 100
ETGSREVVSH VIKQGKIVFV LSSALNPWNK EMGDHLVKHG DGVKDIAFEV
110 120 130 140 150
EDCDYIVQKA RERGAKIMRE PWVEQDKFGK VKFAVLQTYG DTTHTLVEKM
160 170 180 190 200
NYIGQFLPGY EAPAFMDPLL PKLPKCSLEM IDHIVGNQPD QEMVSASEWY
210 220 230 240 250
LKNLQFHRFW SVDDTQVHTE YSSLRSIVVA NYEESIKMPI NEPAPGKKKS
260 270 280 290 300
QIQEYVDYNG GAGVQHIALK TEDIITAIRH LRERGLEFLS VPSTYYKQLR
310 320 330 340 350
EKLKTAKIKV KENIDALEEL KILVDYDEKG YLLQIFTKPV QDRPTLFLEV
360 370 380 390
IQRHNHQGFG AGNFNSLFKA FEEEQNLRGN LTNMETNGVV PGM
Length:393
Mass (Da):44,934
Last modified:January 23, 2007 - v2
Checksum:i4314A16532C33A2F
GO
Isoform 2 (identifier: P32754-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-39: Missing.

Show »
Length:354
Mass (Da):40,497
Checksum:i45F3E405EBD38707
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti162A → P in AAC73008 (PubMed:9325050).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01544433A → T in two patients with hawkinsinuria. 2 PublicationsCorresponds to variant dbSNP:rs1154510Ensembl.1
Natural variantiVAR_048101113R → Q. Corresponds to variant dbSNP:rs11833399Ensembl.1
Natural variantiVAR_015445160Y → C in TYRSN3. 1 PublicationCorresponds to variant dbSNP:rs28934278Ensembl.1
Natural variantiVAR_015446267I → F1 Publication1
Natural variantiVAR_015447268A → V in TYRSN3. 1 Publication1
Natural variantiVAR_015448335I → M in TYRSN3. 1 Publication1
Natural variantiVAR_015449340V → L1 PublicationCorresponds to variant dbSNP:rs36023382Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0443021 – 39Missing in isoform 2. 1 PublicationAdd BLAST39

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D31628 Genomic DNA. Translation: BAA06498.1.
X72389 mRNA. Translation: CAA51082.1.
U29895 Genomic DNA. Translation: AAC73008.1.
AK057510 mRNA. Translation: BAG51925.1.
AK290826 mRNA. Translation: BAF83515.1.
AC069503 Genomic DNA. No translation available.
AC079360 Genomic DNA. No translation available.
CH471054 Genomic DNA. Translation: EAW98292.1.
BC024287 mRNA. Translation: AAH24287.1.
CCDSiCCDS53839.1. [P32754-2]
CCDS9224.1. [P32754-1]
PIRiS32458.
RefSeqiNP_001165464.1. NM_001171993.1. [P32754-2]
NP_002141.1. NM_002150.2. [P32754-1]
UniGeneiHs.2899.

Genome annotation databases

EnsembliENST00000543163; ENSP00000441677; ENSG00000158104. [P32754-2]
GeneIDi3242.
KEGGihsa:3242.
UCSCiuc058ujk.1. human. [P32754-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHPPD_HUMAN
AccessioniPrimary (citable) accession number: P32754
Secondary accession number(s): A8K461, B3KQ63, Q13234
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: January 23, 2007
Last modified: September 27, 2017
This is version 177 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families