Neprilysin
Zinc metalloprotease inactivating peptide hormones and degrading amyloid beta.
Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), CD10, and common acute lymphoblastic leukemia antigen (CALLA), is a zinc-dependent metalloprotease encoded by the MME gene. It cleaves peptides at the amino side of hydrophobic residues, inactivating several peptide hormones and degrading the amyloid beta peptide. The protein is a key cell surface marker for diagnosing human acute lymphocytic leukemia (ALL), particularly in pre-B phenotype cases.
Quick Facts
- Gene
- MME
- Also known as
- MME
- NEP
- CD10
- CALLA
- Enzyme type
- Zinc-dependent metalloprotease
- Substrates inactivated
- Glucagon
- enkephalins
- substance P
- neurotensin
- oxytocin
- bradykinin
- Expression in all
- Present on leukemic cells of pre-B phenotype (85% of ALL cases)
Facts from the source article.
Amyloid beta regulation
Neprilysin-deficient knockout mice exhibit Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain, supporting the protein's role in Alzheimer's disease. Neprilysin is considered the rate-limiting step in amyloid beta degradation, making it a potential therapeutic target; somatostatin can increase its activity. Declining neprilysin activity with age may result from oxidative damage, and higher levels of oxidized neprilysin are found in Alzheimer's patients compared to cognitively normal elderly individuals.
Signaling peptides
Neprilysin is highly expressed in kidney and lung tissues. Inhibitors have been developed as potential analgesic and antihypertensive agents by blocking neprilysin's activity on signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic peptide. In cancer, neprilysin expression varies: it is overexpressed in metastatic carcinoma and some advanced melanomas, but downregulated in lung cancers, where it cannot modulate pro-growth autocrine signaling via secreted peptides like bombesin homologs. Some plant extracts, including methanol extracts of Ceropegia rupicola, Kniphofia sumarae, and Plectranthus cf barbatus, and an aqueous extract of Pavetta longiflora, inhibit neutral endopeptidase activity.
Inhibitors
Inhibitors of neprilysin have been designed for analgesic and antihypertensive purposes, and some target heart failure. Sacubitril/valsartan (Entresto/LCZ696) has been tested against enalapril in heart failure patients. Sacubitril (AHU-377) is a prodrug component of sacubitril/valsartan, and its active form is sacubitrilat (LBQ657). Other inhibitors include RB-101, UK-414,495, omapatrilat (a dual NEP and ACE inhibitor not FDA-approved due to angioedema), ecadotril, and candoxatril.
Immunochemistry
CD10 is used in clinical pathology for diagnosis. Acute lymphoblastic leukemia (ALL) cells are CD10+. Follicular lymphoma and Burkitt lymphoma cells are CD10+. CD10+ diffuse large B cell lymphoma (DLBCL) is a marker for germinal center phenotype, considered a favorable prognostic factor, though CD10+, BCL2+ tumors may have poorer survival; some authors report CD10 expression in DLBCL does not influence survival. Angioimmunoblastic T cell lymphoma (AITL) is CD10+, distinguishing it from other T cell lymphomas. Clear cell renal cell carcinoma is CD10+, helping distinguish it from chromophobe carcinoma and oncocytoma (CD10−). In pancreatic tumors, solid pseudopapillary tumors are CD10+, and CD10 differentiates mucinous cystic neoplasms (CD10+/CK20+) from intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20−). In cutaneous tumors, CD10 staining patterns differentiate basal cell carcinoma, trichoblastoma, and squamous cell carcinoma. CD10 differentiates atypical fibroxanthoma (CD10+) from spindle cell melanoma and sarcomatoid squamous cell carcinoma (CD10−). Urothelial tumors express CD10 in 42–67% of cases, with strong correlation to high tumor grade and stage. Endometrial stromal sarcoma is CD10+, while smooth muscle tumors are usually CD10−. Epithelioid hemangioendothelioma is mostly CD10+, whereas hemangioblastoma is usually CD10−.
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