Neprilysin

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Membrane metallo-endopeptidase
Neprilysin 1r1h.png
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 Ortholog search: PDBe, RCSB
Identifiers
Symbols MME ; CALLA; CD10; NEP; SFE
External IDs OMIM120520 MGI97004 HomoloGene5275 ChEMBL: 1944 GeneCards: MME Gene
EC number 3.4.24.11
RNA expression pattern
PBB GE MME 203434 s at tn.png
PBB GE MME 203435 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4311 17380
Ensembl ENSG00000196549 ENSMUSG00000027820
UniProt P08473 Q61391
RefSeq (mRNA) NM_000902 NM_001289462
RefSeq (protein) NP_000893 NP_001276391
Location (UCSC) Chr 3:
154.74 – 154.9 Mb
Chr 3:
63.3 – 63.38 Mb
PubMed search [1] [2]

Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) 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.[1] It also degrades 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.

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.[1]

Hematopoetic Progenitors expressing CD10 are considered "Common Lymphoid Progenitors," which means they can differentiate into T, B or Natural Killer cells.[2] 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.[3] Hematologic diseases in which it is positive include ALL, angioimmunoblastic T cell lymphoma, Burkitt lymphoma, CML 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 AML, CLL, 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.[4]

Amyloid beta regulation[edit]

Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,[5] 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,[6] 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.[7] 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.[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[edit]

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.[10][11]

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[edit]

Immunochemistry[edit]

CD10 is used in clinical pathology for diagnostic purpose.

In lymphomas and leukemias[edit]

  • 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+ DLBLC)[15]
    • Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,[16][17] but CD10+, BCL2+ tumors could have poorer survival.[18] For some authors, CD10 expression in DLBCL does not influence survival.[19]
  • Angioimmunoblastic T cell lymphoma (AITL) are CD10+[20][21] and distinguishes AITL from other T cell lymphomas (CD10)[22]
    • Some benign T cells can be CD10+[23]

In epithelial tumors[edit]

  • Clear cell renal cell carcinoma (Clear cell RCC)
    • CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10-.[24]
  • Urothelial tumors express CD10 (42-67%).[28]
    • 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.[29]

In other tumors[edit]

See also[edit]

References[edit]

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  2. ^ Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. http://www.ncbi.nlm.nih.gov/pubmed/7584137
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External links[edit]

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