| IED ID | IndEnz0018001565 |
| Enzyme Type ID | peroxidase001565 |
| Protein Name |
Peroxidasin homolog EC 1.11.2.- Melanoma-associated antigen MG50 Peroxidasin 1 hsPxd01 Vascular peroxidase 1 p53-responsive gene 2 protein Cleaved into: PXDN active fragment |
| Gene Name | PXDN KIAA0230 MG50 PRG2 PXD01 VPO VPO1 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAKRSRGPGRRCLLALVLFCAWGTLAVVAQKPGAGCPSRCLCFRTTVRCMHLLLEAVPAVAPQTSILDLRFNRIREIQPGAFRRLRNLNTLLLNNNQIKRIPSGAFEDLENLKYLYLYKNEIQSIDRQAFKGLASLEQLYLHFNQIETLDPDSFQHLPKLERLFLHNNRITHLVPGTFNHLESMKRLRLDSNTLHCDCEILWLADLLKTYAESGNAQAAAICEYPRRIQGRSVATITPEELNCERPRITSEPQDADVTSGNTVYFTCRAEGNPKPEIIWLRNNNELSMKTDSRLNLLDDGTLMIQNTQETDQGIYQCMAKNVAGEVKTQEVTLRYFGSPARPTFVIQPQNTEVLVGESVTLECSATGHPPPRISWTRGDRTPLPVDPRVNITPSGGLYIQNVVQGDSGEYACSATNNIDSVHATAFIIVQALPQFTVTPQDRVVIEGQTVDFQCEAKGNPPPVIAWTKGGSQLSVDRRHLVLSSGTLRISGVALHDQGQYECQAVNIIGSQKVVAHLTVQPRVTPVFASIPSDTTVEVGANVQLPCSSQGEPEPAITWNKDGVQVTESGKFHISPEGFLTINDVGPADAGRYECVARNTIGSASVSMVLSVNVPDVSRNGDPFVATSIVEAIATVDRAINSTRTHLFDSRPRSPNDLLALFRYPRDPYTVEQARAGEIFERTLQLIQEHVQHGLMVDLNGTSYHYNDLVSPQYLNLIANLSGCTAHRRVNNCSDMCFHQKYRTHDGTCNNLQHPMWGASLTAFERLLKSVYENGFNTPRGINPHRLYNGHALPMPRLVSTTLIGTETVTPDEQFTHMLMQWGQFLDHDLDSTVVALSQARFSDGQHCSNVCSNDPPCFSVMIPPNDSRARSGARCMFFVRSSPVCGSGMTSLLMNSVYPREQINQLTSYIDASNVYGSTEHEARSIRDLASHRGLLRQGIVQRSGKPLLPFATGPPTECMRDENESPIPCFLAGDHRANEQLGLTSMHTLWFREHNRIATELLKLNPHWDGDTIYYETRKIVGAEIQHITYQHWLPKILGEVGMRTLGEYHGYDPGINAGIFNAFATAAFRFGHTLVNPLLYRLDENFQPIAQDHLPLHKAFFSPFRIVNEGGIDPLLRGLFGVAGKMRVPSQLLNTELTERLFSMAHTVALDLAAINIQRGRDHGIPPYHDYRVYCNLSAAHTFEDLKNEIKNPEIREKLKRLYGSTLNIDLFPALVVEDLVPGSRLGPTLMCLLSTQFKRLRDGDRLWYENPGVFSPAQLTQIKQTSLARILCDNADNITRVQSDVFRVAEFPHGYGSCDEIPRVDLRVWQDCCEDCRTRGQFNAFSYHFRGRRSLEFSYQEDKPTKKTRPRKIPSVGRQGEHLSNSTSAFSTRSDASGTNDFREFVLEMQKTITDLRTQIKKLESRLSTTECVDAGGESHANNTKWKKDACTICECKDGQVTCFVEACPPATCAVPVNIPGACCPVCLQKRAEEKP |
| Enzyme Length | 1479 |
| Uniprot Accession Number | Q92626 |
| Absorption | |
| Active Site | ACT_SITE 827; /note=Proton acceptor; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298 |
| Activity Regulation | ACTIVITY REGULATION: The hypobromous acid formation is activated by increasing nitrite concentrations and inhibited by increasing urate concentrations. {ECO:0000269|PubMed:31953133}. |
| Binding Site | BINDING 826; /note="Heme b; covalent, via 2 links"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00298"; BINDING 980; /note="Heme b; covalent, via 2 links"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00298" |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=H2O2 + L-lysyl-[collagen] + L-methionyl-[collagen] = [collagen]-L-lysyl-N-S-L-methionyl-[collagen] + H(+) + 2 H2O; Xref=Rhea:RHEA:66020, Rhea:RHEA-COMP:12751, Rhea:RHEA-COMP:16949, Rhea:RHEA-COMP:16951, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16044, ChEBI:CHEBI:16240, ChEBI:CHEBI:29969, ChEBI:CHEBI:166867; Evidence={ECO:0000269|PubMed:22842973};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66021; Evidence={ECO:0000269|PubMed:22842973}; CATALYTIC ACTIVITY: Reaction=bromide + H2O2 = H2O + hypobromite; Xref=Rhea:RHEA:66016, ChEBI:CHEBI:15377, ChEBI:CHEBI:15858, ChEBI:CHEBI:16240, ChEBI:CHEBI:29250; Evidence={ECO:0000269|PubMed:22842973, ECO:0000269|PubMed:25713063, ECO:0000269|PubMed:27697841, ECO:0000269|PubMed:28154175, ECO:0000269|PubMed:29982533, ECO:0000269|PubMed:32571911};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66017; Evidence={ECO:0000269|PubMed:22842973, ECO:0000269|PubMed:28154175, ECO:0000269|PubMed:32571911, ECO:0000305|PubMed:25713063, ECO:0000305|PubMed:27697841}; CATALYTIC ACTIVITY: Reaction=hypobromite + L-lysyl-[collagen] + L-methionyl-[collagen] = [collagen]-L-lysyl-N-S-L-methionyl-[collagen] + bromide + H(+) + H2O; Xref=Rhea:RHEA:66024, Rhea:RHEA-COMP:12751, Rhea:RHEA-COMP:16949, Rhea:RHEA-COMP:16951, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15858, ChEBI:CHEBI:16044, ChEBI:CHEBI:29250, ChEBI:CHEBI:29969, ChEBI:CHEBI:166867; Evidence={ECO:0000269|PubMed:22842973, ECO:0000269|PubMed:27697841};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66025; Evidence={ECO:0000269|PubMed:22842973, ECO:0000269|PubMed:27697841}; CATALYTIC ACTIVITY: Reaction=bromide + H(+) + H2O2 + L-tyrosyl-[protein] = 3-bromo-L-tyrosyl-[protein] + 2 H2O; Xref=Rhea:RHEA:69360, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:17686, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15858, ChEBI:CHEBI:16240, ChEBI:CHEBI:46858, ChEBI:CHEBI:183512; Evidence={ECO:0000269|PubMed:32571911};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69361; Evidence={ECO:0000269|PubMed:32571911}; CATALYTIC ACTIVITY: Reaction=H(+) + hypobromite + L-tyrosyl-[protein] = 3-bromo-L-tyrosyl-[protein] + H2O; Xref=Rhea:RHEA:69356, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:17686, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29250, ChEBI:CHEBI:46858, ChEBI:CHEBI:183512; Evidence={ECO:0000269|PubMed:32571911};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69357; Evidence={ECO:0000269|PubMed:32571911}; |
| DNA Binding | |
| EC Number | 1.11.2.- |
| Enzyme Function | FUNCTION: Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer (PubMed:18929642, PubMed:22842973, PubMed:27697841, PubMed:28154175, PubMed:19590037, PubMed:25708780, PubMed:25713063, PubMed:34679700). In turns, directly contributes to the collagen IV network-dependent fibronectin/FN and laminin assembly, which is required for full extracellular matrix (ECM)-mediated signaling (PubMed:32543734, PubMed:34679700, PubMed:19590037). Thus, sulfilimine cross-links are essential for growth factor-induced cell proliferation and survival in endothelial cells, an event essential to basement membrane integrity (PubMed:32543734). In addition, through the bromide oxidation, may promote tubulogenesis and induce angiogenesis through ERK1/2, Akt, and FAK pathways (PubMed:25713063). Moreover brominates alpha2 collagen IV chain/COL4A2 at 'Tyr-1485' and leads to bromine enrichment of the basement membranes (PubMed:32571911). In vitro, can also catalyze the two-electron oxidation of thiocyanate and iodide and these two substrates could effectively compete with bromide and thus inhibit the formation of sulfilimine bonds (PubMed:28154175). Binds laminins (PubMed:32485152). May play a role in the organization of eyeball structure and lens development during eye development (By similarity). {ECO:0000250|UniProtKB:Q3UQ28, ECO:0000269|PubMed:18929642, ECO:0000269|PubMed:19590037, ECO:0000269|PubMed:22842973, ECO:0000269|PubMed:25708780, ECO:0000269|PubMed:25713063, ECO:0000269|PubMed:27697841, ECO:0000269|PubMed:28154175, ECO:0000269|PubMed:32485152, ECO:0000269|PubMed:32543734, ECO:0000269|PubMed:32571911, ECO:0000269|PubMed:34679700}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (1); Alternative sequence (2); Binding site (2); Chain (2); Compositional bias (1); Disulfide bond (17); Domain (7); Erroneous initiation (2); Glycosylation (10); Metal binding (6); Modified residue (2); Mutagenesis (9); Natural variant (3); Region (2); Repeat (8); Signal peptide (1); Site (2) |
| Keywords | Alternative splicing;Basement membrane;Calcium;Direct protein sequencing;Disease variant;Disulfide bond;Endoplasmic reticulum;Extracellular matrix;Glycoprotein;Heme;Hydrogen peroxide;Immunoglobulin domain;Iron;Leucine-rich repeat;Metal-binding;Oxidoreductase;Peroxidase;Phosphoprotein;Reference proteome;Repeat;Secreted;Signal |
| Interact With | |
| Induction | INDUCTION: By TGFB1 in fibroblasts and up-regulated in apoptotic cells. {ECO:0000269|PubMed:10441517, ECO:0000269|PubMed:19590037}. |
| Subcellular Location | SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix {ECO:0000269|PubMed:18929642, ECO:0000269|PubMed:19590037, ECO:0000269|PubMed:26178375, ECO:0000269|Ref.9}. Endoplasmic reticulum {ECO:0000269|PubMed:19590037, ECO:0000269|PubMed:25708780}. Cell surface {ECO:0000269|PubMed:25708780}. Secreted, extracellular space, extracellular matrix, basement membrane {ECO:0000250|UniProtKB:Q3UQ28}. Note=Enriched in the peritubular space of fibrotic kidneys. Adheres on the cell surface in 'hot spots' (PubMed:25708780). Only the proteolytically processed PXDN integrates into the extracellular matrix (PubMed:34679700). {ECO:0000269|PubMed:25708780, ECO:0000269|PubMed:34679700}.; SUBCELLULAR LOCATION: [PXDN active fragment]: Secreted, extracellular space, extracellular matrix {ECO:0000269|PubMed:34679700}. |
| Modified Residue | MOD_RES 1176; /note=Phosphotyrosine; /evidence=ECO:0007744|PubMed:18318008; MOD_RES 1180; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:18318008 |
| Post Translational Modification | PTM: Glycosylated (PubMed:25713063). Four sites are completely N-glycosylated (Asn-640, Asn-731, Asn-865 and Asn-1425), whereas the others are found partially glycosylated (PubMed:25713063). {ECO:0000269|PubMed:25713063}.; PTM: Processed by FURIN and the proteolytic processing largely depends on the peroxidase activity of PXDN (PubMed:27697841, PubMed:34679700). The proteolytic cleavage occurs after intracellular homotrimerization and releases into the extracellular matrix a large, catalytically active fragment and a smaller fragment consisting primarily of the C-terminal VWFC domain (PubMed:27697841, PubMed:31295557). The processing enhances both peroxidase activity and sulfilimine cross-links formation (PubMed:27697841, PubMed:34679700). {ECO:0000269|PubMed:27697841, ECO:0000269|PubMed:31295557, ECO:0000269|PubMed:34679700}. |
| Signal Peptide | SIGNAL 1..26; /evidence=ECO:0000255 |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 19724895; 19729652; 19851296; 20198315; 20379614; 20800603; 21798344; 21820048; 21988832; 22157634; 22526679; 22982576; 24556843; 24895407; 24939590; 27167346; 27475679; 28005267; 28264790; 29305973; 29661721; 30371171; 30844643; 31234468; 32015378; 32751434; 32813143; 33903591; 33985410; 35317099; |
| Motif | |
| Gene Encoded By | |
| Mass | 165,275 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=0.15 mM for H2O2 {ECO:0000269|PubMed:18929642}; KM=18.6 uM for H2O2 {ECO:0000269|PubMed:25713063}; KM=4.1 mM for bromide {ECO:0000269|PubMed:25713063}; KM=16.6 uM for H2O2 (homotrimeric enzymatic form) {ECO:0000269|PubMed:29982533}; KM=4.1 uM for bromide (homotrimeric enzymatic form) {ECO:0000269|PubMed:29982533}; |
| Metal Binding | METAL 828; /note=Calcium; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298; METAL 907; /note=Calcium; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298; METAL 909; /note=Calcium; via carbonyl oxygen; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298; METAL 911; /note=Calcium; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298; METAL 913; /note=Calcium; /evidence=ECO:0000255|PROSITE-ProRule:PRU00298; METAL 1074; /note=Iron (heme b axial ligand); /evidence=ECO:0000255|PROSITE-ProRule:PRU00298 |
| Rhea ID | RHEA:66020; RHEA:66021; RHEA:66016; RHEA:66017; RHEA:66024; RHEA:66025; RHEA:69360; RHEA:69361; RHEA:69356; RHEA:69357 |
| Cross Reference Brenda | 1.11.1.7; |