PON1

Summary

PON1 (paraoxonase 1, HGNC:9204) is a protein-coding gene on chromosome 7q21.3, encoding Serum paraoxonase/arylesterase 1 (P27169). Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides.

This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7.

Source: NCBI Gene 5444 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Supportive, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 74 total
• Phenotypes (HPO): 47
• Druggable target: yes
• MANE Select transcript: NM_000446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9204
Approved symbol	PON1
Name	paraoxonase 1
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Aliases	ESA
Ensembl gene	ENSG00000005421
Ensembl biotype	protein_coding
OMIM	168820
Entrez	5444

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000222381, ENST00000433729, ENST00000462594, ENST00000470502, ENST00000893036, ENST00000893037, ENST00000893038, ENST00000893039, ENST00000893040

RefSeq mRNA: 1 — MANE Select: NM_000446 NM_000446

CCDS: CCDS5638

Canonical transcript exons

ENST00000222381 — 9 exons

Exon	Start	End
ENSE00000434428	95318323	95318393
ENSE00000877451	95324402	95324532
ENSE00001182780	95297676	95299102
ENSE00003468322	95311451	95311577
ENSE00003580222	95306285	95306366
ENSE00003597883	95308011	95308211
ENSE00003609092	95302205	95302333
ENSE00003622832	95316734	95316789
ENSE00003690212	95315322	95315490

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 99.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4544 / max 651.3045, expressed in 32 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84947	0.6280	20
84945	0.5456	14
84948	0.2527	15
84946	0.0281	7

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.33	gold quality
liver	UBERON:0002107	98.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.45	gold quality
left adrenal gland	UBERON:0001234	77.92	gold quality
secondary oocyte	CL:0000655	74.99	gold quality
adrenal gland	UBERON:0002369	74.99	gold quality
right adrenal gland	UBERON:0001233	74.98	gold quality
right adrenal gland cortex	UBERON:0035827	73.91	gold quality
left adrenal gland cortex	UBERON:0035825	73.78	gold quality
adrenal cortex	UBERON:0001235	72.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.72	gold quality
gall bladder	UBERON:0002110	69.39	gold quality
thymus	UBERON:0002370	68.28	silver quality
oocyte	CL:0000023	66.71	gold quality
islet of Langerhans	UBERON:0000006	66.41	gold quality
adrenal tissue	UBERON:0018303	66.38	gold quality
left ovary	UBERON:0002119	66.14	gold quality
pancreatic ductal cell	CL:0002079	65.65	silver quality
pituitary gland	UBERON:0000007	65.11	gold quality
right ovary	UBERON:0002118	64.31	gold quality
adenohypophysis	UBERON:0002196	63.33	gold quality
amygdala	UBERON:0001876	62.73	gold quality
ovary	UBERON:0000992	61.53	gold quality
cervix squamous epithelium	UBERON:0006922	61.53	gold quality
CA1 field of hippocampus	UBERON:0003881	61.38	gold quality
diaphragm	UBERON:0001103	61.20	gold quality
mucosa of transverse colon	UBERON:0004991	61.06	gold quality
caudate nucleus	UBERON:0001873	60.59	gold quality
nucleus accumbens	UBERON:0001882	60.02	gold quality
hypothalamus	UBERON:0001898	58.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, JUN, NR1H4, SP1, SREBF2

miRNA regulators (miRDB)

38 targeting PON1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-6871-5P	98.90	66.67	671

Literature-anchored findings (GeneRIF, showing 40)

• study suggested a gene-gene interaction between the PON1 and PON2 polymorphisms for CAD risk; may have linkage disequilibrium with a tightly linked PON3 locus or significant atherosclerotic alleles of nearby genes (PMID:11676977)
• association between left ventricular hypertrophy and the C825T allele of the G-protein beta3 subunit gene in Arabs. (G PROTEIN BETA3) (PMID:11768721)
• PON1-192R allele may play an important role in the genesis of coronary spasm, probably by attenuating the suppression of oxidative stress. (PMID:11810302)
• The Gln192Arg polymorphism of the paraoxonase-1 gene may not be involved in the susceptibility to schizophrenia. (PMID:11880198)
• Paraoxonase-1 L55M polymorphism is associated with an abnormal oral glucose tolerance test and differentiates high risk coronary disease families. (PMID:11889198)
• Antioxidant enzymes and paraoxonase show a co-activity in preserving low-density lipoprotein from oxidation. (PMID:11918278)
• diabetic microangiopathy is genetically heterogeneous; PON1 Leu/Leu increases the risk for retinopathy and PON2 Ser/Ser increases the risk for microalbuminuria (PMID:11918623)
• effect of paraoxonase-1 (PON-1) and oxidized low density lipoprotein (ox-LDL) in diabetic nephropathy (DN) (PMID:11940319)
• results suggest that the effects of regular and acute exercise on PON1 activity levels are modulated by PON1-192 polymorphism (PMID:11971942)
• Plasma as well as HDL paraoxonase activity decreased significantly with aging (r =-0.218, P < 0.039) and (r = -0.280, P < 0.006) respectively (PMID:11993715)
• PON1 status (C-108T promoter polymorphism) is useful for identifying individuals at risk for cardiovascular disease (PMID:12052142)
• Paraoxonase Gln-Arg(192) and Leu-Met(55) gene polymorphisms and enzyme activity in a population with a low rate of coronary heart disease (PMID:12074827)
• There is a minor association between BChE-K and early-onset coronary artery disease, especially in the presence of the APOE-epsilon 4 allele (PMID:12074828)
• characterization of oligomeric states of detergent-solubilized PON1 (PMID:12080042)
• genetic variability at PON1 locus affects survival at extreme advanced age (PMID:12082503)
• REVIEW: The paraoxonase gene family and coronary heart disease (PMID:12151850)
• HDL3-related decreased serum paraoxonase (PON) activity in uremic patients: comparison with the PON1 allele polymorphism (PMID:12204423)
• Elevated blood HDL cholesterol level is significantly associated with the arginine variant in position 192 of the PON1 gene. (PMID:12204800)
• The association between the PON1 codon 192 polymorphism and fasting concentrations of glucose, lipids, lipoproteins and PON1 activity greater for postmenopausal women. (PMID:12241013)
• serum activity and gene polymorphism in type 2 diabetic patients with or without vascular complications (PMID:12442067)
• Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study (PMID:12454802)
• determination that paraoxonase 1 has no phospholipase activity toward PAF or pro-atherogenic oxidized phospholipids (PMID:12466264)
• a possible marker of vascular dementia (PMID:12480737)
• polymorphic in Alzheimer’s disease (PMID:12480756)
• paraoxonase-associated high density lipoproteins bind to ghrelin and has a role in lipid transport and metabolism (PMID:12531885)
• biosynthesis of PON1 in human serum stimulated by Cl- and activity of the protein in the presence of other halides. (PMID:12545199)
• The polymorphism of the paraoxonase gene may not be involved in the susceptibility to organophosphorus poisoning in farmers dipping sheep (PMID:12563177)
• An extensive association study has identified the PON1 R160G and -162G/A polymorphisms to be independently associated with coronary heart disease in a Chinese Han population. (PMID:12588779)
• effect of homocysteinylation on high-density lipoprotein-paronoxase activity (PMID:12601623)
• PON1 inhibits macrophage cholesterol biosynthesis and atherogenesis probably through its phospholipase-A2-like activity. (PMID:12615663)
• Paraoxonase 1 gene polymorhism appears to be an independent risk factor for carotid intima thickness in middle-aged women. (PMID:12618279)
• PON R192Q polymorphism could affect HDL-C levels after caloric restriction in nondiabetic healthy males presumably due to decreased HL activity and altered insulin resistance. (PMID:12621166)
• polymorphisms in the paraoxonase (PON1) gene have been described, which have been shown to affect either the catalytic efficiency of hydrolysis or the expression level of PON1–review (PMID:12645966)
• data suggest that paraoxonase-1 activity loss is an event occurring later in the course of diabetes mellitus and it does not affect oxidation of circulating LDL (PMID:12679462)
• in age- and gender-matched subgroups of rheumatoid arthritis and healthy subjects serum paraoxonase activity was found to be significantly decreased (PMID:12697270)
• reported that oxidative stress attenuates insulin signaling in vitro. The PON1 promoter polymorphism C(-108)T may influence insulin sensitivity by modulating serum antioxidant capacity. (PMID:12706315)
• The PON1 genotype clearly determined the oxidative modification of lipoproteins and may play a role in the pathogenesis of atherosclerosis via its protective effect against lipoprotein oxidation in Japanese subjects. (PMID:12740482)
• Low serum PON1 activity toward paraoxon is an independent risk factor for coronary events in men at high risk because of preexisting disease or other CHD risk factors (PMID:12756158)
• PON1 levels plateau between 6 to 15 months of age, and that variability in the age at which PON1 levels plateau is quite variable among individuals (PMID:12777966)
• The PON1 102V allele appears to be associated with an increased risk for prostate cancer. (PMID:12783936)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	pon2	ENSDARG00000016856
danio_rerio	pon1	ENSDARG00000032496
danio_rerio	pon3.1	ENSDARG00000040290
danio_rerio	pon3.2	ENSDARG00000097789
mus_musculus	Pon1	ENSMUSG00000002588
rattus_norvegicus	Pon1	ENSRNOG00000008902
caenorhabditis_elegans	mec-6	WBGENE00003170
caenorhabditis_elegans		WBGENE00010775
caenorhabditis_elegans	poml-2	WBGENE00017089
caenorhabditis_elegans		WBGENE00044697
caenorhabditis_elegans	poml-3	WBGENE00077701

Paralogs (2): PON3 (ENSG00000105852), PON2 (ENSG00000105854)

Protein

Protein identifiers

Serum paraoxonase/arylesterase 1 — P27169 (reviewed: P27169)

Alternative names: Aromatic esterase 1, K-45, Serum aryldialkylphosphatase 1

All UniProt accessions (2): P27169, F8WF42

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and lactones, and a number of aromatic carboxylic acid esters. Mediates an enzymatic protection of low density lipoproteins against oxidative modification and the consequent series of events leading to atheroma formation.

Subunit / interactions. Homodimer. Heterooligomer with phosphate-binding protein (HPBP). Interacts with CLU.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Plasma, associated with HDL (at protein level). Expressed in liver, but not in heart, brain, placenta, lung, skeletal muscle, kidney or pancreas.

Post-translational modifications. Glycosylated. The signal sequence is not cleaved. Present in two forms, form B contains a disulfide bond, form A does not.

Disease relevance. Microvascular complications of diabetes 5 (MVCD5) [MIM:612633] Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Homozygosity for the Leu-55 allele is strongly associated with the development of retinal disease in diabetic patients.

Cofactor. Binds 2 calcium ions per subunit.

Polymorphism. The allelic form of the enzyme with Gln-192 (allozyme A) hydrolyzes paraoxon with a low turnover number and the one with Arg-192 (allozyme B) with a high turnover number.

Miscellaneous. The preferential association of PON1 with HDL is mediated in part by its signal peptide, by binding phospholipids directly, rather than binding apo AI. The retained signal peptide may allow transfer of the protein between phospholipid surfaces.

Similarity. Belongs to the paraoxonase family.

RefSeq proteins (1): NP_000437* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002640	Arylesterase	Family
IPR008363	Paraoxonase1	Family
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR051288	Serum_paraoxonase/arylesterase	Family

Pfam: PF01731

Enzyme classification (BRENDA):

• EC 3.1.1.2 — arylesterase (BRENDA: 43 organisms, 245 substrates, 136 inhibitors, 172 Km, 116 kcat entries)
• EC 3.1.1.25 — 1,4-lactonase (BRENDA: 18 organisms, 263 substrates, 56 inhibitors, 186 Km, 153 kcat entries)
• EC 3.1.1.81 — quorum-quenching N-acyl-homoserine lactonase (BRENDA: 76 organisms, 231 substrates, 60 inhibitors, 238 Km, 241 kcat entries)
• EC 3.1.8.1 — aryldialkylphosphatase (BRENDA: 49 organisms, 600 substrates, 192 inhibitors, 422 Km, 434 kcat entries)
• EC 3.1.8.2 — diisopropyl-fluorophosphatase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

322 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PARAOXON	0.005–24.25	109
PHENYL ACETATE	0.01–16	60
N-DECANOYL-L-HOMOSERINE LACTONE	0.0014–14.88	32
N-BUTYRYL-L-HOMOSERINE LACTONE	0.0094–39.5	29
N-HEXANOYL-L-HOMOSERINE LACTONE	0.0031–10	27
MALATHION	0.001–1.9	27
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIETHYL PH	0.22–20	25
DIETHYL-PARAOXON	0.0017–1.586	23
N-OCTANOYL-L-HOMOSERINE LACTONE	0.0026–10.35	20
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIMETHYL P	0.3–7	20
4-NITROPHENYL ACETATE	—	19
ZEARALENONE	0.011–0.083	17
4-ACETYLPHENYL (S)-2-METHYLPROPYL METHYLPHOSPHON	0.03–4.5	15
4-ACETYLPHENYL (R)-2-METHYLPROPYL METHYLPHOSPHON	0.15–4	14
(S)-[2-[DI(PROPAN-2-YL)AMINO]ETHYL] O,O-DIETHYL	0.35–3.2	13

Catalyzed reactions (Rhea), 2 shown:

• a phenyl acetate + H2O = a phenol + acetate + H(+) (RHEA:17309)
• an N-acyl-L-homoserine lactone + H2O = an N-acyl-L-homoserine + H(+) (RHEA:22576)

UniProt features (59 total): strand 27, binding site 8, sequence variant 4, mutagenesis site 4, helix 4, turn 4, glycosylation site 3, initiator methionine 1, chain 1, disulfide bond 1, signal peptide 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1V04	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27169-F1	96.84	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 115 (proton acceptor)

Ligand- & substrate-binding residues (8): 269; 270; 53; 54; 117; 168; 169; 224

Disulfide bonds (1): 42–353

Glycosylation sites (3): 253, 270, 324

Mutagenesis-validated functional residues (4):

Position	Phenotype
20–21	the signal peptide is cleaved; not associated with hdl.
115	reduces activity 10000-fold.
134	substantially reduced activity.
284	no loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2142688	Synthesis of 5-eicosatetraenoic acids
R-HSA-9754706	Atorvastatin ADME

MSigDB gene sets: 229 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GNF2_GSTM1, GNF2_HPN, GOBP_POSITIVE_REGULATION_OF_CHOLESTEROL_EFFLUX, GOBP_REGULATION_OF_CHOLESTEROL_EFFLUX, GOBP_POSITIVE_REGULATION_OF_STEROL_TRANSPORT, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, COUP_01, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_CHOLESTEROL_EFFLUX

GO Biological Process (7): cholesterol metabolic process (GO:0008203), response to toxic substance (GO:0009636), positive regulation of cholesterol efflux (GO:0010875), carboxylic acid catabolic process (GO:0046395), organophosphate catabolic process (GO:0046434), phosphatidylcholine metabolic process (GO:0046470), lactone catabolic process (GO:1901335)

GO Molecular Function (8): aryldialkylphosphatase activity (GO:0004063), arylesterase activity (GO:0004064), calcium ion binding (GO:0005509), phospholipid binding (GO:0005543), protein homodimerization activity (GO:0042803), acyl-L-homoserine-lactone lactonohydrolase activity (GO:0102007), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), high-density lipoprotein particle (GO:0034364), spherical high-density lipoprotein particle (GO:0034366), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Arachidonate metabolism	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catabolic process	2
cellular anatomical structure	2
sterol metabolic process	1
secondary alcohol metabolic process	1
response to chemical	1
regulation of cholesterol efflux	1
positive regulation of cholesterol transport	1
cholesterol efflux	1
carboxylic acid metabolic process	1
small molecule catabolic process	1
organophosphate metabolic process	1
glycerophospholipid metabolic process	1
lactone metabolic process	1
phosphoric triester hydrolase activity	1
carboxylic ester hydrolase activity	1
metal ion binding	1
lipid binding	1
identical protein binding	1
protein dimerization activity	1
lactonohydrolase activity	1
catalytic activity	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
plasma lipoprotein particle	1
high-density lipoprotein particle	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

1600 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PON1	APOA1	P02647	996
PON1	CLU	P10909	983
PON1	APOE	P02649	918
PON1	CETP	P11597	890
PON1	LCAT	P04180	874
PON1	APOA2	P02652	845
PON1	ALB	P02768	845
PON1	HPR	P00739	833
PON1	APOB	P04114	818
PON1	BCHE	P06276	788
PON1	HP	P00737	783
PON1	MPO	P05164	774
PON1	APOA4	P06727	749
PON1	GPX3	P22352	745
PON1	GPX5	O75715	744
PON1	GPX6	P59796	744

IntAct

28 interactions, top by confidence:

A	B	Type	Score
PON1	PON3	psi-mi:“MI:0914”(association)	0.530
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
PON1	PTCHD1	psi-mi:“MI:0915”(physical association)	0.370
PON1	NDUFB6	psi-mi:“MI:0914”(association)	0.350
NFYC	NFKB1	psi-mi:“MI:0914”(association)	0.350
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
MATN2	IGLL5	psi-mi:“MI:0914”(association)	0.350
UBE2U	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
ATF2	ABLIM1	psi-mi:“MI:0914”(association)	0.350
CEBPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
MYB	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
MYC	ALB	psi-mi:“MI:0914”(association)	0.350
STAT3	IGF2BP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): PON1 (Affinity Capture-MS), NDUFB6 (Affinity Capture-MS), PON3 (Affinity Capture-MS), SFXN5 (Affinity Capture-MS), RDH13 (Affinity Capture-MS), MICU2 (Affinity Capture-MS), PON1 (Affinity Capture-MS), PON1 (Affinity Capture-MS), PON1 (Affinity Capture-MS), SFXN5 (Affinity Capture-MS), RDH13 (Affinity Capture-MS), MICU2 (Affinity Capture-MS), PON3 (Affinity Capture-MS), PON1 (Affinity Capture-MS), PON1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QP51, A4IG53, B5X3B2, F1N2K1, F4ZGF2, O95497, P27169, P27170, P52430, P54832, P55159, P70665, P82450, P98192, Q08C93, Q15165, Q15166, Q1LWG4, Q2TAA5, Q3T0E5, Q3TZM9, Q4V3D9, Q58CQ9, Q58DS7, Q5I047, Q5R748, Q5R7Z6, Q5RFU0, Q5ZIF1, Q5ZK82, Q62086, Q62087, Q68FP2, Q6AXM8, Q6P9A2, Q7TP48, Q803F5, Q8K1B9, Q90678, Q90952

Diamond homologs: P27169, P27170, P52430, P54832, P55159, Q15165, Q15166, Q58DS7, Q62086, Q62087, Q68FP2, Q6AXM8, Q90952, Q91090, Q9BGN0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	PON1	“transcriptional regulation”
SREBF2	“up-regulates quantity by expression”	PON1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

74 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	8
Benign	30

Top pathogenic / likely-pathogenic (0)

SpliceAI

1289 predictions. Top by Δscore:

Variant	Effect	Δscore
7:95299099:GCAC:G	acceptor_gain	1.0000
7:95299100:CAC:C	acceptor_gain	1.0000
7:95299100:CACC:C	acceptor_gain	1.0000
7:95299100:CACCT:C	acceptor_loss	1.0000
7:95299101:AC:A	acceptor_gain	1.0000
7:95299102:CC:C	acceptor_gain	1.0000
7:95299102:CCTG:C	acceptor_loss	1.0000
7:95299103:C:CC	acceptor_gain	1.0000
7:95299103:CTGTG:C	acceptor_loss	1.0000
7:95299104:T:A	acceptor_loss	1.0000
7:95302200:CTTA:C	donor_loss	1.0000
7:95302201:TTA:T	donor_loss	1.0000
7:95302202:TACCT:T	donor_loss	1.0000
7:95302203:A:AC	donor_gain	1.0000
7:95302204:C:CC	donor_gain	1.0000
7:95302204:CCT:C	donor_gain	1.0000
7:95302329:AGGGA:A	acceptor_gain	1.0000
7:95302330:GGGA:G	acceptor_gain	1.0000
7:95302331:GGA:G	acceptor_gain	1.0000
7:95302332:GA:G	acceptor_gain	1.0000
7:95302334:C:CC	acceptor_gain	1.0000
7:95302335:T:C	acceptor_gain	1.0000
7:95302335:T:TC	acceptor_gain	1.0000
7:95302342:A:C	acceptor_gain	1.0000
7:95302343:T:C	acceptor_gain	1.0000
7:95302343:T:TC	acceptor_gain	1.0000
7:95311449:A:AC	donor_gain	1.0000
7:95311450:C:CC	donor_gain	1.0000
7:95311453:A:AC	donor_gain	1.0000
7:95311453:AGG:A	donor_gain	1.0000

AlphaMissense

2324 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:95316737:G:C	S66R	0.995
7:95316737:G:T	S66R	0.995
7:95316739:T:G	S66R	0.995
7:95299019:A:C	S331R	0.986
7:95299019:A:T	S331R	0.986
7:95299021:T:G	S331R	0.986
7:95302308:T:A	D269V	0.984
7:95315346:C:A	G116W	0.980
7:95311562:A:G	L129P	0.979
7:95311517:A:G	F144S	0.978
7:95298981:C:T	G344D	0.975
7:95302309:C:G	D269H	0.975
7:95302307:A:C	D269E	0.973
7:95302307:A:T	D269E	0.973
7:95311556:A:T	V131E	0.972
7:95299011:G:T	A334D	0.971
7:95302308:T:G	D269A	0.969
7:95315338:G:C	S118R	0.969
7:95315338:G:T	S118R	0.969
7:95315340:T:G	S118R	0.969
7:95315438:A:T	I85K	0.969
7:95302262:G:C	C284W	0.967
7:95316744:A:G	F64S	0.966
7:95315438:A:C	I85R	0.963
7:95316777:T:A	E53V	0.962
7:95298990:A:G	L341P	0.961
7:95302261:G:C	H285D	0.961
7:95315345:C:T	G116E	0.960
7:95299024:C:G	G330R	0.959
7:95302266:C:T	G283E	0.959

dbSNP variants (sampled 300 via entrez): RS1000364356 (7:95301019 A>G), RS1000446864 (7:95326151 G>A), RS1000459805 (7:95320953 T>A,C), RS1000519387 (7:95325846 C>A,T), RS1000787038 (7:95305929 A>G), RS1001097816 (7:95312210 T>C), RS1001284319 (7:95317573 C>A), RS1001566093 (7:95307699 A>C,G), RS1001623749 (7:95312494 T>C), RS1001736971 (7:95319447 C>T), RS1001759917 (7:95320392 G>A), RS1001816242 (7:95312642 G>A,T), RS1001959199 (7:95311177 A>G), RS1002122621 (7:95320111 T>A), RS1002190537 (7:95324221 G>A)

Disease associations

OMIM: gene MIM:168820 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

Mondo (1): amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003693	Distal amyotrophy
HP:0004326	Cachexia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000211_6	Response to TNF antagonist treatment	2.000000e-06
GCST001882_7	Metabolite levels	7.000000e-15
GCST008513_13	Health literacy	6.000000e-06
GCST010242_393	HDL cholesterol levels	5.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0004725	metabolite measurement
EFO:0010104	health literacy measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3167 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs662	Efficacy	3	epirubicin;fluorouracil;oxaliplatin	Neoplasms;Stomach Neoplasms
rs662	Efficacy	3	atorvastatin;simvastatin	Hypercholesterolemia
rs662	Efficacy,Toxicity	4	clopidogrel	Angina Pectoris;Coronary Artery Disease;Myocardial Infarction;Myocardial Ischemia;Thrombotic disease
rs705379	Efficacy	3	atorvastatin;simvastatin	Hypercholesterolemia
rs705379	Efficacy	3	atorvastatin	Hypercholesterolemia
rs854547	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis
rs854548	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis
rs854555	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs662	PON1	3	3.75	3	epirubicin;fluorouracil;oxaliplatin;clopidogrel;atorvastatin;simvastatin
rs705379	PON1	3	2.25	2	atorvastatin;simvastatin;atorvastatin
rs854547	PON1, PPP1R9A	3	0.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs854548	PON1, PPP1R9A	3	0.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs854552	PON1		0.00	0
rs854555	PON1, PPP1R9A	3	2.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs854560	PON1		0.00	0
rs854565	PON1		0.00	0
rs854568	PON1		0.00	0
rs854572	PON1		0.00	0
rs854573	PON1		0.00	0
rs13306698	PON1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Paraoxonase (PON) family

Binding affinities (BindingDB)

9 measured of 26 human assays (28 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CID148124	IC50	0.2 nM
ARTHROTEC	KI	150 nM
1,3,4-Thiadiazole-2-sulfonamide, 6	IC50	2700 nM
Lornoxicam	KI	9000 nM
Cetamide	KI	86000 nM
4-chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic acid	IC50	125000 nM
Sulfosalazine, 3	IC50	260000 nM
Tenoxicam	KI	306000 nM
Lincomycine	KI	1.11e+07 nM

ChEMBL bioactivities

5 potent at pChembl≥5 of 11 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.62	Ki	2390	nM	CHEMBL3759162
5.52	IC50	3000	nM	CHEMBL3760002
5.20	IC50	6370	nM	CHEMBL3759162
5.11	IC50	7840	nM	CHEMBL5174712
5.06	IC50	8760	nM	CHEMBL3759251

PubChem BioAssay actives

6 with measured affinity, of 124 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[(3-butylimidazol-1-ium-1-yl)methyl]-5,7-dimethylchromen-2-one chloride	1275953: Competitive inhibition of human serum PON1 using paraoxon as substrate by Lineweaver-Burk plot analysis	ki	2.3900	uM
6,7-dihydroxy-3-(4-methylphenyl)chromen-2-one	1275952: Inhibition of human serum PON1 using paraoxon as substrate by spectrophotometric analysis	ic50	3.0000	uM
7-hydroxy-4-[[3-[(2,3,4,5,6-pentamethylphenyl)methyl]benzimidazol-1-ium-1-yl]methyl]chromen-2-one chloride	1871456: Inhibition of human PON1 using paraoxon as a substrate by regression analysis	ic50	7.8400	uM
6-[2-[3-(benzotriazol-1-ylmethyl)benzimidazol-3-ium-1-yl]acetyl]-4H-1,4-benzoxazin-3-one chloride	1275952: Inhibition of human serum PON1 using paraoxon as substrate by spectrophotometric analysis	ic50	8.7600	uM
6-chloro-4-hydroxy-2-methyl-1,1-dioxo-N-pyridin-2-ylthieno[2,3-e]thiazine-3-carboxamide	1799750: Paraoxonase Activity Assay from Article 10.1080/14756360802608351: “Effect of some analgesics on paraoxonase-1 purified from human serum.”	ki	9.0000	uM

CTD chemical–gene interactions

191 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Paraoxon	increases reaction, decreases response to substance, increases response to substance, affects response to substance, affects reaction (+9 more)	23
Pesticides	decreases activity, increases activity, affects response to substance, affects cotreatment, affects reaction (+3 more)	20
Organophosphates	affects metabolic processing, affects reaction, decreases activity, affects activity, affects response to substance (+3 more)	11
diazoxon	affects hydrolysis, decreases hydrolysis, affects metabolic processing, affects reaction, increases hydrolysis (+1 more)	9
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects binding, affects hydrolysis, decreases activity, increases hydrolysis, affects expression (+5 more)	8
phenylacetic acid	affects cotreatment, decreases hydrolysis, affects metabolic processing, decreases reaction, increases hydrolysis	8
Diazinon	increases hydrolysis, affects response to substance, affects metabolic processing, decreases activity, decreases reaction	7
Chlorpyrifos	affects expression, affects response to substance, affects metabolic processing, increases response to substance, increases hydrolysis (+3 more)	7
Insecticides	increases mutagenesis, affects response to substance, affects metabolic processing, affects reaction, decreases activity (+1 more)	7
Organophosphorus Compounds	decreases expression, decreases activity, increases hydrolysis, increases reaction, affects response to substance (+2 more)	7
Resveratrol	decreases reaction, increases expression, increases reaction, affects cotreatment, decreases expression (+1 more)	6
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression, decreases activity	6
Ascorbic Acid	affects cotreatment, decreases activity, decreases reaction, increases reaction, increases metabolic processing (+4 more)	5
Benzo(a)pyrene	decreases expression, increases abundance, affects methylation, increases expression	5
Cholesterol, HDL	affects reaction, increases abundance, affects binding, increases activity, affects abundance	5
Atorvastatin	increases activity, increases expression, affects reaction, increases abundance	4
Copper	decreases activity, decreases reaction, increases reaction, affects cotreatment, decreases expression (+1 more)	4
Sarin	decreases activity, decreases reaction, decreases response to substance, increases hydrolysis	4
Soman	increases hydrolysis, decreases activity, decreases reaction, decreases response to substance	4
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	4
cyclohexyl methylphosphonofluoridate	decreases activity, decreases reaction, increases hydrolysis	3
phenyl acetate	affects binding, increases hydrolysis, affects hydrolysis, affects metabolic processing	3
Cholesterol	decreases chemical synthesis, increases export	3
Oleic Acid	decreases activity, decreases reaction, increases reaction, increases hydrolysis, affects cotreatment (+1 more)	3
Copper Sulfate	affects cotreatment, decreases activity, decreases reaction, increases hydrolysis, decreases expression	3
Simvastatin	decreases reaction, increases expression, affects binding, increases reaction, affects reaction (+2 more)	3
7-ketocholesterol	decreases reaction, increases expression	2
farnesyl pyrophosphate	decreases reaction, increases expression	2
palmitoleic acid	decreases activity, decreases reaction, increases hydrolysis, affects cotreatment	2
VX-agent	decreases response to substance, increases hydrolysis	2

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2389932	Binding	Activation of recombinant paraoxonase-1 (unknown origin) expressed in Escherichia coli assessed as delaying of Cu2+-induced LDL oxidation time after 15 mins by UV ELISA	The effects and mechanism of flavonoid-rePON1 interactions. Structure-activity relationship study. — Bioorg Med Chem

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS