ID SODE_HUMAN Reviewed; 240 AA. AC P08294; Q5U781; Q6FHA2; DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2006, sequence version 2. DT 27-MAR-2024, entry version 226. DE RecName: Full=Extracellular superoxide dismutase [Cu-Zn]; DE Short=EC-SOD; DE EC=1.15.1.1; DE Flags: Precursor; GN Name=SOD3; 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], PARTIAL PROTEIN SEQUENCE, AND VARIANT THR-58. RX PubMed=3476950; DOI=10.1073/pnas.84.18.6340; RA Hjalmarsson K., Marklund S.L., Engstroem A., Edlund T.; RT "Isolation and sequence of complementary DNA encoding human extracellular RT superoxide dismutase."; RL Proc. Natl. Acad. Sci. U.S.A. 84:6340-6344(1987). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-58. RC TISSUE=Blood; RX PubMed=7959763; DOI=10.1006/geno.1994.1357; RA Folz R.J., Crapo J.D.; RT "Extracellular superoxide dismutase (SOD3): tissue-specific expression, RT genomic characterization, and computer-assisted sequence analysis of the RT human EC SOD gene."; RL Genomics 22:162-171(1994). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-58. RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., RA LaBaer J.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-58; THR-91 AND GLY-231. RG NIEHS SNPs program; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-58. RC TISSUE=Colon; 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 [6] RP GLYCATION AT LYS-229 AND LYS-230. RX PubMed=1505778; DOI=10.1016/0891-5849(92)90016-a; RA Adachi T., Ohta H., Hayashi K., Hirano K., Marklund S.L.; RT "The site of nonenzymic glycation of human extracellular-superoxide RT dismutase in vitro."; RL Free Radic. Biol. Med. 13:205-210(1992). RN [7] RP REVIEW. RX PubMed=16087389; DOI=10.1016/j.biocel.2005.06.012; RA Nozik-Grayck E., Suliman H.B., Piantadosi C.A.; RT "Extracellular superoxide dismutase."; RL Int. J. Biochem. Cell Biol. 37:2466-2471(2005). RN [8] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-107. 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 [9] RP INTERACTION WITH SOD3. RX PubMed=16371425; DOI=10.1096/fj.05-4564fje; RA Qin Z., Itoh S., Jeney V., Ushio-Fukai M., Fukai T.; RT "Essential role for the Menkes ATPase in activation of extracellular RT superoxide dismutase: implication for vascular oxidative stress."; RL FASEB J. 20:334-336(2006). RN [10] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-107. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [11] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 19-240, SUBUNIT, METAL-BINDING RP SITES, AND DISULFIDE BONDS. RX PubMed=19289127; DOI=10.1016/j.jmb.2009.03.026; RA Antonyuk S.V., Strange R.W., Marklund S.L., Hasnain S.S.; RT "The structure of human extracellular copper-zinc superoxide dismutase at RT 1.7 A resolution: insights into heparin and collagen binding."; RL J. Mol. Biol. 388:310-326(2009). RN [12] RP VARIANT GLY-231. RX PubMed=8034674; DOI=10.1016/s0021-9258(17)32289-5; RA Sandstrom J., Nilsson P., Karlsson K., Marklund S.L.; RT "10-fold increase in human plasma extracellular superoxide dismutase RT content caused by a mutation in heparin-binding domain."; RL J. Biol. Chem. 269:19163-19166(1994). RN [13] RP VARIANT GLY-231. RX PubMed=7662997; DOI=10.1007/bf01883574; RA Yamada H., Yamada Y., Adachi T., Goto H., Ogasawara N., Futenma A., RA Kitano M., Hirano K., Kato K.; RT "Molecular analysis of extracellular-superoxide dismutase gene associated RT with high level in serum."; RL Jpn. J. Hum. Genet. 40:177-184(1995). RN [14] RP VARIANT GLY-231. RX PubMed=8546689; DOI=10.1042/bj3130235; RA Adachi T., Yamada H., Yamada Y., Morihara N., Yamazaki N., Murakami T., RA Futenma A., Kato K., Hirano K.; RT "Substitution of glycine for arginine-213 in extracellular-superoxide RT dismutase impairs affinity for heparin and endothelial cell surface."; RL Biochem. J. 313:235-239(1996). RN [15] RP VARIANT GLY-231. RX PubMed=8864862; DOI=10.1093/oxfordjournals.jbchem.a021383; RA Adachi T., Morihara N., Yamazaki N., Yamada H., Futenma A., Kato K., RA Hirano K.; RT "An arginine-213 to glycine mutation in human extracellular-superoxide RT dismutase reduces susceptibility to trypsin-like proteinases."; RL J. Biochem. 120:184-188(1996). CC -!- FUNCTION: Protect the extracellular space from toxic effect of reactive CC oxygen intermediates by converting superoxide radicals into hydrogen CC peroxide and oxygen. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 H(+) + 2 superoxide = H2O2 + O2; Xref=Rhea:RHEA:20696, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, CC ChEBI:CHEBI:18421; EC=1.15.1.1; CC -!- COFACTOR: CC Name=Cu cation; Xref=ChEBI:CHEBI:23378; Evidence={ECO:0000250}; CC Note=Binds 1 copper ion per subunit. {ECO:0000250}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000250}; CC -!- SUBUNIT: Homotetramer (PubMed:19289127). Directly interacts with ATP7A; CC this interaction is copper-dependent and is required for SOD3 activity CC (PubMed:16371425). {ECO:0000269|PubMed:16371425, CC ECO:0000269|PubMed:19289127}. CC -!- INTERACTION: CC P08294; Q12797-6: ASPH; NbExp=3; IntAct=EBI-10195782, EBI-12092171; CC P08294; Q9NZI2-2: KCNIP1; NbExp=3; IntAct=EBI-10195782, EBI-22452746; CC P08294; Q9Y2W7: KCNIP3; NbExp=6; IntAct=EBI-10195782, EBI-751501; CC P08294; O43765: SGTA; NbExp=3; IntAct=EBI-10195782, EBI-347996; CC P08294; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-10195782, EBI-744081; CC P08294; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-10195782, EBI-741480; CC P08294; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-10195782, EBI-947187; CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space. Golgi apparatus, CC trans-Golgi network {ECO:0000250|UniProtKB:O09164}. Note=99% of EC-SOD CC is anchored to heparan sulfate proteoglycans in the tissue CC interstitium, and 1% is located in the vasculature in equilibrium CC between the plasma and the endothelium. CC -!- TISSUE SPECIFICITY: Expressed in blood vessels, heart, lung, kidney and CC placenta. Major SOD isoenzyme in extracellular fluids such as plasma, CC lymph and synovial fluid. CC -!- POLYMORPHISM: The variant Gly-231 which is found in about 2.2% of CC individual displays a 10-fold increased plasma EC-SOD content due to CC reduced heparin-binding affinity and thus the impairment of its binding CC ability to endothelial cell surface. {ECO:0000269|PubMed:7662997, CC ECO:0000269|PubMed:8034674, ECO:0000269|PubMed:8546689}. CC -!- SIMILARITY: Belongs to the Cu-Zn superoxide dismutase family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/sod3/"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Superoxide dismutase entry; CC URL="https://en.wikipedia.org/wiki/Superoxide_dismutase"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J02947; AAA66000.1; -; mRNA. DR EMBL; U10116; AAA62278.1; -; Genomic_DNA. DR EMBL; CR541853; CAG46651.1; -; mRNA. DR EMBL; AY787834; AAV40827.1; -; Genomic_DNA. DR EMBL; BC014418; AAH14418.1; -; mRNA. DR CCDS; CCDS3430.1; -. DR PIR; A28301; DSHUEC. DR RefSeq; NP_003093.2; NM_003102.2. DR PDB; 2JLP; X-ray; 1.70 A; A/B/C/D=19-240. DR PDBsum; 2JLP; -. DR AlphaFoldDB; P08294; -. DR SMR; P08294; -. DR BioGRID; 112532; 10. DR IntAct; P08294; 7. DR STRING; 9606.ENSP00000371554; -. DR BindingDB; P08294; -. DR ChEMBL; CHEMBL2069159; -. DR DrugBank; DB09096; Benzoyl peroxide. DR GlyConnect; 1233; 3 N-Linked glycans (1 site). DR GlyCosmos; P08294; 4 sites, 3 glycans. DR GlyGen; P08294; 2 sites, 2 N-linked glycans (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P08294; -. DR PhosphoSitePlus; P08294; -. DR BioMuta; SOD3; -. DR DMDM; 108885292; -. DR EPD; P08294; -. DR jPOST; P08294; -. DR MassIVE; P08294; -. DR MaxQB; P08294; -. DR PaxDb; 9606-ENSP00000371554; -. DR PeptideAtlas; P08294; -. DR ProteomicsDB; 52104; -. DR Antibodypedia; 3278; 621 antibodies from 36 providers. DR DNASU; 6649; -. DR Ensembl; ENST00000382120.4; ENSP00000371554.3; ENSG00000109610.6. DR GeneID; 6649; -. DR KEGG; hsa:6649; -. DR MANE-Select; ENST00000382120.4; ENSP00000371554.3; NM_003102.4; NP_003093.2. DR UCSC; uc003gqz.4; human. DR AGR; HGNC:11181; -. DR DisGeNET; 6649; -. DR GeneCards; SOD3; -. DR HGNC; HGNC:11181; SOD3. DR HPA; ENSG00000109610; Tissue enriched (choroid). DR MIM; 185490; gene. DR neXtProt; NX_P08294; -. DR OpenTargets; ENSG00000109610; -. DR PharmGKB; PA36018; -. DR VEuPathDB; HostDB:ENSG00000109610; -. DR eggNOG; KOG0441; Eukaryota. DR GeneTree; ENSGT00940000162224; -. DR HOGENOM; CLU_056632_3_1_1; -. DR InParanoid; P08294; -. DR OMA; DGSLWKY; -. DR OrthoDB; 3470597at2759; -. DR PhylomeDB; P08294; -. DR TreeFam; TF105133; -. DR BioCyc; MetaCyc:HS03242-MONOMER; -. DR BRENDA; 1.15.1.1; 2681. DR PathwayCommons; P08294; -. DR Reactome; R-HSA-3299685; Detoxification of Reactive Oxygen Species. DR Reactome; R-HSA-9818027; NFE2L2 regulating anti-oxidant/detoxification enzymes. DR SignaLink; P08294; -. DR SIGNOR; P08294; -. DR BioGRID-ORCS; 6649; 11 hits in 1153 CRISPR screens. DR ChiTaRS; SOD3; human. DR EvolutionaryTrace; P08294; -. DR GeneWiki; SOD3; -. DR GenomeRNAi; 6649; -. DR Pharos; P08294; Tbio. DR PRO; PR:P08294; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P08294; Protein. DR Bgee; ENSG00000109610; Expressed in descending thoracic aorta and 150 other cell types or tissues. DR ExpressionAtlas; P08294; baseline and differential. DR GO; GO:0062023; C:collagen-containing extracellular matrix; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; HDA:BHF-UCL. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0005507; F:copper ion binding; IBA:GO_Central. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0060090; F:molecular adaptor activity; EXP:DisProt. DR GO; GO:0004784; F:superoxide dismutase activity; IBA:GO_Central. DR GO; GO:0097746; P:blood vessel diameter maintenance; IEA:Ensembl. DR GO; GO:0019430; P:removal of superoxide radicals; IBA:GO_Central. DR GO; GO:0046688; P:response to copper ion; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR CDD; cd00305; Cu-Zn_Superoxide_Dismutase; 1. DR DisProt; DP02656; -. DR Gene3D; 2.60.40.200; Superoxide dismutase, copper/zinc binding domain; 1. DR InterPro; IPR036423; SOD-like_Cu/Zn_dom_sf. DR InterPro; IPR024134; SOD_Cu/Zn_/chaperone. DR InterPro; IPR018152; SOD_Cu/Zn_BS. DR InterPro; IPR001424; SOD_Cu_Zn_dom. DR PANTHER; PTHR10003:SF77; EXTRACELLULAR SUPEROXIDE DISMUTASE [CU-ZN]; 1. DR PANTHER; PTHR10003; SUPEROXIDE DISMUTASE CU-ZN -RELATED; 1. DR Pfam; PF00080; Sod_Cu; 1. DR PRINTS; PR00068; CUZNDISMTASE. DR SUPFAM; SSF49329; Cu,Zn superoxide dismutase-like; 1. DR PROSITE; PS00087; SOD_CU_ZN_1; 1. DR PROSITE; PS00332; SOD_CU_ZN_2; 1. DR Genevisible; P08294; HS. PE 1: Evidence at protein level; KW 3D-structure; Antioxidant; Copper; Direct protein sequencing; KW Disulfide bond; Glycation; Glycoprotein; Golgi apparatus; Heparin-binding; KW Metal-binding; Oxidoreductase; Reference proteome; Secreted; Signal; Zinc. FT SIGNAL 1..18 FT CHAIN 19..240 FT /note="Extracellular superoxide dismutase [Cu-Zn]" FT /id="PRO_0000032855" FT BINDING 114 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /ligand_note="catalytic" FT BINDING 116 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /ligand_note="catalytic" FT BINDING 131 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /ligand_note="catalytic" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="structural" FT BINDING 139 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="structural" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="structural" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="structural" FT BINDING 181 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /ligand_note="catalytic" FT SITE 41 FT /note="Not glycated" FT SITE 92 FT /note="Not glycated" FT SITE 238 FT /note="Not glycated" FT CARBOHYD 107 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:19159218" FT CARBOHYD 229 FT /note="N-linked (Glc) (glycation) lysine; in vitro" FT /evidence="ECO:0000269|PubMed:1505778" FT CARBOHYD 230 FT /note="N-linked (Glc) (glycation) lysine; in vitro" FT /evidence="ECO:0000269|PubMed:1505778" FT DISULFID 63..208 FT /evidence="ECO:0000269|PubMed:19289127" FT DISULFID 125..207 FT /evidence="ECO:0000269|PubMed:19289127" FT VARIANT 58 FT /note="A -> T (in dbSNP:rs2536512)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:3476950, ECO:0000269|PubMed:7959763, FT ECO:0000269|Ref.3, ECO:0000269|Ref.4" FT /id="VAR_020776" FT VARIANT 91 FT /note="A -> T (in dbSNP:rs17879876)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_020777" FT VARIANT 231 FT /note="R -> G (in dbSNP:rs1799895)" FT /evidence="ECO:0000269|PubMed:7662997, FT ECO:0000269|PubMed:8034674, ECO:0000269|PubMed:8546689, FT ECO:0000269|PubMed:8864862, ECO:0000269|Ref.4" FT /id="VAR_014705" FT STRAND 59..67 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 79..88 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 93..100 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 104..117 FT /evidence="ECO:0007829|PDB:2JLP" FT HELIX 124..128 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 145..152 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 155..164 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 166..169 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 176..183 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 190..192 FT /evidence="ECO:0007829|PDB:2JLP" FT HELIX 195..198 FT /evidence="ECO:0007829|PDB:2JLP" FT STRAND 204..209 FT /evidence="ECO:0007829|PDB:2JLP" FT HELIX 216..222 FT /evidence="ECO:0007829|PDB:2JLP" SQ SEQUENCE 240 AA; 25851 MW; 585B8DEBFC506CF4 CRC64; MLALLCSCLL LAAGASDAWT GEDSAEPNSD SAEWIRDMYA KVTEIWQEVM QRRDDDGALH AACQVQPSAT LDAAQPRVTG VVLFRQLAPR AKLDAFFALE GFPTEPNSSS RAIHVHQFGD LSQGCESTGP HYNPLAVPHP QHPGDFGNFA VRDGSLWRYR AGLAASLAGP HSIVGRAVVV HAGEDDLGRG GNQASVENGN AGRRLACCVV GVCGPGLWER QAREHSERKK RRRESECKAA //