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Neprilysin
Mammalian protein found in Homo sapiens

Neprilysin is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. It also degrades the amyloid beta peptide whose abnormal folding 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.

Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.

Hematopoietic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells. CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node germinal centers. Hematologic diseases in which it is positive include ALL, angioimmunoblastic T cell lymphoma, Burkitt lymphoma, chronic myelogenous leukemia in blast crisis (90%), diffuse large B-cell lymphoma (variable), follicular center cells (70%), hairy cell leukemia (10%), and myeloma (some). It tends to be negative in acute myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.

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Amyloid beta regulation

Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,6 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,7 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.8 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.9

Signaling peptides

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 peptide.1011

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;12 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.13 Some plant 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.14

Inhibitors

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 peptide.1516

Some are intended to treat heart failure.17

Other dual inhibitors of NEP with ACE/angiotensin receptor were (in 2003) being developed by pharmaceutical companies.19

Immunochemistry

CD10 is used in clinical pathology for diagnostic purpose.

In lymphomas and leukemias

  • Acute lymphoblastic leukemia (ALL) cells are CD10+.
  • Follicular lymphoma (follicle centre cell lymphoma) are CD10+.
  • Burkitt Lymphoma cells are CD10+.
  • CD10+ diffuse large B cell lymphoma (CD10+ DLBCL)20
    • Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,2122 but CD10+, BCL2+ tumors could have poorer survival.23 For some authors, CD10 expression in DLBCL does not influence survival.24
  • Angioimmunoblastic T cell lymphoma (AITL) are CD10+2526 and distinguishes AITL from other T cell lymphomas (CD10−)27
    • Some benign T cells can be CD10+28

In epithelial tumors

In other tumors

See also

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

References

  1. "Entrez Gene: Membrane metallo-endopeptidase". https://www.ncbi.nlm.nih.gov/gene/4311 ↩

  2. "Entrez Gene: Membrane metallo-endopeptidase". https://www.ncbi.nlm.nih.gov/gene/4311 ↩

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  6. Madani R, Poirier R, Wolfer DP, Welzl H, Groscurth P, Lipp HP, et al. (December 2006). "Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo". J. Neurosci. Res. 84 (8): 1871–8. doi:10.1002/jnr.21074. PMID 16998901. S2CID 46527377. /wiki/Doi_(identifier) ↩

  7. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, et al. (February 2000). "Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition". Nat. Med. 6 (2): 143–50. doi:10.1038/72237. PMID 10655101. S2CID 22431826. /wiki/Doi_(identifier) ↩

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  9. Wang DS, Iwata N, Hama E, Saido TC, Dickson DW (October 2003). "Oxidized neprilysin in aging and Alzheimer's disease brains". Biochem. Biophys. Res. Commun. 310 (1): 236–41. doi:10.1016/j.bbrc.2003.09.003. PMID 14511676. /wiki/Doi_(identifier) ↩

  10. Sahli S, Stump B, Welti T, Schweizer WB, Diederich R, Blum-Kaelin D, et al. (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. https://doi.org/10.1002%2Fhlca.200590050 ↩

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  13. Cohen AJ, Bunn PA, Franklin W, Magill-Solc C, Hartmann C, Helfrich B, et al. (February 1996). "Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux". Cancer Res. 56 (4): 831–9. PMID 8631021. http://cancerres.aacrjournals.org/cgi/reprint/56/4/831 ↩

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  15. Sahli S, Stump B, Welti T, Schweizer WB, Diederich R, Blum-Kaelin D, et al. (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. https://doi.org/10.1002%2Fhlca.200590050 ↩

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  17. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. (Sep 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. hdl:10993/27659. PMID 25176015. S2CID 11383. http://www.hirsla.lsh.is/lsh/handle/2336/552372 ↩

  18. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. (Sep 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. hdl:10993/27659. PMID 25176015. S2CID 11383. http://www.hirsla.lsh.is/lsh/handle/2336/552372 ↩

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