Function
Neprilysin (NEP), also known as neutral endopeptidase, is a Zn-dependent metalloprotease which degrades small secreted peptides like the beta-amyloid peptide, tachykinin, neurotensin and enkephalins.[1][2][3][4][5][6][7][8] NEP turns off peptide signaling events at the cell surface. NEP is found in brain tissue and is an integral membrane protein.
Relevance
NEP signaling has also been implicated in cardiovascular disease.[9] NEP level increases in Alzheimer's disease patients[10]. NEP inhibitors like Sacubitril and Sacubitril/valsartan are tested as analgesics and anti-hypertensive agents.
Structural highlights
A and is involved in the catalysis[11]. . Water molecules are shown as red spheres.
3D structures of neprilysin
Updated on 21-January-2024
6gid - hNEP extracellular domain 52-750 - human
6sh1 - hNEP extracellular domain (mutant)
6sh2 - hNEP extracellular domain (mutant) + natriuretic peptide
1dmt – hNEP extracellular domain + Zn + phosphoramidon
4cth - hNEP extracellular domain (mutant) + Zn + phosphoramidon
5jmy - hNEP extracellular domain + subitril
1r1h, 1r1i, 1r1j, 1y8j, 2qpj, 2yb9, 6suk, 6svy, 6thp, 6xvp - hNEP extracellular domain + Zn + inhibitor
2yvc – NEP cytoplasmic tail + radixin - mouse
4xbh - rNEP - rabbit
4zr5 - rNEP + phosphoramidon
5v48 - rNEP + thiorphan
References
- ↑ Skidgel RA, Erdos EG. Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. Peptides. 2004 Mar;25(3):521-5. PMID:15134871 doi:http://dx.doi.org/10.1016/j.peptides.2003.12.010
- ↑ Ouimet T. Neprilysin 2: a novel messenger peptide-inactivating metalloprotease. Protein Pept Lett. 2004 Oct;11(5):479-89. PMID:15544569
- ↑ Hui KS. Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration. Neurochem Res. 2007 Dec;32(12):2062-71. Epub 2007 May 3. PMID:17476590 doi:http://dx.doi.org/10.1007/s11064-007-9356-3
- ↑ Hersh LB, Rodgers DW. Neprilysin and amyloid beta peptide degradation. Curr Alzheimer Res. 2008 Apr;5(2):225-31. PMID:18393807
- ↑ Malito E, Hulse RE, Tang WJ. Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin. Cell Mol Life Sci. 2008 Aug;65(16):2574-85. doi: 10.1007/s00018-008-8112-4. PMID:18470479 doi:http://dx.doi.org/10.1007/s00018-008-8112-4
- ↑ Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 2013 Jun 27;587(13):2046-54. doi: 10.1016/j.febslet.2013.05.010. Epub , 2013 May 16. PMID:23684647 doi:http://dx.doi.org/10.1016/j.febslet.2013.05.010
- ↑ Saido TC. Metabolism of amyloid beta peptide and pathogenesis of Alzheimer's disease. Proc Jpn Acad Ser B Phys Biol Sci. 2013;89(7):321-39. PMID:23883611
- ↑ Grimm MO, Mett J, Stahlmann CP, Haupenthal VJ, Zimmer VC, Hartmann T. Neprilysin and Abeta Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease. Front Aging Neurosci. 2013 Dec 23;5:98. doi: 10.3389/fnagi.2013.00098. PMID:24391587 doi:http://dx.doi.org/10.3389/fnagi.2013.00098
- ↑ Segura J, Ruilope LM. Dual-acting angiotensin receptor-neprilysin inhibition. Curr Hypertens Rep. 2011 Feb;13(1):74-8. doi: 10.1007/s11906-010-0166-7. PMID:21046489 doi:http://dx.doi.org/10.1007/s11906-010-0166-7
- ↑ Miners JS, Baig S, Tayler H, Kehoe PG, Love S. Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. J Neuropathol Exp Neurol. 2009 Aug;68(8):902-14. doi:, 10.1097/NEN.0b013e3181afe475. PMID:19606063 doi:http://dx.doi.org/10.1097/NEN.0b013e3181afe475
- ↑ 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. PMID:10669592 doi:10.1006/jmbi.1999.3492
