Neprilysin (/ˌnɛprɪˈlaɪsɪn/; also known asmembrane metallo-endopeptidase (MME),neutral endopeptidase (NEP),cluster of differentiation 10 (CD10) andcommon acute lymphoblastic leukemia antigen (CALLA)) is anenzyme that in humans is encoded by theMME gene. Neprilysin is azinc-dependentmetalloprotease that cleavespeptides at the amino side of hydrophobic residues and inactivates several peptide hormones includingglucagon,enkephalins,substance P,neurotensin,oxytocin, andbradykinin.[5] It also degrades theamyloid beta peptide whose abnormalfolding and aggregation inneural tissue has been implicated as a cause ofAlzheimer's disease. Synthesized as amembrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from theGolgi apparatus to the cell surface.
Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a commonacute 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.[5]
Neprilysin-deficientknockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,[9] providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be therate-limiting step in amyloid beta degradation,[10] it has been considered a potential therapeutic target; compounds such as thepeptide hormonesomatostatin have been identified that increase the enzyme's activity level.[11] Declining neprilysin activity with increasing age may also be explained byoxidative 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.[12]
Associations have been observed between neprilysin expression and various types ofcancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancerbiomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such asmetastaticcarcinoma and some advancedmelanomas, neprilysin is overexpressed;[15] in other types, most notablylung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growthautocrine signaling of cancer cells via secreted peptides such as mammalianhomologs related tobombesin.[16]Some plant extracts (methanol extracts ofCeropegia rupicola,Kniphofia sumarae,Plectranthus cf barbatus, and an aqueous extract ofPavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.[17]
CD10+ diffuse large B cell lymphoma (CD10+ DLBCL)[20]
Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,[21][22] but CD10+,BCL2+tumors could have poorer survival.[23] For some authors, CD10 expression in DLBCL does not influence survival.[24]
CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.[29]
CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.[34]
^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.PMID16998901.S2CID46527377.
^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.PMID10655101.S2CID22431826.
^abOefner C, Roques BP, Fournie-Zaluski MC, Dale GE (February 2004). "Structural analysis of neprilysin with various specific and potent inhibitors".Acta Crystallogr. D.60 (Pt 2):392–6.doi:10.1107/S0907444903027410.PMID14747736.
^Alasbahi R, Melzig MF (January 2008). "Screening of some Yemeni medicinal plants for inhibitory activity against peptidases".Pharmazie.63 (1):86–8.doi:10.1055/s-2008-1047849.PMID18271311.
^Venugopal J (2003). "Pharmacological modulation of the natriuretic peptide system".Expert Opinion on Therapeutic Patents.13 (9):1389–1409.doi:10.1517/13543776.13.9.1389.S2CID85007768.
^Fabiani B, Delmer A, Lepage E, Guettier C, Petrella T, Brière J, et al. (2004). "CD10 expression in diffuse large B-cell lymphomas does not influence survival".Virchows Arch.445 (6):545–51.doi:10.1007/s00428-004-1129-7.PMID15517363.S2CID23189608.
^Yuan CM, Vergilio JA, Zhao XF, Smith TK, Harris NL, Bagg A (2005). "CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10+ T cells by flow cytometry".Hum. Pathol.36 (7):784–91.doi:10.1016/j.humpath.2005.05.008.PMID16084948.
^Attygalle AD, Diss TC, Munson P, Isaacson PG, Du MQ, Dogan A (2004). "CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma".Am. J. Surg. Pathol.28 (1):54–61.doi:10.1097/00000478-200401000-00005.PMID14707864.S2CID25639416.
^Yasir S, Herrera L, Gomez-Fernandez C, Reis IM, Umar S, Leveillee R, et al. (2012). "CD10+ and CK7/RON- immunophenotype distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers".Appl. Immunohistochem. Mol. Morphol.20 (5):454–61.doi:10.1097/PAI.0b013e31823fecd3.PMID22417859.S2CID1348915.
^abNotohara K, Hamazaki S, Tsukayama C, Nakamoto S, Kawabata K, Mizobuchi K, et al. (2000). "Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10".Am. J. Surg. Pathol.24 (10):1361–71.doi:10.1097/00000478-200010000-00005.PMID11023097.S2CID3211829.
^Córdoba A, Guerrero D, Larrinaga B, Iglesias ME, Arrechea MA, Yanguas JI (2009). "Bcl-2 and CD10 expression in the differential diagnosis of trichoblastoma, basal cell carcinoma, and basal cell carcinoma with follicular differentiation".Int. J. Dermatol.48 (7):713–7.doi:10.1111/j.1365-4632.2009.04076.x.PMID19570076.S2CID205395744.
^Weinreb I, Cunningham KS, Perez-Ordoñez B, Hwang DM (2009). "CD10 is expressed in most epithelioid hemangioendotheliomas: a potential diagnostic pitfall".Arch. Pathol. Lab. Med.133 (12):1965–8.doi:10.5858/133.12.1965.PMID19961253.
![1y8j: Crystal Structure of human NEP complexed with an imidazo[4,5-c]pyridine inhibitor](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aPDB_1y8j_EBI.jpg)
