Details for: HPD

Gene ID: 3242

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HPD

Ensembl ID: ENSG00000158104

Description: 4-hydroxyphenylpyruvate dioxygenase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • centrilobular region hepatocyte CL0019029
    CSI 9.54
    rCSI 24.89%
    PRS 93.42
  • hepatocyte CL0000182
    CSI 7.36
    rCSI 13.17%
    PRS 95.2
  • midzonal region hepatocyte CL0019028
    CSI 6
    rCSI 14.08%
    PRS 94.35
  • hepatic stellate cell CL0000632
    CSI 4.49
    rCSI 16.8%
    PRS 95.28
  • epithelial cell of proximal tubule CL0002306
    CSI 3.93
    rCSI 9.61%
    PRS 92.73
  • intrahepatic cholangiocyte CL0002538
    CSI 3.75
    rCSI 8.99%
    PRS 96.26
  • Kupffer cell CL0000091
    CSI 2.97
    rCSI 6.79%
    PRS 97.23
  • periportal region hepatocyte CL0019026
    CSI 2.94
    rCSI 11.44%
    PRS 93.9
  • parietal epithelial cell CL1000452
    CSI 2.89
    rCSI 7.72%
    PRS 94.56
  • choroid plexus epithelial cell CL0000706
    CSI 2.29
    rCSI 3.74%
    PRS 93.53
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.93
    rCSI 5.94%
    PRS 97.14
  • epithelial cell of proximal tubule segment 3 CL4030011
    CSI 1.6
    rCSI 12.69%
    PRS 93.77
  • cholangiocyte CL1000488
    CSI 1.44
    rCSI 8.61%
    PRS 95.09

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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  • Node Size: Proportional to Target Cell CSI magnitude
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  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HPD](/details-gene/3242), or 4-hydroxyphenylpyruvate dioxygenase, is a protein-coding gene located on chromosome 12q24.31. It encodes the enzyme 4-hydroxyphenylpyruvate dioxygenase, a key catalyst in the catabolic pathways of tyrosine and phenylalanine. Functionally, this enzyme is critical for breaking down these amino acids, and its activity is predominantly localized to the cytosol. Consistent with its role in amino acid metabolism, expression of [HPD](/details-gene/3242) is exceptionally high in liver cells, particularly [centrilobular region hepatocytes](/details-cell/CL0019029), and also significant in the [epithelial cells of the kidney's proximal tubule](/details-cell/CL0002306). Clinically, mutations in [HPD](/details-gene/3242) are associated with autosomal recessive tyrosinemia type III ([276710](https://omim.org/entry/276710)) and hawkinsinuria ([140350](https://omim.org/entry/140350)), both of which are inborn errors of metabolism ([Link](https://doi.org/10.1007/s004390000307), [Link](https://doi.org/10.1006/mgme.2000.3085)). ## Cellular Roles and Expression Landscape The expression profile of [HPD](/details-gene/3242) highlights its specialized role in metabolic tissues, primarily the liver and kidneys. **Overall**, the gene shows the highest significance and expression in liver parenchymal cells. It is a defining marker for [centrilobular region hepatocytes](/details-cell/CL0019029) (CSI: 9.54), general [hepatocytes](/details-cell/CL0000182) (CSI: 7.36), and [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 6.00). This distinct zonal pattern suggests its activity is tightly regulated within the liver lobule microenvironment. Significant expression is also observed in other liver-resident cells, including [hepatic stellate cells](/details-cell/CL0000632) and [Kupffer cells](/details-cell/CL0000091), albeit at lower levels, indicating a central role in overall liver function. Beyond the liver, [HPD](/details-gene/3242) demonstrates a notable role in the kidney, with high significance in the [epithelial cell of the proximal tubule](/details-cell/CL0002306) (CSI: 3.93). This expression is consistent with the kidney's function in filtering and reabsorbing metabolites from the blood. The collective data suggest that [HPD](/details-gene/3242) is a highly specialized enzyme whose function is largely restricted to the primary metabolic organs of the body. ## Pathways and Molecular Function The function of the [HPD](/details-gene/3242) protein is well-defined within the context of amino acid metabolism. Its primary molecular function is 4-hydroxyphenylpyruvate dioxygenase activity ([GO:0003868](/details-go/GO:0003868)), which involves metal ion binding ([GO:0046872](/details-go/GO:0046872)) and protein homodimerization ([GO:0042803](/details-go/GO:0042803)) to form the active enzyme ([Link](https://doi.org/10.1016/s0021-9258(18)35755-7)). This enzymatic activity is a critical step in major biological processes, including the L-phenylalanine catabolic process ([GO:0006559](/details-go/GO:0006559)) and, more directly, the tyrosine catabolic process ([GO:0006572](/details-go/GO:0006572)). These roles are further delineated in the Reactome database, which places [HPD](/details-gene/3242) within the broader pathways of Metabolism ([R-HSA-1430728](https://reactome.org/content/detail/R-HSA-1430728)) and Metabolism of amino acids and derivatives ([R-HSA-71291](https://reactome.org/content/detail/R-HSA-71291)), and specifically within Phenylalanine and tyrosine metabolism ([R-HSA-8963691](https://reactome.org/content/detail/R-HSA-8963691)) and Tyrosine catabolism ([R-HSA-8963684](https://reactome.org/content/detail/R-HSA-8963684)). The enzyme is predominantly found in the [cytosol](/details-go/GO:0005829), consistent with its function in cellular metabolic pathways. ## Research Directions Given that [HPD](/details-gene/3242) deficiency is the direct cause of tyrosinemia type III, research should focus on the gene's regulation in both healthy and diseased states, its specific roles in different cellular contexts, and the development of therapeutic interventions. ### Testable Hypotheses 1. **Zonal Regulation in Liver Homeostasis:** The markedly higher significance of [HPD](/details-gene/3242) in [centrilobular hepatocytes](/details-cell/CL0019029) compared to [periportal hepatocytes](/details-cell/CL0019026) suggests its expression is governed by the metabolic zonation of the liver lobule. We hypothesize that local factors such as lower oxygen tension and Wnt/beta-catenin signaling, which are characteristic of the centrilobular zone, are key transcriptional drivers of [HPD](/details-gene/3242) expression. Disruption of this zonation in liver diseases like cirrhosis or non-alcoholic steatohepatitis (NASH) may lead to impaired tyrosine metabolism, contributing to the pathology. 2. **Role in Renal Proximal Tubule Function:** The significant expression of [HPD](/details-gene/3242) in the [epithelial cell of the proximal tubule](/details-cell/CL0002306) suggests a role beyond hepatic metabolism. We hypothesize that renal [HPD](/details-gene/3242) activity is essential for the local catabolism of filtered 4-hydroxyphenylpyruvate, preventing its accumulation and potential toxicity in the kidneys. Reduced renal [HPD](/details-gene/3242) function could exacerbate the systemic metabolic imbalances seen in tyrosinemia. ### Key Experiment To test the hypothesis of zonal regulation in the liver, a multi-modal approach could be employed. Spatial transcriptomics (e.g., Visium) performed on healthy and fibrotic human liver sections would allow for the simultaneous mapping of [HPD](/details-gene/3242) mRNA levels alongside established zonation markers (e.g., *GLUL* for centrilobular, *ALB* for periportal). This would quantitatively correlate [HPD](/details-gene/3242) expression with specific metabolic zones and assess how this relationship is altered in disease. These findings could be functionally validated using an *in vitro* model of primary human [hepatocytes](/details-cell/CL0000182) cultured in co-culture with [hepatic stellate cells](/details-cell/CL0000632) under varying oxygen concentrations to mimic the lobular oxygen gradient and measure the direct impact on [HPD](/details-gene/3242) transcription and protein levels. ### Therapeutic Potential As loss-of-function mutations in [HPD](/details-gene/3242) cause metabolic disease, it is not a candidate for therapeutic inhibition. Instead, it represents a key target for replacement or correction strategies. The therapeutic potential lies in gene therapy approaches aimed at delivering a functional copy of the [HPD](/details-gene/3242) gene to patient [hepatocytes](/details-cell/CL0000182), potentially using AAV-based vectors, to restore normal tyrosine metabolism. Alternatively, mRNA-based therapies or enzyme replacement therapies could be explored to provide the functional HPD protein directly. Such strategies would aim to correct the underlying enzymatic deficiency responsible for tyrosinemia type III ([276710](https://omim.org/entry/276710)).

Genular Protein ID: 1738342095

Symbol: HPPD_HUMAN

Name: 4-hydroxyphenylpyruvate dioxygenase

UniProtKB Accession Codes:

P32754 A0A0B4J1R4 A8K461 B3KQ63 Q13234

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 ChEBI 8 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 2 DrugCentral 1 EC 1 EMBL 9 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 9 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PIRSF 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 1 RefSeq 2 Rhea 2 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7851880

Title: Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD).

PubMed ID: 7851880

DOI: 10.1006/geno.1994.1540

PubMed ID: 8521727

Title: Regional assignment of the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) to 12q24-->qter by fluorescence in situ hybridization.

PubMed ID: 8521727

DOI: 10.1159/000134142

PubMed ID: 9325050

Title: Human 4-hydroxyphenylpyruvate dioxygenase gene (HPD).

PubMed ID: 9325050

DOI: 10.1006/geno.1997.4887

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 1339442

Title: Primary structure deduced from complementary DNA sequence and expression in cultured cells of mammalian 4-hydroxyphenylpyruvic acid dioxygenase. Evidence that the enzyme is a homodimer of identical subunits homologous to rat liver-specific alloantigen F.

PubMed ID: 1339442

DOI: 10.1016/s0021-9258(18)35755-7

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 10942115

Title: Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III.

PubMed ID: 10942115

DOI: 10.1007/s004390000307

PubMed ID: 11073718

Title: Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria.

PubMed ID: 11073718

DOI: 10.1006/mgme.2000.3085

Sequence Information:

  • Length: 393
  • Mass: 44964
  • Checksum: 5B75BBCF9C788E3E
  • Sequence:
    • MTTYSDKGAK PERGRFLHFH SVTFWVGNAK QATSFYCSKM GFEPLAYRGL ETGSREVVSH 
VIKQGKIVFV LSSALNPWNK EMGDHLVKHG DGVKDIAFEV EDCDYIVQKA RERGAKIMRE 
PWVEQDKFGK VKFAVLQTYG DTTHTLVEKM NYIGQFLPGY EAPAFMDPLL PKLPKCSLEM 
IDHIVGNQPD QEMVSASEWY LKNLQFHRFW SVDDTQVHTE YSSLRSIVVA NYEESIKMPI 
NEPAPGKKKS QIQEYVDYNG GAGVQHIALK TEDIITAIRH LRERGLEFLS VPSTYYKQLR 
EKLKTAKIKV KENIDALEEL KILVDYDEKG YLLQIFTKPV QDRPTLFLEV IQRHNHQGFG 
AGNFNSLFKA FEEEQNLRGN LTNMETNGVV PGM