Neprilysin

Details

Name
Neprilysin
Synonyms
  • 3.4.24.11
  • Atriopeptidase
  • CALLA
  • Common acute lymphocytic leukemia antigen
  • Enkephalinase
  • EPN
  • NEP
  • Neutral endopeptidase
  • Neutral endopeptidase 24.11
  • SFE
  • Skin fibroblast elastase
Gene Name
MME
UniProtKB Entry
P08473Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0036982|Neprilysin
MGKSESQMDITDINTPKPKKKQRWTPLEISLSVLVLLLTIIAVTMIALYATYDDGICKSS
DCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKD
VLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGA
SWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKE
ACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLY
NKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILT
KYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNME
NAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERI
GYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAA
VVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKD
GDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYR
AYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVHSPGNFRII
GTLQNSAEFSEAFHCRKNSYMNPEKKCRVW
Number of residues
750
Molecular Weight
85513.225
Theoretical pI
5.43
GO Classification
Functions
cardiolipin binding / oligopeptidase activity / phosphatidylserine binding / protein homodimerization activity
Processes
amyloid-beta clearance / amyloid-beta clearance by cellular catabolic process / amyloid-beta metabolic process / bradykinin catabolic process / hormone catabolic process / learning or memory / lung development / neuropeptide processing / placenta development / positive regulation of long-term synaptic potentiation / positive regulation of neurogenesis / protein catabolic process / protein processing / response to estrogen / substance P catabolic process
Components
cell surface / cytoplasmic vesicle / early endosome / membrane / membrane raft / neuronal cell body / presynapse / secretory granule membrane / trans-Golgi network
General Function
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:6208535, PubMed:6349683, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991, PubMed:6349683). Catalyzes cleavage of bradykinin, substance P and neurotensin peptides (PubMed:6208535). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675, PubMed:6349683). Involved in the degradation of atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-32)) (PubMed:16254193, PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573)
Specific Function
cardiolipin binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
29-51
Cellular Location
Cell membrane
Gene sequence
>lcl|BSEQ0018931|Neprilysin (MME)
ATGGGCAAGTCAGAAAGTCAGATGGATATAACTGATATCAACACTCCAAAGCCAAAGAAG
AAACAGCGATGGACTCCACTGGAGATCAGCCTCTCGGTCCTTGTCCTGCTCCTCACCATC
ATAGCTGTGACAATGATCGCACTCTATGCAACCTACGATGATGGTATTTGCAAGTCATCA
GACTGCATAAAATCAGCTGCTCGACTGATCCAAAACATGGATGCCACCACTGAGCCTTGT
ACAGACTTTTTCAAATATGCTTGCGGAGGCTGGTTGAAACGTAATGTCATTCCCGAGACC
AGCTCCCGTTACGGCAACTTTGACATTTTAAGAGATGAACTAGAAGTCGTTTTGAAAGAT
GTCCTTCAAGAACCCAAAACTGAAGATATAGTAGCAGTGCAGAAAGCAAAAGCATTGTAC
AGGTCTTGTATAAATGAATCTGCTATTGATAGCAGAGGTGGAGAACCTCTACTCAAACTG
TTACCAGACATATATGGGTGGCCAGTAGCAACAGAAAACTGGGAGCAAAAATATGGTGCT
TCTTGGACAGCTGAAAAAGCTATTGCACAACTGAATTCTAAATATGGGAAAAAAGTCCTT
ATTAATTTGTTTGTTGGCACTGATGATAAGAATTCTGTGAATCATGTAATTCATATTGAC
CAACCTCGACTTGGCCTCCCTTCTAGAGATTACTATGAATGCACTGGAATCTATAAAGAG
GCTTGTACAGCATATGTGGATTTTATGATTTCTGTGGCCAGATTGATTCGTCAGGAAGAA
AGATTGCCCATCGATGAAAACCAGCTTGCTTTGGAAATGAATAAAGTTATGGAATTGGAA
AAAGAAATTGCCAATGCTACGGCTAAACCTGAAGATCGAAATGATCCAATGCTTCTGTAT
AACAAGATGACATTGGCCCAGATCCAAAATAACTTTTCACTAGAGATCAATGGGAAGCCA
TTCAGCTGGTTGAATTTCACAAATGAAATCATGTCAACTGTGAATATTAGTATTACAAAT
GAGGAAGATGTGGTTGTTTATGCTCCAGAATATTTAACCAAACTTAAGCCCATTCTTACC
AAATATTCTGCCAGAGATCTTCAAAATTTAATGTCCTGGAGATTCATAATGGATCTTGTA
AGCAGCCTCAGCCGAACCTACAAGGAGTCCAGAAATGCTTTCCGCAAGGCCCTTTATGGT
ACAACCTCAGAAACAGCAACTTGGAGACGTTGTGCAAACTATGTCAATGGGAATATGGAA
AATGCTGTGGGGAGGCTTTATGTGGAAGCAGCATTTGCTGGAGAGAGTAAACATGTGGTC
GAGGATTTGATTGCACAGATCCGAGAAGTTTTTATTCAGACTTTAGATGACCTCACTTGG
ATGGATGCCGAGACAAAAAAGAGAGCTGAAGAAAAGGCCTTAGCAATTAAAGAAAGGATC
GGCTATCCTGATGACATTGTTTCAAATGATAACAAACTGAATAATGAGTACCTCGAGTTG
AACTACAAAGAAGATGAATACTTCGAGAACATAATTCAAAATTTGAAATTCAGCCAAAGT
AAACAACTGAAGAAGCTCCGAGAAAAGGTGGACAAAGATGAGTGGATAAGTGGAGCAGCT
GTAGTCAATGCATTTTACTCTTCAGGAAGAAATCAGATAGTCTTCCCAGCCGGCATTCTG
CAGCCCCCCTTCTTTAGTGCCCAGCAGTCCAACTCATTGAACTATGGGGGCATCGGCATG
GTCATAGGACACGAAATCACCCATGGCTTCGATGACAATGGCAGAAACTTTAACAAAGAT
GGAGACCTCGTTGACTGGTGGACTCAACAGTCTGCAAGTAACTTTAAGGAGCAATCCCAG
TGCATGGTGTATCAGTATGGAAACTTTTCCTGGGACCTGGCAGGTGGACAGCACCTTAAT
GGAATTAATACACTGGGAGAAAACATTGCTGATAATGGAGGTCTTGGTCAAGCATACAGA
GCCTATCAGAATTATATTAAAAAGAATGGCGAAGAAAAATTACTTCCTGGACTTGACCTA
AATCACAAACAACTATTTTTCTTGAACTTTGCACAGGTGTGGTGTGGAACCTATAGGCCA
GAGTATGCGGTTAACTCCATTAAAACAGATGTGCACAGTCCAGGCAATTTCAGGATTATT
GGGACTTTGCAGAACTCTGCAGAGTTTTCAGAAGCCTTTCACTGCCGCAAGAATTCATAC
ATGAATCCAGAAAAGAAGTGCCGGGTTTGGTGA
Chromosome Location
3
Locus
3q25.2
External Identifiers
ResourceLink
UniProtKB IDP08473
UniProtKB Entry NameNEP_HUMAN
GenBank Protein ID34758
GenBank Gene IDX07166
GeneCard IDMME
GenAtlas IDMME
HGNC IDHGNC:7154
PDB ID(s)1DMT, 1R1H, 1R1I, 1R1J, 1Y8J, 2QPJ, 2YB9, 4CTH, 5JMY, 6GID, 6SH1, 6SH2, 6SUK, 6SVY, 6THP, 6XVP
KEGG IDhsa:4311
IUPHAR/Guide To Pharmacology ID1611
NCBI Gene ID4311
General References
  1. Letarte M, Vera S, Tran R, Addis JB, Onizuka RJ, Quackenbush EJ, Jongeneel CV, McInnes RR: Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J Exp Med. 1988 Oct 1;168(4):1247-53. [Article]
  2. Shipp MA, Richardson NE, Sayre PH, Brown NR, Masteller EL, Clayton LK, Ritz J, Reinherz EL: Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4819-23. [Article]
  3. D'Adamio L, Shipp MA, Masteller EL, Reinherz EL: Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5' untranslated regions. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7103-7. [Article]
  4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  6. Malfroy B, Kuang WJ, Seeburg PH, Mason AJ, Schofield PR: Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase). FEBS Lett. 1988 Feb 29;229(1):206-10. [Article]
  7. Vanneste Y, Michel A, Dimaline R, Najdovski T, Deschodt-Lanckman M: Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site. Biochem J. 1988 Sep 1;254(2):531-7. [Article]
  8. Yandle TG, Brennan SO, Espiner EA, Nicholls MG, Richards AM: Endopeptidase-24.11 in human plasma degrades atrial natriuretic factor (ANF) to ANF(99-105/106-126). Peptides. 1989 Jul-Aug;10(4):891-4. [Article]
  9. Le Moual H, Dion N, Roques BP, Crine P, Boileau G: Asp650 is crucial for catalytic activity of neutral endopeptidase 24-11. Eur J Biochem. 1994 Apr 1;221(1):475-80. [Article]
  10. Zhang H, Li XJ, Martin DB, Aebersold R: Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nat Biotechnol. 2003 Jun;21(6):660-6. Epub 2003 May 18. [Article]
  11. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM: Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004 Oct 1;383(Pt 1):45-51. [Article]
  12. Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, Rougeot C: Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17979-84. Epub 2006 Nov 13. [Article]
  13. Morisaki N, Moriwaki S, Sugiyama-Nakagiri Y, Haketa K, Takema Y, Imokawa G: Neprilysin is identical to skin fibroblast elastase: its role in skin aging and UV responses. J Biol Chem. 2010 Dec 17;285(51):39819-27. doi: 10.1074/jbc.M110.161547. Epub 2010 Sep 28. [Article]
  14. Zheng R, Horiguchi A, Iida K, Lee J, Shen R, Goodman OB Jr, Nanus DM: Neutral endopeptidase is a myristoylated protein. Mol Cell Biochem. 2010 Feb;335(1-2):173-80. doi: 10.1007/s11010-009-0253-8. Epub 2009 Sep 15. [Article]
  15. Sato B, Katagiri YU, Iijima K, Yamada H, Ito S, Kawasaki N, Okita H, Fujimoto J, Kiyokawa N: The human CD10 lacking an N-glycan at Asn(628) is deficient in surface expression and neutral endopeptidase activity. Biochim Biophys Acta. 2012 Nov;1820(11):1715-23. doi: 10.1016/j.bbagen.2012.06.017. Epub 2012 Jul 3. [Article]
  16. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [Article]
  17. Oefner C, D'Arcy A, Hennig M, Winkler FK, Dale GE: Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon. J Mol Biol. 2000 Feb 18;296(2):341-9. [Article]
  18. Oefner C, Roques BP, Fournie-Zaluski MC, Dale GE: Structural analysis of neprilysin with various specific and potent inhibitors. Acta Crystallogr D Biol Crystallogr. 2004 Feb;60(Pt 2):392-6. Epub 2004 Jan 23. [Article]
  19. Oefner C, Pierau S, Schulz H, Dale GE: Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV. Acta Crystallogr D Biol Crystallogr. 2007 Sep;63(Pt 9):975-81. Epub 2007 Aug 17. [Article]

Associated Data

Bio-Entities
Bio-EntityType
Neprilysin (Humans)protein
primary
Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
CandoxatrilexperimentalyestargetinhibitorDetails
OmapatrilatinvestigationalyestargetmodulatorDetails
N-[3-[(1-Aminoethyl)(Hydroxy)Phosphoryl]-2-(1,1'-Biphenyl-4-Ylmethyl)Propanoyl]AlanineexperimentalunknowntargetDetails
PhosphoramidonexperimentalyestargetinhibitorDetails
N-(3-Phenyl-2-Sulfanylpropanoyl)PhenylalanylalanineexperimentalunknowntargetDetails
[2(R,S)-2-Sulfanylheptanoyl]-Phe-AlaexperimentalyestargetinhibitorDetails
DaglutrilinvestigationalyestargetmodulatorDetails
2-[(1S)-1-BENZYL-2-SULFANYLETHYL]-1H-IMIDAZO[4,5-C]PYRIDIN-5-IUMexperimentalunknowntargetDetails
ThiorphanexperimentalyestargetinhibitorDetails
LiraglutideapprovedunknownenzymesubstrateDetails
SacubitrilapprovedyestargetantagonistinhibitorDetails
CandoxatrilatexperimentalyestargetinhibitorDetails
Semaglutideapproved, investigationalnoenzymesubstrateDetails
SacubitrilatexperimentalyestargetinhibitorDetails
IlepatrilinvestigationalyestargetmodulatorDetails
GallopamilinvestigationalyestargetinhibitorDetails
SLV-334investigationalyestargetmodulatorDetails