This group of metallopeptidases belong to the MEROPS peptidase family M13 (neprilysin family, clan MA(E)). The M13 family includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, [ec:3.4.24.11]), endothelin-converting enzyme I (ECE-1, [ec:3.4.24.71]), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. The cytoplasmic domain contains a conformationally-restrained octapeptide, which is thought to act as a stop transfer sequence that prevents proteolysis and secretion [[cite:PUB00003579], [cite:PUB00000181]]. Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity [[cite:PUB00003579], [cite:PUB00080115]]. The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH [[cite:PUB00003579]].
\r\n\r\nM13 peptidases are well-studied proteases found in a wide range of organisms including mammals and bacteria. In mammals they participate in processes such as cardiovascular development, blood-pressure regulation, nervous control of respiration, and regulation of the function of neuropeptides in the central nervous system. In bacteria they may be used for digestion of milk [[cite:PUB00011643], [cite:PUB00003579]]. The family includes eukaryotic and prokaryotic oligopeptidases, as well as some of the proteins responsible for the molecular basis of the blood group antigens e.g. Kell [[cite:PUB00003579]].
","llm":false,"checked":false,"updated":false},{"text":"ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta. Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homologue of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well. Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition [[cite:PUB00003579], [cite:PUB00080115], [cite:PUB00080116], [cite:PUB00030479], [cite:PUB00051515], [cite:PUB00011643], [cite:PUB00080117], [cite:PUB00035235], [cite:PUB00080118], [cite:PUB00080119], [cite:PUB00038711], [cite:PUB00080120]].
","llm":false,"checked":false,"updated":false}],"wikipedia":null,"literature":{"PUB00003579":{"PMID":7674922,"ISBN":null,"volume":"248","issue":null,"year":1995,"title":"Evolutionary families of metallopeptidases.","URL":null,"raw_pages":"183-228","medline_journal":"Methods Enzymol","ISO_journal":"Meth. Enzymol.","authors":["Rawlings ND","Barrett AJ."],"DOI_URL":"http://dx.doi.org/10.1016/0076-6879(95)48015-3"},"PUB00001657":{"PMID":8099556,"ISBN":null,"volume":"324","issue":"2","year":1993,"title":"Substitution of potential metal-coordinating amino acid residues in the zinc-binding site of endopeptidase-24.11.","URL":null,"raw_pages":"196-200","medline_journal":"FEBS Lett","ISO_journal":"FEBS Lett.","authors":["Le Moual H","Roques BP","Crine P","Boileau G."],"DOI_URL":"http://dx.doi.org/10.1016/0014-5793(93)81392-D"},"PUB00000181":{"PMID":3555489,"ISBN":null,"volume":"144","issue":"1","year":1987,"title":"Molecular cloning and amino acid sequence of rat enkephalinase.","URL":null,"raw_pages":"59-66","medline_journal":"Biochem Biophys Res Commun","ISO_journal":"Biochem. Biophys. Res. Commun.","authors":["Malfroy B","Schofield PR","Kuang WJ","Seeburg PH","Mason AJ","Henzel WJ."],"DOI_URL":"http://dx.doi.org/10.1016/S0006-291X(87)80475-8"},"PUB00011643":{"PMID":11223883,"ISBN":null,"volume":"23","issue":"3","year":2001,"title":"The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.","URL":null,"raw_pages":"261-9","medline_journal":"Bioessays","ISO_journal":"Bioessays","authors":["Turner AJ","Isaac RE","Coates D."],"DOI_URL":"http://dx.doi.org/10.1002/1521-1878(200103)23:3<261::AID-BIES1036>3.0.CO;2-K"},"PUB00080115":{"PMID":10849750,"ISBN":null,"volume":"477","issue":null,"year":2000,"title":"The neprilysin family in health and disease.","URL":null,"raw_pages":"229-40","medline_journal":"Adv Exp Med Biol","ISO_journal":"Adv. Exp. Med. 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Biol.","authors":["Schulz H","Dale GE","Karimi-Nejad Y","Oefner C."],"DOI_URL":"http://dx.doi.org/10.1016/j.jmb.2008.10.052"},"PUB00080117":{"PMID":16526590,"ISBN":null,"volume":"81","issue":"1","year":2006,"title":"Identification and functional analysis of damage-induced neuronal endopeptidase (DINE), a nerve injury associated molecule.","URL":null,"raw_pages":"1-6","medline_journal":"Anat Sci Int","ISO_journal":"Anat Sci Int","authors":["Kiryu-Seo S."],"DOI_URL":"http://dx.doi.org/10.1111/j.1447-073X.2006.00136.x"},"PUB00035235":{"PMID":15544566,"ISBN":null,"volume":"11","issue":"5","year":2004,"title":"DINE (damage induced neuronal endopeptidase).","URL":null,"raw_pages":"451-60","medline_journal":"Protein Pept Lett","ISO_journal":"Protein Pept. Lett.","authors":["Kiryu-Seo S","Kiyama H."],"DOI_URL":"http://dx.doi.org/10.2174/0929866043406526"},"PUB00080118":{"PMID":16423827,"ISBN":null,"volume":"281","issue":"11","year":2006,"title":"Endothelin-3-converting enzyme activity of the KEL1 and KEL6 phenotypes of the Kell blood group system.","URL":null,"raw_pages":"7180-2","medline_journal":"J Biol Chem","ISO_journal":"J. Biol. Chem.","authors":["Sha Q","Redman CM","Lee S."],"DOI_URL":"http://dx.doi.org/10.1074/jbc.M507776200"},"PUB00080119":{"PMID":10791880,"ISBN":null,"volume":"37","issue":"2","year":2000,"title":"The Kell blood group system: Kell and XK membrane proteins.","URL":null,"raw_pages":"113-21","medline_journal":"Semin Hematol","ISO_journal":"Semin. Hematol.","authors":["Lee S","Russo D","Redman CM."],"DOI_URL":"http://dx.doi.org/10.1016/S0037-1963(00)90036-2"},"PUB00038711":{"PMID":15893768,"ISBN":null,"volume":"349","issue":"4","year":2005,"title":"Crystal structures of the tricorn interacting factor F3 from Thermoplasma acidophilum, a zinc aminopeptidase in three different conformations.","URL":null,"raw_pages":"787-800","medline_journal":"J Mol Biol","ISO_journal":"J. Mol. Biol.","authors":["Kyrieleis OJ","Goettig P","Kiefersauer R","Huber R","Brandstetter H."],"DOI_URL":"http://dx.doi.org/10.1016/j.jmb.2005.03.070"},"PUB00080120":{"PMID":9141502,"ISBN":null,"volume":"11","issue":"5","year":1997,"title":"Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX.","URL":null,"raw_pages":"355-64","medline_journal":"FASEB J","ISO_journal":"FASEB J.","authors":["Turner AJ","Tanzawa K."],"DOI_URL":null},"PUB00080116":{"PMID":10698686,"ISBN":null,"volume":"346 Pt 3","issue":null,"year":2000,"title":"Organization and chromosomal localization of the human ECEL1 (XCE) gene encoding a zinc metallopeptidase involved in the nervous control of respiration.","URL":null,"raw_pages":"611-6","medline_journal":"Biochem J","ISO_journal":"Biochem. J.","authors":["Valdenaire O","Rohrbacher E","Langeveld A","Schweizer A","Meijers C."],"DOI_URL":"http://dx.doi.org/10.1042/bj3460611"}},"set_info":null,"overlaps_with":[{"accession":"IPR024079","name":"Metallopeptidase, catalytic domain superfamily","type":"homologous_superfamily"},{"accession":"IPR042089","name":"Peptidase M13, domain 2","type":"homologous_superfamily"}],"counters":{"subfamilies":0,"domain_architectures":0,"interactions":0,"matches":48342,"pathways":20,"proteins":47965,"proteomes":9028,"sets":0,"structural_models":{"alphafold":39786,"bfvd":1},"structures":27,"taxa":19476},"entry_annotations":{},"cross_references":{"ec":{"displayName":"ENZYME","description":"ENZYME is a repository of information relative to the nomenclature of enzymes. 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