PON3_HUMAN
ID PON3_HUMAN Reviewed; 354 AA.
AC Q15166; A4D1H8; O75855; O76060; Q6IRU9; Q8IX97; Q9BZH9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 3.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Serum paraoxonase/lactonase 3;
DE EC=3.1.1.2;
DE EC=3.1.1.81;
DE EC=3.1.8.1;
GN Name=PON3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Hepatoma;
RA Reddy S.T., Wadleigh D.J., Grijalva V., Ng C., Hama S., Gangopadhyay A.,
RA Khorsan R., Shih D., Lusis A.J., Navab M., Fogelman A.M.;
RT "Human paraoxanase-3 is an HDL-associated enzyme.";
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Draganov D.I., Watson C.E.;
RT "Human PON3 has lactonase activity.";
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-146 AND ASP-179.
RG SeattleSNPs variation discovery resource;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 14-354.
RC TISSUE=Liver;
RX PubMed=8661009; DOI=10.1006/geno.1996.0225;
RA Primo-Parmo S.L., Sorenson R.C., Teiber J., La Du B.N.;
RT "The human serum paraoxonase/arylesterase gene (PON1) is one member of a
RT multigene family.";
RL Genomics 33:498-507(1996).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=15772423; DOI=10.1194/jlr.m400511-jlr200;
RA Draganov D.I., Teiber J.F., Speelman A., Osawa Y., Sunahara R., La Du B.N.;
RT "Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping
RT and distinct substrate specificities.";
RL J. Lipid Res. 46:1239-1247(2005).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-323.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-165, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
CC -!- FUNCTION: Has low activity towards the organophosphate paraxon and
CC aromatic carboxylic acid esters. Rapidly hydrolyzes lactones such as
CC statin prodrugs (e.g. lovastatin). Hydrolyzes aromatic lactones and
CC 5- or 6-member ring lactones with aliphatic substituents but not simple
CC lactones or those with polar substituents.
CC {ECO:0000269|PubMed:15772423}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a phenyl acetate + H2O = a phenol + acetate + H(+);
CC Xref=Rhea:RHEA:17309, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30089, ChEBI:CHEBI:33853, ChEBI:CHEBI:140310; EC=3.1.1.2;
CC Evidence={ECO:0000269|PubMed:15772423};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=An aryl dialkyl phosphate + H2O = dialkyl phosphate + an aryl
CC alcohol.; EC=3.1.8.1; Evidence={ECO:0000269|PubMed:15772423};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-acyl-L-homoserine lactone + H2O = an N-acyl-L-homoserine
CC + H(+); Xref=Rhea:RHEA:22576, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:55474, ChEBI:CHEBI:58921; EC=3.1.1.81;
CC Evidence={ECO:0000269|PubMed:15772423};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC Note=Binds 2 calcium ions per subunit. {ECO:0000250};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:15772423}.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space {ECO:0000250}.
CC -!- PTM: The signal sequence is not cleaved. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the paraoxonase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/pon3/";
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DR EMBL; AF320003; AAK07629.1; -; mRNA.
DR EMBL; AF329433; AAO15365.1; -; mRNA.
DR EMBL; AY805220; AAV50000.1; -; Genomic_DNA.
DR EMBL; AC004022; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005021; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236949; EAL24132.1; -; Genomic_DNA.
DR EMBL; CH471091; EAW76768.1; -; Genomic_DNA.
DR EMBL; BC070374; AAH70374.1; -; mRNA.
DR EMBL; L48516; AAC41996.1; -; mRNA.
DR CCDS; CCDS5639.1; -.
DR RefSeq; NP_000931.1; NM_000940.2.
DR AlphaFoldDB; Q15166; -.
DR SMR; Q15166; -.
DR BioGRID; 111442; 6.
DR IntAct; Q15166; 3.
DR STRING; 9606.ENSP00000265627; -.
DR BindingDB; Q15166; -.
DR ChEMBL; CHEMBL4295824; -.
DR DrugBank; DB14598; Edetate calcium disodium anhydrous.
DR DrugBank; DB14600; Edetate disodium anhydrous.
DR DrugBank; DB00974; Edetic acid.
DR DrugBank; DB00227; Lovastatin.
DR GlyGen; Q15166; 3 sites.
DR iPTMnet; Q15166; -.
DR PhosphoSitePlus; Q15166; -.
DR BioMuta; PON3; -.
DR DMDM; 50403778; -.
DR CPTAC; non-CPTAC-2696; -.
DR CPTAC; non-CPTAC-2697; -.
DR jPOST; Q15166; -.
DR MassIVE; Q15166; -.
DR MaxQB; Q15166; -.
DR PaxDb; Q15166; -.
DR PeptideAtlas; Q15166; -.
DR PRIDE; Q15166; -.
DR ProteomicsDB; 60478; -.
DR Antibodypedia; 15863; 302 antibodies from 30 providers.
DR DNASU; 5446; -.
DR Ensembl; ENST00000265627.10; ENSP00000265627.5; ENSG00000105852.11.
DR GeneID; 5446; -.
DR KEGG; hsa:5446; -.
DR MANE-Select; ENST00000265627.10; ENSP00000265627.5; NM_000940.3; NP_000931.1.
DR UCSC; uc003unt.4; human.
DR CTD; 5446; -.
DR DisGeNET; 5446; -.
DR GeneCards; PON3; -.
DR HGNC; HGNC:9206; PON3.
DR HPA; ENSG00000105852; Tissue enriched (liver).
DR MalaCards; PON3; -.
DR MIM; 602720; gene.
DR neXtProt; NX_Q15166; -.
DR OpenTargets; ENSG00000105852; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA33531; -.
DR VEuPathDB; HostDB:ENSG00000105852; -.
DR eggNOG; ENOG502S6UP; Eukaryota.
DR GeneTree; ENSGT00390000008932; -.
DR HOGENOM; CLU_049839_0_1_1; -.
DR InParanoid; Q15166; -.
DR OMA; TFIDKDH; -.
DR OrthoDB; 888266at2759; -.
DR PhylomeDB; Q15166; -.
DR TreeFam; TF322436; -.
DR BRENDA; 3.1.1.2; 2681.
DR BRENDA; 3.1.1.25; 2681.
DR BRENDA; 3.1.8.1; 2681.
DR PathwayCommons; Q15166; -.
DR Reactome; R-HSA-2142688; Synthesis of 5-eicosatetraenoic acids.
DR Reactome; R-HSA-9754706; Atorvastatin ADME.
DR SignaLink; Q15166; -.
DR BioGRID-ORCS; 5446; 6 hits in 1069 CRISPR screens.
DR GeneWiki; PON3; -.
DR GenomeRNAi; 5446; -.
DR Pharos; Q15166; Tbio.
DR PRO; PR:Q15166; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q15166; protein.
DR Bgee; ENSG00000105852; Expressed in right lobe of liver and 124 other tissues.
DR ExpressionAtlas; Q15166; baseline and differential.
DR Genevisible; Q15166; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IEA:Ensembl.
DR GO; GO:0018733; F:3,4-dihydrocoumarin hydrolase activity; IEA:Ensembl.
DR GO; GO:0102007; F:acyl-L-homoserine-lactone lactonohydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0004063; F:aryldialkylphosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004064; F:arylesterase activity; IDA:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0019439; P:aromatic compound catabolic process; IDA:BHF-UCL.
DR GO; GO:0046395; P:carboxylic acid catabolic process; IDA:BHF-UCL.
DR GO; GO:0046226; P:coumarin catabolic process; IEA:Ensembl.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0032929; P:negative regulation of superoxide anion generation; IEA:Ensembl.
DR GO; GO:0010124; P:phenylacetate catabolic process; IEA:Ensembl.
DR GO; GO:0003096; P:renal sodium ion transport; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IBA:GO_Central.
DR Gene3D; 2.120.10.30; -; 1.
DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like.
DR InterPro; IPR002640; Arylesterase.
DR InterPro; IPR008364; Paraoxonase2.
DR Pfam; PF01731; Arylesterase; 1.
DR PRINTS; PR01785; PARAOXONASE.
DR PRINTS; PR01787; PARAOXONASE2.
PE 1: Evidence at protein level;
KW Calcium; Disulfide bond; Glycoprotein; Hydrolase; Metal-binding;
KW Phosphoprotein; Reference proteome; Secreted; Signal.
FT CHAIN 1..354
FT /note="Serum paraoxonase/lactonase 3"
FT /id="PRO_0000223290"
FT SIGNAL 1..?
FT /note="Not cleaved"
FT /evidence="ECO:0000255"
FT ACT_SITE 114
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 53
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 54
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 116
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 167
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 168
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 223
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 268
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 269
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT MOD_RES 165
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT CARBOHYD 29
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 269
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 323
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT DISULFID 42..352
FT /evidence="ECO:0000250"
FT VARIANT 146
FT /note="E -> K (in dbSNP:rs17878827)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_021082"
FT VARIANT 179
FT /note="A -> D (in dbSNP:rs17883013)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_021083"
FT CONFLICT 18
FT /note="G -> E (in Ref. 8; AAC41996)"
FT /evidence="ECO:0000305"
FT CONFLICT 32
FT /note="R -> Q (in Ref. 8; AAC41996)"
FT /evidence="ECO:0000305"
FT CONFLICT 50
FT /note="S -> N (in Ref. 7; AAH70374)"
FT /evidence="ECO:0000305"
FT CONFLICT 58..59
FT /note="LP -> FL (in Ref. 1; AAK07629)"
FT /evidence="ECO:0000305"
FT CONFLICT 63
FT /note="A -> S (in Ref. 8; AAC41996)"
FT /evidence="ECO:0000305"
FT CONFLICT 68
FT /note="G -> E (in Ref. 8; AAC41996)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 354 AA; 39607 MW; 1B861B35E8533921 CRC64;
MGKLVALVLL GVGLSLVGEM FLAFRERVNA SREVEPVEPE NCHLIEELES GSEDIDILPS
GLAFISSGLK YPGMPNFAPD EPGKIFLMDL NEQNPRAQAL EISGGFDKEL FNPHGISIFI
DKDNTVYLYV VNHPHMKSTV EIFKFEEQQR SLVYLKTIKH ELLKSVNDIV VLGPEQFYAT
RDHYFTNSLL SFFEMILDLR WTYVLFYSPR EVKVVAKGFC SANGITVSAD QKYVYVADVA
AKNIHIMEKH DNWDLTQLKV IQLGTLVDNL TVDPATGDIL AGCHPNPMKL LNYNPEDPPG
SEVLRIQNVL SEKPRVSTVY ANNGSVLQGT SVASVYHGKI LIGTVFHKTL YCEL
