Neprilysin

Membrane metallo-endopeptidase
The structure of the neprilysin ectodomain in complex with a zinc-chelating inhibitor. The zinc atom is shown as a gray sphere and the inhibitor is shown in green. Rendering based on 1r1h.
Available structures PDB 1DL9, 1DMT, 1QVD, 1R1H, 1R1I, 1R1J, 1Y8J, 2QPJ
Identifiers
Symbols	MME; CALLA; CD10; DKFZp686O16152; MGC126681; MGC126707; NEP; SFE
External IDs	OMIM: 120520 MGI: 97004 HomoloGene: 5275 GeneCards: MME Gene
EC number	3.4.24.11
Gene Ontology Molecular function • metalloendopeptidase activity • protein binding • peptidase activity • metallopeptidase activity • zinc ion binding • peptide binding • metal ion binding Cellular component • membrane fraction • plasma membrane • integral to plasma membrane Biological process • proteolysis • peptide metabolic process • cell-cell signaling Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4311	17380
Ensembl	ENSG00000196549	ENSMUSG00000027820
UniProt	P08473	Q8BNU9
RefSeq (mRNA)	NM_000902.3	NM_008604.3
RefSeq (protein)	NP_000893.2	NP_032630.2
Location (UCSC)	Chr 3: 154.74 – 154.9 Mb	Chr 3: 63.1 – 63.19 Mb
PubMed search	[1]	[2]

Neprilysin, also known as membrane metallo-endopeptidase, neutral endopeptidase (NEP), CD10, and common acute lymphoblastic leukemia antigen (CALLA), is a zinc-dependent metalloprotease enzyme that degrades a number of small secreted peptides, most notably the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface. In neurons, neprilysin is regulated by the protein nicastrin, a component of the gamma secretase complex that performs a necessary step in processing amyloid precursor protein to amyloid beta.^[1]

Amyloid beta regulation

Mutations in the neprilysin gene have been associated with familial forms of Alzheimer's disease,^[2] and neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,^[3] providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation,^[4] it has been considered a potential therapeutic target; compounds such as the peptide hormone somatostatin have been identified that increase the enzyme's activity level.^[5] One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.^[6] Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.^[7]

Signaling peptides

Neprilysin immunohistochemical staining of normal kidney.

Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic factor.^[8][9]

Associations have been observed between neprilysin expression and various types of cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma and some advanced melanomas, neprilysin is overexpressed;^[10] in other types, most notably lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to bombesin.^[11] Some plant extracts extracts (methanol extracts of Ceropegia rupicola, Kniphofia sumarae, Plectranthus cf barbatus, and an aqueous extract of Pavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.^[12]

Inhibitors

• Omapatrilat
• RB-101
• UK-414,495

References

1. ^ Pardossi-Piquard, R.; Dunys J., Yu G., St George-Hyslop P., Alves da Costa C. and Checler F. (May 2006). "Neprilysin activity and expression are controlled by nicastrin". Journal of Neurochemistry 97 (4): 1052–6. doi:10.1111/j.1471-4159.2006.03822.x. PMID 16606360. 
2. ^ Helisalmi, S; M. Hiltunen, S. Vepsäläinen, S. Iivonen, A. Mannermaa, M. Lehtovirta, A. M. Koivisto, I. Alafuzoff and H. Soininen (2004). "Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients". Journal of Neurology Neurosurgery and Psychiatry 75 (12): 1746–8. doi:10.1136/jnnp.2004.036574. PMC 1738829. PMID 15548496. http://jnnp.bmj.com/cgi/content/full/75/12/1746. Retrieved 2007-03-11. 
3. ^ Madan, Rime; Raphael Poirier, David P. Wolfer, Hans Welzl, Peter Groscurth, Hans-Peter Lipp, Bao Lu, Mohammed El Mouedden, Marc Mercken, Roger M. Nitsch and M. Hasan Mohajeri (December 2006). "Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo". Journal of Neuroscience Research 84 (8): 1871–8. doi:10.1002/jnr.21074. PMID 16998901. 
4. ^ Iwata, Nobuhisa; Satoshi Tsubuki, Yoshie Takaki, Kaori Watanabe, Misaki Sekiguchi, Emi Hosoki, Maho Kawashima-Morishima, Hahn-Jun Lee, Emi Hama, Yoko Sekine-Aizawa and Takaomi C. Saido (February 2000). "Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition". Nature Medicine 6 (2): 143–50. doi:10.1038/72237. PMID 10655101. 
5. ^ Iwata, Nobuhisa; Makoto Higuchi and Takaomi C. Saido (November 2005). "Metabolism of amyloid-beta peptide and Alzheimer's disease". Pharmacology & Therapeutics 108 (2): 129–48. doi:10.1016/j.pharmthera.2005.03.010. PMID 16112736. 
6. ^ Hama, Emi; Takaomi C. Saido (2005). "Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide". Medical Hypotheses 65 (3): 498–500. doi:10.1016/j.mehy.2005.02.045. PMID 15921860. 
7. ^ Wang, Deng-Shun; Nobuhisa Iwata, Emi Hama, Takaomi C. Saido and Dennis W. Dickson (October 2003). "Oxidized neprilysin in aging and Alzheimer's disease brains". Biochemical and Biophysical Research Communications 310 (1): 236–41. doi:10.1016/j.bbrc.2003.09.003. PMID 14511676. 
8. ^ Sahli, Stefan; Bernhard Stump, Tobias Welti, W. Bernd Schweizer, François Diederich, Denise Blum-Kaelin, Johannes D. Aebi and Hans-Joachim Böhm (April 2005). "A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold". Helvetica Chimica Acta 88 (4): 707–730. doi:10.1002/hlca.200590050. 
9. ^ Oefner, C.; B. P. Roques, M.-C. Fournie-Zaluski and G. E. Dale (February 2004). "Structural analysis of neprilysin with various specific and potent inhibitors". Acta Crystallographica D 60 (Pt 2): 392–396. doi:10.1107/S0907444903027410. PMID 14747736. 
10. ^ Velasquez, Elsa F.; Molly Yancovitz, Anna Pavlick, Russell Berman, Richard Shapiro, Dusan Bogunovic, David O'Neill, Yi-Lo Yu, Joanna Spira, Paul J Christos, Xi Kathy Zhou, Madhu Mazumdar4, David M Nanus, Leonard Liebes, Nina Bhardwaj, David Polsky and Iman Osman (January 2007). "Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma". Journal of Translational Medicine 5 (2): 2. doi:10.1186/1479-5876-5-2. PMC 1770905. PMID 17207277. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1770905. 
11. ^ Cohen, Andrea J.; Paul A. Bunn, Wilbur Franklin, Catherine Magill-Solc, Christa Hartmann, Barbara Heifrich, Laura Gilman, Joy Folkvord, Karen Helm, and York E. Miller (15 February 1996). "Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux". Cancer Research 56 (4): 831–9. PMID 8631021. http://cancerres.aacrjournals.org/cgi/reprint/56/4/831. Retrieved 2006-03-11. 
12. ^ Alasbahi R, Melzig MF.,"Screening of some Yemeni medicinal plants for inhibitory activity against peptidases." Pharmazie. 2008 Jan;63(1):86-8

External links

• The MEROPS online database for peptidases and their inhibitors: M13.001
• MeSH Neprilysin