Details for: PON1

Gene ID: 5444

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: PON1

Ensembl ID: ENSG00000005421

Description: paraoxonase 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • midzonal region hepatocyte CL0019028
    CSI 8.97
    rCSI 21.05%
    PRS 99.67
  • periportal region hepatocyte CL0019026
    CSI 4.87
    rCSI 18.92%
    PRS 99.54
  • hepatic stellate cell CL0000632
    CSI 4.74
    rCSI 17.76%
    PRS 99.77
  • Kupffer cell CL0000091
    CSI 4.5
    rCSI 10.3%
    PRS 99.84
  • intrahepatic cholangiocyte CL0002538
    CSI 4.29
    rCSI 10.31%
    PRS 99.84
  • hepatocyte CL0000182
    CSI 3.6
    rCSI 6.45%
    PRS 99.47
  • centrilobular region hepatocyte CL0019029
    CSI 3.29
    rCSI 8.58%
    PRS 99.48

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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  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • 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 [PON1](/details-gene/5444), or paraoxonase 1, is a protein-coding gene located on chromosome 7q21.3. It encodes a calcium-dependent esterase primarily synthesized in the liver and associated with high-density lipoprotein (HDL) particles in the circulation. The enzyme plays a crucial dual role in xenobiotic detoxification and lipid metabolism. It is known to hydrolyze and inactivate toxic organophosphates, and it also protects lipoproteins from oxidative modification, which is a key process in the development of atherosclerosis. Expression data indicates that **Overall**, [PON1](/details-gene/5444) is most significantly and abundantly expressed in liver cells, particularly [midzonal region hepatocytes](/details-cell/CL0019028), highlighting its central role in hepatic function. Clinically, variations in the [PON1](/details-gene/5444) gene are associated with susceptibility to organophosphate poisoning and cardiovascular disease ([168820](https://omim.org/entry/168820)). ## Cellular Roles and Expression Landscape The expression profile of [PON1](/details-gene/5444) establishes its identity as a key gene for hepatic function. **Overall**, its significance is overwhelmingly concentrated in the liver, with the highest Cell Significance Index (CSI) observed in [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 8.97), followed by other liver-resident cells such as [periportal region hepatocytes](/details-cell/CL0019026), [hepatic stellate cells](/details-cell/CL0000632), and [Kupffer cells](/details-cell/CL0000091). This zonal and cell-specific expression pattern within the liver suggests a specialized role in the complex metabolic and detoxification processes managed by this organ. The production of [PON1](/details-gene/5444) by [hepatocytes](/details-cell/CL0000182) and its subsequent secretion into the bloodstream allows it to exert systemic effects. Studies have noted differential expression of [PON1](/details-gene/5444) when comparing healthy liver tissue to hepatic cancer, suggesting its expression levels may be linked to the pathological state of the liver ([Link](https://doi.org/10.1038/cr.1997.9)). ## Pathways and Molecular Function Functionally, [PON1](/details-gene/5444) is annotated as an enzyme with arylesterase ([GO:0004064](https://www.ebi.ac.uk/QuickGO/term/GO:0004064)) and aryldialkylphosphatase activity ([GO:0004063](https://www.ebi.ac.uk/QuickGO/term/GO:0004063)). This enzymatic capacity is central to its biological roles. The gene is a key participant in the organophosphate catabolic process ([GO:0046434](https://www.ebi.ac.uk/QuickGO/term/GO:0046434)), which is consistent with its role in detoxifying pesticides and nerve agents. In parallel, [PON1](/details-gene/5444) is deeply integrated into lipid metabolism, as evidenced by its involvement in pathways such as the cholesterol metabolic process ([GO:0008203](https://www.ebi.ac.uk/QuickGO/term/GO:0008203)) and the metabolism of lipids ([R-HSA-556833](https://reactome.org/content/detail/R-HSA-556833)). A critical function is its negative regulation of plasma lipoprotein oxidation ([GO:0034445](https://www.ebi.ac.uk/QuickGO/term/GO:0034445)), which is thought to be a primary mechanism for its anti-atherogenic properties. This function is facilitated by its physical association with [high-density lipoprotein particles](/details-cell/GO0034364) in the [extracellular space](/details-cell/GO0005615) ([Link](https://doi.org/10.1111/j.1432-1033.1993.tb17620.x)). Its participation in broader metabolic pathways, including drug ADME ([R-HSA-9748784](https://reactome.org/content/detail/R-HSA-9748784)), further underscores its importance in processing both endogenous and exogenous compounds, a role consistent with its high expression in the liver. ## Research Directions The well-defined roles of [PON1](/details-gene/5444) in detoxification and lipid metabolism, combined with its high liver-specific expression, lead to several testable hypotheses. 1. **Hypothesis on Atherosclerosis:** Given its role in preventing lipoprotein oxidation ([GO:0034445](https://www.ebi.ac.uk/QuickGO/term/GO:0034445)), it is hypothesized that individuals with lower-activity [PON1](/details-gene/5444) genetic polymorphisms exhibit faster progression of atherosclerosis. This is because their HDL particles are less efficient at hydrolyzing oxidized lipids, leading to increased macrophage foam cell formation in the arterial wall. 2. **Hypothesis on Hepatocellular Carcinoma:** Based on reports of its altered expression in liver cancer ([Link](https://doi.org/10.1038/cr.1997.9)), it is hypothesized that downregulation of [PON1](/details-gene/5444) in developing [hepatocytes](/details-cell/CL0000182) compromises their ability to mitigate oxidative stress, thereby increasing genomic instability and promoting malignant transformation. To test the hypothesis regarding the role of [PON1](/details-gene/5444) in protecting against hepatocellular carcinoma, a key experiment could be designed. One could utilize CRISPR-Cas9 to create a [PON1](/details-gene/5444) knockout in a non-transformed human hepatocyte cell line. These knockout cells, along with isogenic wild-type controls, would be exposed to a known carcinogen or chronic oxidative stress. The subsequent impact on cell proliferation, DNA damage (e.g., measuring 8-oxoguanine levels), and activation of oncogenic signaling pathways could be quantified via RNA-sequencing, western blotting, and cell-based assays. **Therapeutic Potential:** [PON1](/details-gene/5444) represents a compelling target for therapeutic **activation** or supplementation rather than inhibition. Its protective functions against cardiovascular disease and toxic exposures suggest that enhancing its activity could be beneficial. Strategies might include the development of small-molecule activators that boost its catalytic efficiency or gene therapy approaches aimed at increasing its expression in the liver for patients with high-risk genetic variants or chronic inflammatory conditions. Such interventions could potentially reduce the risk of atherosclerosis or enhance detoxification capacity in vulnerable populations.

Genular Protein ID: 579250619

Symbol: PON1_HUMAN

Name: Aromatic esterase 1

UniProtKB Accession Codes:

P27169 B2RA40 Q16052 Q6B0J6 Q9UCB1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 5 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CPTAC 2 CTD 1 ChEBI 18 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 12 EC 3 EMBL 25 Ensembl 1 ExpressionAtlas 1 GO 20 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRINTS 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 1 Rhea 2 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1657140

Title: Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence.

PubMed ID: 1657140

DOI: 10.1021/bi00106a010

PubMed ID: 7916578

Title: Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes.

PubMed ID: 7916578

PubMed ID: 8393742

Title: Studies on human serum paraoxonase/arylesterase.

PubMed ID: 8393742

DOI: 10.1016/0009-2797(93)90022-q

PubMed ID: 8393745

Title: Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification.

PubMed ID: 8393745

DOI: 10.1016/0009-2797(93)90023-r

PubMed ID: 8812495

Title: Structural organization of the human PON1 gene.

PubMed ID: 8812495

DOI: 10.1006/geno.1996.0401

PubMed ID: 9261565

Title: Differential expression of a cDNA clone in human liver versus hepatic cancer -- highly homologous to aryl-dialkyl-phosphatase.

PubMed ID: 9261565

DOI: 10.1038/cr.1997.9

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 12690205

Title: Human chromosome 7: DNA sequence and biology.

PubMed ID: 12690205

DOI: 10.1126/science.1083423

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: 8382160

Title: Identification of a distinct human high-density lipoprotein subspecies defined by a lipoprotein-associated protein, K-45. Identity of K-45 with paraoxonase.

PubMed ID: 8382160

DOI: 10.1111/j.1432-1033.1993.tb17620.x

PubMed ID: 8292612

Title: Apolipoprotein J is associated with paraoxonase in human plasma.

PubMed ID: 8292612

DOI: 10.1021/bi00169a026

PubMed ID: 1718413

Title: Purification of rabbit and human serum paraoxonase.

PubMed ID: 1718413

DOI: 10.1021/bi00106a009

PubMed ID: 1673382

Title: Purification of human serum paraoxonase/arylesterase. Evidence for one esterase catalyzing both activities.

PubMed ID: 1673382

PubMed ID: 7638166

Title: Reconsideration of the catalytic center and mechanism of mammalian paraoxonase/arylesterase.

PubMed ID: 7638166

DOI: 10.1073/pnas.92.16.7187

PubMed ID: 10479665

Title: Human serum paraoxonase/arylesterase's retained hydrophobic N-terminal leader sequence associates with HDLs by binding phospholipids: apolipoprotein A-I stabilizes activity.

PubMed ID: 10479665

DOI: 10.1161/01.atv.19.9.2214

PubMed ID: 14760718

Title: Screening for N-glycosylated proteins by liquid chromatography mass spectrometry.

PubMed ID: 14760718

DOI: 10.1002/pmic.200300556

PubMed ID: 15772423

Title: Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities.

PubMed ID: 15772423

DOI: 10.1194/jlr.m400511-jlr200

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 16531243

Title: Serendipitous discovery and X-ray structure of a human phosphate binding apolipoprotein.

PubMed ID: 16531243

DOI: 10.1016/j.str.2005.12.012

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

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: 15098021

Title: Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes.

PubMed ID: 15098021

DOI: 10.1038/nsmb767

PubMed ID: 8098250

Title: The molecular basis of the human serum paraoxonase activity polymorphism.

PubMed ID: 8098250

DOI: 10.1038/ng0193-73

PubMed ID: 9661650

Title: A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM.

PubMed ID: 9661650

DOI: 10.1210/jcem.83.7.5096

PubMed ID: 12783936

Title: New paraoxonase 1 polymorphism I102V and the risk of prostate cancer in Finnish men.

PubMed ID: 12783936

DOI: 10.1093/jnci/95.11.812

PubMed ID: 18987736

Title: DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

PubMed ID: 18987736

DOI: 10.1038/nature07485

Sequence Information:

  • Length: 355
  • Mass: 39731
  • Checksum: 9B5895509166167E
  • Sequence:
    • MAKLIALTLL GMGLALFRNH QSSYQTRLNA LREVQPVELP NCNLVKGIET GSEDLEILPN 
GLAFISSGLK YPGIKSFNPN SPGKILLMDL NEEDPTVLEL GITGSKFDVS SFNPHGISTF 
TDEDNAMYLL VVNHPDAKST VELFKFQEEE KSLLHLKTIR HKLLPNLNDI VAVGPEHFYG 
TNDHYFLDPY LQSWEMYLGL AWSYVVYYSP SEVRVVAEGF DFANGINISP DGKYVYIAEL 
LAHKIHVYEK HANWTLTPLK SLDFNTLVDN ISVDPETGDL WVGCHPNGMK IFFYDSENPP 
ASEVLRIQNI LTEEPKVTQV YAENGTVLQG STVASVYKGK LLIGTVFHKA LYCEL