Neprilysin: Difference between revisions
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|Name=membrane metallo-endopeptidase | |Name=membrane metallo-endopeptidase | ||
Revision as of 14:14, 17 August 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
| membrane metallo-endopeptidase | |
|---|---|
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| Identifiers | |
| Symbol | MME |
| Entrez | 4311 |
| HUGO | 7154 |
| OMIM | 120520 |
| RefSeq | NM_000902 |
| UniProt | P08473 |
| Other data | |
| EC number | 3.4.24.11 |
| Locus | Chr. 3 q21-q27 |
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Overview
Neprilysin, also known as 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 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
Fluid balance
Neprilysin is highly expressed in kidney and lung tissues. Inhibitors are natriuretic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as endothelin, and atrial natriuretic factor.[8][9]
Randomized control trials have found that sacubitril, a neprilysin inhibitor that increases levels of natriuretic peptides, can reduce death and of hospitalization for heart failure. [10]
Pain
Neprilysin inhibitors have been designed with analgesic properties that inhibit neprilysin's activity against signaling peptides such as enkephalins and substance P.[8][9]
Tumor growth
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;[11] 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.[12]
References
- ↑ Pardossi-Piquard, R. (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Helisalmi, S coauthors= 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. PMID 15548496. Retrieved 2007-03-11.
- ↑ Madan, Rime (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Iwata, Nobuhisa (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Iwata, Nobuhisa (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Hama, Emi (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. Unknown parameter
|coauthors=ignored (help) - ↑ Wang, Deng-Shun (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ 8.0 8.1 Sahli, Stefan B (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. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ 9.0 9.1 Oefner, C. (2004). "Structural analysis of neprilysin with various specific and potent inhibitors". Acta Crystallographica Section D Biological Crystallography. 60, prt 2: 392–396. doi:10.1107/S0907444903027410. PMID 14747736. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR; et al. (2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". N Engl J Med. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015. Review in: Ann Intern Med. 2015 Feb 17;162(4):JC2 Review in: Evid Based Med. 2015 Apr;20(2):61
- ↑ Velasquez, Elsa F. (2007). "Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma". Journal of Translational Medicine. 5 (2). doi:10.1186/1479-5876-5-2. PMID 17207277. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Cohen, Andrea J. (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. Retrieved 2006-03-11. Unknown parameter
|month=ignored (help); Unknown parameter|coauthors=ignored (help)
External links
- Neprilysin at the US National Library of Medicine Medical Subject Headings (MeSH)