Affinage

PON2

Serum paraoxonase/arylesterase 2 · UniProt Q15165

Length
354 aa
Mass
39.4 kDa
Annotated
2026-06-10
81 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PON2 is a membrane-associated lactonase that couples enzymatic hydrolysis of lactones to a distinct antioxidant function safeguarding mitochondrial integrity (PMID:15772423, PMID:20530481). As an enzyme, recombinant PON2 efficiently hydrolyzes aromatic lactones, oxidized fatty-acid lactones, and bacterial N-acyl-homoserine lactone quorum-sensing signals, displaying the highest acyl-homoserine lactonase activity among the paronoxase family; catalysis depends on active-site residues His114 and His133 and is stabilized by high-mannose glycosylation and the ER reducing environment, but neither glycosylation nor the N-terminal transmembrane anchor is strictly required for activity in refolded engineered protein (PMID:15772423, PMID:20530481, PMID:21036357, PMID:26656916). This lactonase function operates independently of PON2's second activity: localized to the inner mitochondrial membrane and ER, PON2 suppresses superoxide formation at complexes I and III, likely through interaction with coenzyme Q10, thereby blocking cardiolipin peroxidation, cytochrome c release, caspase activation, and JNK/CHOP-driven ER-stress apoptosis—point mutants that abolish lactonase activity retain full antioxidant/antiapoptotic protection (PMID:20530481, PMID:21368884, PMID:22666600). Genetic loss of PON2 sensitizes neurons, astrocytes, and tumor cells to oxidant- and chemotherapy-induced death and impairs antibacterial defense, with PON2-deficient mice showing reduced Pseudomonas aeruginosa clearance, defective PI3K/AKT activation, and impaired phagocytosis (PMID:21368884, PMID:21354197, PMID:23911207, PMID:23743621). PON2 lactonase activity also converts the quorum-sensing molecule 3OC12-HSL into a reactive metabolite that disrupts mitochondrial bioenergetics and selectively kills epithelial and B-ALL leukemia cells (PMID:33531346, PMID:36094147). In leukemia, PON2 additionally enables glucose uptake by releasing the transporter GLUT1 from its inhibitor stomatin (PMID:33531346). PON2 transcription is induced by oxidative and metabolic stimuli through AP-1 (downstream of JNK and NADPH-oxidase ROS), PPARγ, SREBP-2, glucocorticoid receptor, FOXA1, and Wnt/β-catenin signaling (PMID:15544923, PMID:17292903, PMID:19497963, PMID:19643039, PMID:27322774, PMID:38935306). Loss-of-function mouse studies link PON2 to systemic metabolic, renal, hematopoietic, and neuroprotective phenotypes, reflecting its broad role in limiting redox-driven tissue injury (PMID:30641857, PMID:36429053, PMID:34257800, PMID:38935306).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2005 High

    Establishing PON2 as a bona fide enzyme answered what biochemical activity the protein carries, identifying it as a broad-spectrum lactonase with notable activity against bacterial quorum-sensing signals.

    Evidence Baculovirus-expressed purified recombinant PON2 assayed against defined lactone substrates

    PMID:15772423

    Open questions at the time
    • Did not resolve physiological substrate in vivo
    • No structural basis for catalysis defined
    • Showed no LDL-protective activity, leaving antioxidant role unexplained
  2. 2010 High

    Active-site mutagenesis dissected PON2 into two mechanistically independent functions, showing its mitochondrial antioxidant/antiapoptotic activity does not require lactonase catalysis.

    Evidence Site-directed mutagenesis of His114/His133, mitochondrial superoxide and apoptosis assays in cells

    PMID:20530481

    Open questions at the time
    • Molecular mechanism of superoxide suppression (quinone modulation) inferred not proven
    • Did not identify the structural domain mediating the antioxidant function
  3. 2011 High

    Pathway-level studies placed PON2 in the intrinsic and ER-stress apoptotic axis and confirmed mitochondrial/ER localization and CoQ10 association as the basis of its protection.

    Evidence siRNA/overexpression in cancer cells with JNK/CHOP inhibitors, ROS, cardiolipin, cytochrome c, caspase readouts; subcellular fractionation and CoQ10 interaction; PON2 KO mouse neural cells

    PMID:21354197 PMID:21368884 PMID:22666600

    Open questions at the time
    • Direct biophysical evidence of PON2–CoQ10 binding limited to fractionation
    • How PON2 acts on both complex I and III mechanistically unresolved
  4. 2013 High

    PON2-deficient infection models established a host-defense role, linking its lactonase activity against 3OC12-HSL to bacterial clearance and PI3K/AKT-dependent macrophage function.

    Evidence PON2-deficient macrophages and P. aeruginosa mouse infection model, hydrolysis, phagocytosis, and signaling assays

    PMID:23911207

    Open questions at the time
    • Whether antioxidant vs lactonase function dominates antibacterial defense not separated
    • Mechanism linking ER/oxidative stress to PI3K/AKT defect unresolved
  5. 2015 High

    Engineering and refolding a truncated PON2 showed catalysis is independent of the N-terminus and glycosylation, and identified Lys168 ubiquitination as a modulator of activity.

    Evidence E. coli expression/refolding, kinetics, in vitro ubiquitination with HeLa extract, mass spectrometry, mutagenesis

    PMID:26656916

    Open questions at the time
    • Physiological E3 ligase not identified in this study
    • Stabilizing substitutions are non-native, limiting inference about wild-type folding
  6. 2020 Medium

    PTM and structural analysis identified WTAP and BIRC3 as post-transcriptional regulators of PON2 and showed SNPs and isoform variation alter activity and folding.

    Evidence Cell-based PTM detection, in vitro ubiquitination, SAXS, mutagenesis, WTAP/BIRC3 knockdown

    PMID:32382056

    Open questions at the time
    • WTAP/BIRC3 regulatory mechanism characterized in single cell type
    • No high-resolution structure of full-length protein
  7. 2021 High

    Leukemia models revealed a catalysis-dependent and a catalysis-independent oncometabolic role: 3OC12 activation kills B-ALL cells while PON2 releases GLUT1 from stomatin to enable glucose uptake.

    Evidence Pon2 KO B-ALL mouse models, STOM knockout epistasis rescue, glucose uptake and ATP assays, transplant models

    PMID:33531346

    Open questions at the time
    • How PON2 mechanistically disrupts the STOM-GLUT1 interaction unknown
    • Whether GLUT1 regulation requires enzymatic or membrane scaffolding activity unresolved
  8. 2022 High

    PON2-dependent metabolism of subtoxic C12 was shown to disrupt mitochondrial bioenergetics, and a separate study placed PON2 downstream of RHOA G17V/NF-κB in T-cell lymphoma oncogenesis.

    Evidence PON2-KO tracheal epithelial cells with Seahorse/morphology readouts; RHOA G17V CD4+ T cells with Pon2 KO and NF-κB analysis

    PMID:36094147 PMID:36249275

    Open questions at the time
    • Identity of the cytotoxic C12-derived metabolite not defined
    • NF-κB-driven PON2 induction mechanism in lymphoma not fully mapped
  9. 2022 High

    Tissue-specific KO studies extended PON2's antioxidant role to renal podocyte lipid homeostasis and TRPC6 channel regulation in glomerular disease.

    Evidence PON2 KO mice, adriamycin nephropathy, lipidomics, podocyte voltage clamp, TRPC6/PON2 double KO epistasis

    PMID:36429053

    Open questions at the time
    • Mechanism connecting PON2 loss to ceramide/cholesterol accumulation unresolved
    • How lipid changes alter TRPC6 conductance not fully defined
  10. 2024 Medium

    Transcription factor and agonist studies identified FOXA1 as a direct PON2 activator and demonstrated PON2-dependent neuroprotection and mitochondrial preservation in disease and senescence models.

    Evidence FOXA1 promoter binding, MPTP/MPP+ Parkinson's models with PON2 gain/loss; vutiglabridin agonist in PON2 KO hepatocytes

    PMID:38935306 PMID:41300445

    Open questions at the time
    • Whether FOXA1 regulation occurs in non-neuronal tissues unknown
    • Direct molecular target of vutiglabridin on PON2 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for how PON2 simultaneously performs lactone hydrolysis and modulates electron-transport-chain superoxide, and whether its reported physical partners (CANX, ASGR1, GLUT1/stomatin) act through enzymatic or scaffolding mechanisms, remain unresolved.
  • No full-length high-resolution structure
  • CANX and ASGR1 interactions rest on single Co-IP/IP-MS experiments without reciprocal validation
  • Mechanism of mitochondrial superoxide suppression at complexes I and III not biochemically reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0016209 antioxidant activity 3 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-168256 Immune System 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ASGR1BIRC3CANXGLUT1STOMWTAP

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 PON2 (along with PON1 and PON3) functions as a lactonase/lactonizing enzyme. Purified recombinant PON2 efficiently hydrolyzes aromatic lactones, 5-hydroxy-eicosatetraenoic acid 1,5-lactone, 4-hydroxy-docosahexaenoic acid, and N-acyl-homoserine lactones (quorum-sensing signals of pathogenic bacteria). PON2 showed the highest activity among the three PONs toward N-acyl-homoserine lactone hydrolysis. Recombinant PONs are glycosylated with high-mannose-type sugars important for protein stability but not essential for enzymatic activity. Notably, none of the recombinant PONs protected LDL against copper-induced oxidation in vitro. Baculovirus expression system, purification of recombinant proteins, in vitro enzymatic assays with defined substrates Journal of lipid research High 15772423
2010 PON2 has two mechanistically independent functions: (1) lactonase activity requiring active-site residues His114 and His133, and (2) reduction of mitochondrial superoxide formation from the inner mitochondrial membrane (acting on both complex I and complex III of the electron transport chain), likely by modulating quinones. Point mutations abolishing lactonase activity (H114 and H133 mutations) did not alter the anti-oxidative/anti-apoptotic function, demonstrating these are unrelated activities of the same protein. Glycosylation (but not the Ser/Cys311 polymorphism) was critical for lactonase activity. Site-directed mutagenesis, mitochondrial superoxide measurements, glycosylation mapping, apoptosis assays in cell culture with point mutants The Journal of biological chemistry High 20530481
2011 PON2 reduces ER stress-induced apoptosis by lowering redox-triggered induction of pro-apoptotic CHOP via the JNK pathway, thereby preventing mitochondrial cell death signaling. PON2 also prevents mitochondrial superoxide formation, cardiolipin peroxidation, cytochrome c release, and caspase activation in intrinsic apoptosis. PON2 knockdown in tumor cells caused apoptosis per se and sensitized cells to multiple chemotherapeutics. Ligand-stimulated apoptosis via TRAIL or TNFα remained unchanged by PON2. siRNA knockdown, overexpression in multiple cancer cell lines, measurement of ROS, cardiolipin peroxidation, cytochrome c release, caspase activity, CHOP/JNK pathway inhibitor experiments Cell death & disease High 21368884
2011 PON2 and PON3 localize to mitochondrial membranes where they interact with coenzyme Q10 (ubiquinone), and this interaction diminishes mitochondrial oxidative stress and reduces ROS-triggered mitochondrial apoptosis. Review summarizing localization and interaction studies; mitochondrial fractionation and interaction data cited from primary work Journal of lipids Medium 22666600
2011 Mouse brain PON2 localizes primarily in microsomes and mitochondria (subcellular fractionation). Cells from PON2 knockout mice showed greater susceptibility to oxidative-stress-induced toxicity (DMNQ and H2O2) compared to wild-type cells, despite similar glutathione levels, establishing a direct neuroprotective role for PON2 against oxidative stress. Subcellular fractionation, PON2 knockout mouse neurons and astrocytes, cell viability assays with oxidants, lactonase activity assay Toxicology and applied pharmacology High 21354197
2013 PON2 is required for efficient hydrolysis of the quorum-sensing molecule 3OC12-HSL in macrophages. PON2-deficient macrophages showed markedly impaired ability to hydrolyze 3OC12-HSL in intact cells and in membrane-enriched protein lysates. In vivo, PON2-deficient mice had significantly reduced bacterial clearance of Pseudomonas aeruginosa PAO1 in lungs, liver, and spleen. PON2 deficiency also led to increased ER and oxidative stress, defective PI3K/AKT activation, and reduced phagocytosis. PON2-deficient macrophages vs. wild-type, in vitro 3OC12-HSL hydrolysis assay, mouse infection model with PAO1, PI3K/AKT signaling assays, phagocytosis assay, antioxidant rescue experiments Molecular genetics and metabolism High 23911207
2021 PON2 enables glucose uptake in B-ALL leukemia cells by releasing the glucose transporter GLUT1 from its inhibitor stomatin (STOM). Genetic deletion of STOM largely rescued the metabolic defects caused by PON2 deficiency, placing PON2 upstream of the STOM-GLUT1 axis. Separately, the PON2 lactonase activity hydrolyzes the lactone-prodrug 3OC12 to form a cytotoxic intermediate, which selectively kills B-ALL cells. Genetic deletion of Pon2 in B-ALL mouse models, STOM knockout rescue experiments, glucose uptake assays, ATP production assays, mouse transplant models Proceedings of the National Academy of Sciences of the United States of America High 33531346
2004 PON2 expression in macrophages is upregulated during monocyte-to-macrophage differentiation via NADPH oxidase-dependent superoxide production. PON2 expression was 9-fold lower in peritoneal macrophages from P47(phox-/-) mice (inactive NADPH oxidase) versus controls. The transcription factor AP-1 (regulated by JNK signaling) mediates this upregulation, as JNK inhibitor SP600125 decreased PON2 expression. THP-1 differentiation in vitro, mouse peritoneal macrophage isolation, P47(phox-/-) knockout mice, JNK inhibitor treatment, mRNA and protein quantification, vitamin E supplementation Free radical biology & medicine High 15544923
2007 Macrophage PON2 expression is upregulated by pomegranate juice polyphenols (punicalagin and gallic acid) via two transcription factor pathways: PPARγ (inhibition with GW9662 reduced the effect by 40%) and AP-1 (inhibition with SP600125 reduced the effect by 40%). PPARγ ligand rosiglitazone alone increased PON2 expression by up to 80%. J774A.1 macrophage cell culture, pharmacological inhibitors of PPARγ (GW9662) and AP-1 (SP600125), rosiglitazone stimulation, mRNA and protein analysis Atherosclerosis Medium 17292903
2009 Urokinase plasminogen activator (uPA) upregulates macrophage PON2 gene transcription via a signaling cascade: uPA binds PDGFR-β → PI3K activation → NADPH oxidase → ROS → MEK/ERK1/2 → SREBP-2 maturation → PON2 promoter activation. LDL abolished these effects. Macrophage cell culture, promoter reporter assays, pathway inhibitors (PI3K, MEK, NADPH oxidase), SREBP-2 maturation inhibitor, mRNA quantification Cardiovascular research Medium 19497963
2007 Macrophage PON2 expression is upregulated when macrophages are enriched with unesterified cholesterol (UC) but not cholesteryl ester (CE), and this effect is mediated through activation of the PI3K signaling pathway (inhibited by wortmannin or LY294002 by ~50%), with accompanying increased Akt phosphorylation. J774A.1 macrophage cholesterol loading with acetylated LDL ± ACAT inhibitor, PI3K inhibitors wortmannin/LY294002, mRNA and protein quantification, Akt phosphorylation Biological chemistry Medium 18020951
2009 PON2 deficiency in macrophages leads to increased triglyceride (TG) accumulation, elevated TG biosynthesis, and increased DGAT1 activity under high glucose (diabetic) conditions. The NADPH oxidase inhibitor apocynin abolished these effects, indicating PON2 suppresses macrophage TG accumulation through attenuation of NADPH oxidase activity. PON2-deficient mouse peritoneal macrophages vs. C57BL/6 controls, high glucose culture, DGAT1 activity assay, NADPH oxidase inhibitor (apocynin), RAGE expression measurement Atherosclerosis Medium 19748094
2012 Macrophage triglyceride accumulation (induced by VLDL) upregulates PON2 expression via ROS-mediated activation of the MEK/JNK/c-Jun signaling pathway. JNK inhibitor (SP600125) and MEK inhibitor (UO126) blocked VLDL-induced PON2 upregulation; VLDL activated JNK and c-Jun phosphorylation, and antioxidant GSH abolished these effects. J774A.1 and THP-1 macrophages with VLDL, synthetic TG, or carotid lesion TG; pathway inhibitors for MEK (UO126), p38 (SB203580), JNK (SP600125); c-Jun phosphorylation; antioxidant rescue with GSH BioFactors Medium 23047827
2009 Dexamethasone (glucocorticoid analogue) transcriptionally activates mouse Pon2 gene expression. Glucocorticoid receptors bind to glucocorticoid response elements located between -593 bp and -575 bp of the mPon2 promoter; mutation of this element completely blocked transcriptional activation. Cell culture with dexamethasone, actinomycin D transcription inhibitor, promoter reporter assay with glucocorticoid response element mutation BMB reports Medium 19643039
2013 Quercetin increases PON2 expression in mouse striatal astrocytes (highest PON2-expressing brain cells), possibly by activating the JNK/AP-1 pathway. Quercetin-induced neuroprotection against oxidants was significantly diminished in cells from PON2 knockout mice, establishing PON2 induction as a key mechanism of quercetin's neuroprotective action. Mouse striatal astrocyte cultures, PON2 KO vs. WT cells, quercetin treatment, JNK/AP-1 pathway analysis, oxidant-induced toxicity assays Neurochemical research High 23743621
2010 The endoplasmic reticulum (ER) fraction of macrophages stabilizes PON2 lactonase activity through ER proteins and the reducing environment (NADPH). NADPH (but not NADP) increased recombinant PON2 lactonase activity. ER from oxidized or cholesterol-loaded macrophages failed to protect PON2 and instead increased its inactivation. Subcellular fractionation of J774A.1 macrophages, incubation of recombinant PON2 with isolated fractions, proteinase K treatment, heat inactivation controls, NADPH/NADP/DTT supplementation Atherosclerosis Medium 21036357
2015 An engineered form of PON2 lacking the N-terminal transmembrane domain and with six stabilizing amino acid substitutions retains full lactonase activity (primary activity on 3OC12-HSL) when expressed in E. coli and refolded, demonstrating that catalytic activity is independent of the N-terminus and glycosylation. Mass spectrometry identified ubiquitination of Lys168 (in the full-length protein, corresponding to Lys144 in the engineered form) induced by HeLa cell extract; mutational analysis of this residue confirmed it modulates catalytic activity. E. coli expression and refolding of engineered PON2, kinetic characterization, in vitro ubiquitination with HeLa extract, mass spectrometry, site-directed mutagenesis of ubiquitination site, biofilm inhibition assay PloS one High 26656916
2020 PON2 undergoes post-translational modifications (PTMs) in HeLa cells, including ubiquitination at Lys168 (clustering near the A148G and S311C SNP sites). WTAP (Wilms tumor 1 associated protein) and the E3 ubiquitin ligase BIRC3 control PON2 expression post-transcriptionally. Mutational analysis showed that the A148G and S311C SNPs and a 12-amino-acid deletion (present in Isoform 2) affect PON2 activity. SAXS analysis indicated Isoform 2 is largely unstructured compared to wild type. Cell-based PTM detection, in vitro ubiquitination assay with cell extracts, site-directed mutagenesis, SAXS structural analysis, WTAP/BIRC3 knockdown experiments Cell death & disease Medium 32382056
2016 PON2 protein expression is regulated by the Wnt/GSK3β/β-catenin signaling pathway. Treatment of leukemia (K562) and OSCC (SCC-4, PCI-13) cells with Wnt ligands or inhibitors modulated PON2 expression in a β-catenin-dependent manner, confirmed by promoter reporter studies and in silico analysis. Ex vivo analysis of OSCC patient tissue revealed correlation between PON2 and β-catenin expression. Promoter reporter assays, Wnt ligand/inhibitor treatment in multiple cell lines, in silico promoter analysis, ex vivo patient tissue correlation Oncotarget Medium 27322774
2022 PON2 mediates cytotoxic effects of the P. aeruginosa quorum-sensing molecule C12 (3OC12-HSL) at subtoxic concentrations by hydrolyzing it to a reactive metabolite that disrupts mitochondrial bioenergetics and network morphology in tracheal epithelial cells. At subtoxic C12 concentrations, this PON2-dependent effect hinders cellular proliferation without affecting mitochondrial membrane potential. At higher C12 concentrations, membrane depolarization and caspase-dependent apoptosis occur. PON2-KO vs. WT murine tracheal epithelial cells, bioenergetic measurements (Seahorse), mitochondrial morphology imaging, membrane potential assay, caspase assays The Biochemical journal High 36094147
2024 FOXA1 acts as a transcription factor that binds the PON2 promoter and activates its transcription. In a Parkinson's disease model (MPTP-treated mice and MPP+-treated SH-SY5Y cells), PON2 overexpression mitigated ER stress (reduced GRP94, GRP78, CHOP, caspase-12), oxidative stress (reduced ROS, malondialdehyde), and neuronal apoptosis. The neuroprotective effects of FOXA1 upregulation were abrogated by PON2 silencing. MPTP mouse model, SH-SY5Y cell model, PON2 overexpression and silencing, FOXA1 promoter binding assay, ER/OS markers (western blot, biochemical assays), motor coordination tests Neurotoxicity research Medium 38935306
2022 RHOA G17V mutation in CD4+ T cells upregulates Pon2 expression through an NF-κB-dependent mechanism. Loss of Pon2 attenuated the oncogenic function (cell proliferation, T follicular helper cell specification) induced by RHOA G17V, placing PON2 downstream of RHOA G17V/NF-κB signaling in angioimmunoblastic T-cell lymphoma. Rhoa G17V expression in CD4+ T cells, Pon2 knockout, NF-κB pathway analysis, proliferation and T follicular helper specification assays, patient AITL tissue analysis Oncoimmunology Medium 36249275
2023 PON2 interacts with Calnexin (CANX) in cardiomyocytes, as determined by co-immunoprecipitation. PON2 mediates CANX/NOX4 signaling to inhibit oxidative stress, inflammation, hypertrophy, and damage in angiotensin II-induced cardiomyocyte injury. Co-immunoprecipitation (PON2 and CANX), database interaction analysis (BioGRID/GeneMania), simultaneous overexpression of PON2 and CANX in Ang II-treated AC16 cells, ROS assay, western blot for apoptosis/hypertrophy markers Immunity, inflammation and disease Low 36840500
2024 Vutiglabridin, a PON2 agonist, attenuates oxidative stress-induced cellular senescence in LO2 hepatocytes by preserving mitochondrial structure and network connectivity. These protective effects were absent in PON2 knockout cells, confirming PON2 dependency. H2O2-induced senescence model, PON2 KO cells, TEM and STED microscopy for mitochondrial morphology, β-galactosidase staining, p16/p21 expression, Western blot Antioxidants Medium 41300445
2019 PON2-deficient mice fed an obesifying diet develop increased adiposity and impaired glucose tolerance due in part to decreased oxygen consumption and energy expenditure. PON2-deficient subcutaneous fat pads showed lower oxygen consumption rates and decreased expression of beige adipocyte markers, linking PON2 to mitochondrial function in white adipose tissue. PON2-def mice on high-fat diet, metabolic cage measurements (oxygen consumption, energy expenditure), fat pad oxygen consumption rate, gene expression analysis of beige adipocyte markers, glucose tolerance test Antioxidants Medium 30641857
2011 PON2 deficiency is associated with impaired hepatic insulin signaling (inhibitory IRS-1 phosphorylation). Factors secreted from PON2-deficient macrophage cultures were sufficient to modulate insulin signaling in cultured hepatocytes. Protection from insulin signaling impairment in PON2-def/apoE(-/-) double KO mice was mediated by an altered balance of NO and peroxynitrite (ONOO−) production from macrophages, not by changes in intracellular oxidative stress. PON2-def and PON2-def/apoE(-/-) mouse models, hepatic IRS-1 phosphorylation measurement, macrophage conditioned medium transfer to hepatocytes, NO/ONOO- measurement The Biochemical journal Medium 21361875
2022 PON2 deficiency in podocytes leads to increased ceramide and cholesterol content (reproducing features of diabetic/inflammatory glomerular disease), increased TRPC6 channel conductance upon membrane stretch, and greater susceptibility to adriamycin-induced nephropathy. Double knockout of TRPC6 and PON2 partially rescued the aggravated glomerular phenotype, establishing PON2 upstream of TRPC6 signaling. PON2 KO mice, adriamycin nephropathy model, lipidomic analysis, voltage clamp experiments in cultured podocytes, TRPC6/PON2 double KO genetic epistasis Cells High 36429053
2021 PON2 deficiency in mice (Pon2-/-) leads to increased numbers of long-term hematopoietic stem cells (LT-HSCs), reduced progenitor cell frequency, elevated ROS in bulk bone marrow, myeloid skewing and premature aging phenotype in older mice, and disturbed erythropoiesis. RNA-seq in Pon2-/- LT-HSCs identified overrepresentation of CXCR4 signaling genes as potential compensatory mechanism. Pon2-/- mouse model, flow cytometry of hematopoietic populations, competitive transplantation, ROS measurement, apoptosis assay, RNA-seq Oxidative medicine and cellular longevity Medium 34257800
2024 PON2 interacts with and promotes degradation of asialoglycoprotein receptor 1 (ASGR1) in a dose-dependent manner, reducing lipid levels in mice. Immunoprecipitation combined with mass spectrometry (IP-MS) to identify PON2-ASGR1 interaction, dose-dependent degradation assay, lipid level measurement in mice iScience Low 39055948

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. Journal of lipid research 538 15772423
1998 DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. American journal of human genetics 210 9443862
1998 Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. Gene 136 9714608
2010 One enzyme, two functions: PON2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity. The Journal of biological chemistry 135 20530481
2007 Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPAR gamma and AP-1 pathway activation. Atherosclerosis 87 17292903
1997 Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus. The Journal of clinical endocrinology and metabolism 82 9329371
2011 Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells. Cell death & disease 78 21368884
2011 Paraoxonase 2 (PON2) in the mouse central nervous system: a neuroprotective role? Toxicology and applied pharmacology 72 21354197
2004 Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR. International journal of epidemiology 71 15256524
2013 Paraoxonase-2 (PON2) in brain and its potential role in neuroprotection. Neurotoxicology 67 24012887
2012 Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer. Journal of lipids 67 22666600
2009 The roles of PON1 and PON2 in cardiovascular disease and innate immunity. Current opinion in lipidology 66 19474728
2005 Paraoxonases (PONs) 1, 2, and 3 are expressed in human and mouse gastrointestinal tract and in Caco-2 cell line: selective secretion of PON1 and PON2. Free radical biology & medicine 66 15993332
2001 PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Atherosclerosis 59 11257265
2021 Human Paraoxonase-2 (PON2): Protein Functions and Modulation. Antioxidants (Basel, Switzerland) 56 33562328
2013 Modulation of paraoxonase 2 (PON2) in mouse brain by the polyphenol quercetin: a mechanism of neuroprotection? Neurochemical research 52 23743621
2004 Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. Free radical biology & medicine 52 15544923
2004 Interaction between smoking and PON2 Ser311Cys polymorphism as a determinant of the risk of myocardial infarction. European journal of clinical investigation 43 14984433
2009 Urokinase activates macrophage PON2 gene transcription via the PI3K/ROS/MEK/SREBP-2 signalling cascade mediated by the PDGFR-beta. Cardiovascular research 38 19497963
2008 Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases. Methods in molecular biology (Clifton, N.J.) 38 19082953
2015 Paraoxonase-2 (PON2) protects oral squamous cell cancer cells against irradiation-induced apoptosis. Journal of cancer research and clinical oncology 33 25708945
2013 Role of PON2 in innate immune response in an acute infection model. Molecular genetics and metabolism 32 23911207
2016 The anti-apoptotic PON2 protein is Wnt/β-catenin-regulated and correlates with radiotherapy resistance in OSCC patients. Oncotarget 31 27322774
2009 Paraoxonase 2 (PON2) decreases high glucose-induced macrophage triglycerides (TG) accumulation, via inhibition of NADPH-oxidase and DGAT1 activity: studies in PON2-deficient mice. Atherosclerosis 31 19748094
2006 A biphasic U-shape effect of cellular oxidative stress on the macrophage anti-oxidant paraoxonase 2 (PON2) enzymatic activity. Biochemical and biophysical research communications 30 16970920
2010 Pomegranate juice (PJ) consumption antioxidative properties on mouse macrophages, but not PJ beneficial effects on macrophage cholesterol and triglyceride metabolism, are mediated via PJ-induced stimulation of macrophage PON2. Atherosclerosis 29 20537330
2011 Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response. The Biochemical journal 27 21361875
2019 Association of SOD2 A16V and PON2 S311C polymorphisms with polycystic ovary syndrome in Chinese women. Journal of endocrinological investigation 23 30607774
2019 PON2 Deficiency Leads to Increased Susceptibility to Diet-Induced Obesity. Antioxidants (Basel, Switzerland) 21 30641857
2007 Macrophage paraoxonase 2 (PON2) expression is upregulated by unesterified cholesterol through activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Biological chemistry 21 18020951
2022 CircHIPK3 prevents chondrocyte apoptosis and cartilage degradation by sponging miR-30a-3p and promoting PON2. Cell proliferation 20 35716032
2021 Fisetin Alleviates Neointimal Hyperplasia via PPARγ/PON2 Antioxidative Pathway in SHR Rat Artery Injury Model. Oxidative medicine and cellular longevity 20 33968295
2012 Triglyceride accumulation in macrophages upregulates paraoxonase 2 (PON2) expression via ROS-mediated JNK/c-Jun signaling pathway activation. BioFactors (Oxford, England) 20 23047827
2009 Increased macrophage cholesterol biosynthesis and decreased cellular paraoxonase 2 (PON2) expression in Delta6-desaturase knockout (6-DS KO) mice: beneficial effects of arachidonic acid. Atherosclerosis 19 20042190
2002 The risk of coronary artery disease in population of Taiwan is associated with Cys-Ser 311 polymorphism of human paraoxonase (PON)-2 gene. Zhonghua yi xue za zhi = Chinese medical journal; Free China ed 17 12433026
2009 Transcriptional activation of an anti-oxidant mouse Pon2 gene by dexamethasone. BMB reports 16 19643039
2021 PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings of the National Academy of Sciences of the United States of America 15 33531346
2021 Long non-coding RNA LINC00488 facilitates thyroid cancer cell progression through miR-376a-3p/PON2. Bioscience reports 14 33600548
2016 PON2 and ATP2B2 gene polymorphisms with noise-induced hearing loss. Journal of thoracic disease 14 27076938
2015 An Engineered Version of Human PON2 Opens the Way to Understand the Role of Its Post-Translational Modifications in Modulating Catalytic Activity. PloS one 14 26656916
2006 Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76. Diabetologia 14 17096118
2022 RHOA G17V induces T follicular helper cell specification and involves angioimmunoblastic T-cell lymphoma via upregulating the expression of PON2 through an NF-κB-dependent mechanism. Oncoimmunology 13 36249275
2020 WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2. Cell death & disease 13 32382056
2018 PON2 and PPARG polymorphisms as biomarkers of risk for coronary heart disease. Biomarkers in medicine 11 29441810
2025 Deepening Cisplatin sensitivity on Oral Squamous cell Carcinoma cell lines after PON2 knockdown: A FTIRM investigation. Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy 10 39805243
2010 Macrophage endoplasmic reticulum (ER) proteins and reducing elements stabilize paraoxonase 2 (PON2). Atherosclerosis 10 21036357
2010 Expression and genomic imprinting of DCN, PON2 and PEG3 genes in porcine placenta. Animal reproduction science 9 21232885
2009 Evaluation of polymorphisms in paraoxonase 2 (PON2) gene and their association with cardiovascular-renal disease risk in Mexican Americans. Kidney & blood pressure research 9 19546579
2022 PON2 blockade overcomes dexamethasone resistance in acute lymphoblastic leukemia. Hematology (Amsterdam, Netherlands) 8 34957927
2012 [Association study of polymorphic markers of F12, PON1, PON2, NOS2, PDE4D, HIF1a, GPIba, CYP11B2 genes with ischemic stroke in Russian patients]. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova 8 22677666
2023 Paraoxonase 2 (PON2) plays a limited role in murine lung tumorigenesis. Scientific reports 7 37337025
2023 PON2 ameliorates Ang II-induced cardiomyocyte injury by targeting the CANX/NOX4 signaling pathway. Immunity, inflammation and disease 6 36840500
2022 Paraoxonase 2 (PON2) Deficiency Reproduces Lipid Alterations of Diabetic and Inflammatory Glomerular Disease and Affects TRPC6 Signaling. Cells 6 36429053
2020 [Association between PON2 gene polymorphisms and susceptibility to noise-induced hearing loss]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 6 32306677
2011 Polymorphisms of pon1 and pon2 genes in hemodialyzed patients. Clinical biochemistry 6 21620813
2024 Antiapoptotic PON2 expression and its clinical implications in locally advanced oral squamous cell carcinoma. Cancer science 5 38602182
2024 FOXA1 Suppresses Endoplasmic Reticulum Stress, Oxidative Stress, and Neuronal Apoptosis in Parkinson's Disease by Activating PON2 Transcription. Neurotoxicity research 5 38935306
2022 Expression of PON1, PON2, PON3 and MPO Genes in Patients with Depressive Disorders. Journal of clinical medicine 5 35743392
2017 Effect of certain non-steroidal anti-inflammatory drugs on the paraoxonase 2 (PON2) in human monocytic cell line U937. Archives of physiology and biochemistry 4 29199478
2013 [Association between single nucleotide polymorphisms of PON2 gene and susceptibility to occupational noise-induced deafness among Chinese Han population exposed to high noise levels]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 4 24148949
2025 Role of paraoxonase 2 (PON2) as a potential biomarker and therapeutic target in cancer treatment. Journal of cancer research and clinical oncology 3 40794328
2024 Polygenic markers of survival and longevity in the antioxidant genes PON1, PON2, MTHFR, MSRA, SOD1, NQO1, and CAT in a 20-year follow-up study in the population from the Volga-Ural region. Gene 3 38679184
2021 Deficiency of Antioxidative Paraoxonase 2 (Pon2) Leads to Increased Number of Phenotypic LT-HSCs and Disturbed Erythropoiesis. Oxidative medicine and cellular longevity 3 34257800
2021 Expression of PON2 isoforms varies among brain regions in male and female African green monkeys. Free radical biology & medicine 3 34890766
2019 Association of PON2 and PON3 polymorphism with risk of developing cataract. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society 3 31384158
2018 Association of PON2 Gene Polymorphisms (Ser311Cys and Ala148Gly) With the Risk of Developing Type 2 Diabetes Mellitus in the Chinese Population. Frontiers in endocrinology 3 30210454
2016 An improved polymerase chain reaction-restriction fragment length polymorphism assay for the detection of a PON2 gene polymorphism. Biomedical reports 3 27330753
2023 Interactome of Paraoxonase PON2 Reveals New Pathways for Tumor Growth Regulation. Doklady. Biochemistry and biophysics 2 36653584
2018 Low transcriptional activity of PON2 in recurrent abortion: A novel therapeutic agent? Journal of gynecology obstetrics and human reproduction 2 29908950
2014 Gene-environment interaction among GSTT1, PON2 polymorphisms and organic solvents on gestational age in a Chinese women cohort. Journal of assisted reproduction and genetics 2 24845160
2003 [Associations of Rsa I polymorphism at the 5' flanking region of CYP2E1 and PON2 148 polymorphism in neonates with preterm delivery]. Yi chuan xue bao = Acta genetica Sinica 2 12939804
2002 [Genetic polymorphism of pyruvate dehydrogenase kinase 4 (PDK4), paraoxonase 2 (PON2), and fatty acid binding protein 2 (FABP2) in the NIDDM population of Senegal]. Dakar medical 2 15776585
2002 [Association of PON2 gene polymorphisms in neonates with preterm]. Yi chuan = Hereditas 2 16135439
2024 ASGR1 is a promising target for lipid reduction in pigs with PON2 as its inhibitor. iScience 1 39055948
2023 A multi-centre, double-blind, randomized, placebo-controlled trial to evaluate the effectiveness and safety of ramelteon for the prevention of postoperative delirium in elderly cancer patients: a study protocol for JORTC-PON2/J-SUPPORT2103/NCCH2103. Japanese journal of clinical oncology 1 37340766
2022 PON2 mediates mitochondrial dysfunction in tracheal epithelial cells in response to a quorum sensing molecule N-(-3-oxododecanoyl)-l-homoserine lactone. The Biochemical journal 1 36094147
2005 [A search for association between the polymorphic markers of PON1 and PON2 genes and diabetic nephropathy in patients with type I diabetes mellitus]. Genetika 1 16080611
2025 Diagnostic utility of p53, SMAD4, and the novel biomarker PON2 in FNA of pancreatic ductal adenocarcinoma. Cancer cytopathology 0 41159799
2025 Targeting PON2 with Vutiglabridin Restores Mitochondrial Integrity and Attenuates Oxidative Stress-Induced Senescence. Antioxidants (Basel, Switzerland) 0 41300445
2009 [Preparation and identification of PON2 monoclonal antibodies.]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 19961799
2008 [Preparation and preliminary application of rabbit anti-human PON2 antibodies(paraoxonase-2)]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 18616915

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