Neprilysin II: A Putative Novel Metalloprotease and Its Isoforms in CNS and Testis

Ouimet, Tanja; Facchinetti, Patricia; Rose, Christiane; Bonhomme, Marie-Chantal; Gros, Claude P.; Schwartz, Jean‐Charles

doi:10.1006/bbrc.2000.3262

Cited by 4 publications

(8 citation statements)

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“…Another NEP homologue termed soluble secreted endopeptidase (SEP), because it can exist both in a membrane-bound form and a secreted or shed form, has recently been cloned and characterized from ECE-1 knockout mouse embryos (53) and similar activities have subsequently been cloned and characterized from mouse testis (referred to as neprilysin-like 1; NL1) (54) and from rat brain (NEPII). (55) The enzyme most closely resembled NEP in its specificity and was inhibited both by phosphoramidon and thiorphan. (53,54) As yet, little is known of its localization or possible physiological roles.…”

Section: Endothelin Converting Enzyme (Ece)mentioning

confidence: 90%

“…Its presence in testis and brain, however, suggests roles in fertility and neuropeptide inactivation, respectively, particularly since it appears to localize to specific neuronal populations in the CNS. (55) Quite distinct chromosomal locations are seen for the genes encoding the human NEP-like enzymes. NEP, KELL, PEX, ECE-1 and XCE (ECEL1) are found at positions 3q25, 7q33, Xp22, 1p36 and 2q36-37, respectively, implying that the gene duplications are ancient.…”

Section: Endothelin Converting Enzyme (Ece)mentioning

confidence: 99%

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The neprilysin (NEP) family of zinc metalloendopeptidases: Genomics and function

2001

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Neprilysin (NEP), a thermolysin-like zinc metalloendopeptidase, plays an important role in turning off peptide signalling events at the cell surface. It is involved in the metabolism of a number of regulatory peptides of the mammalian nervous, cardiovascular, inflammatory and immune systems. Examples include enkephalins, tachykinins, natriuretic and chemotactic peptides. NEP is an integral plasma membrane ectopeptidase of the M13 family of zinc peptidases. Other related mammalian NEP-like enzymes include the endothelin-converting enzymes (ECE-1 and ECE-2), KELL and PEX. A number of novel mammalian homologues of NEP have also recently been described. NEP family members are potential therapeutic targets, for example in cardiovascular and inflammatory disorders, and potent and selective inhibitors such as phosphoramidon have contributed to understanding enzyme function. Inhibitor design should be facilitated by the recent three-dimensional structural solution of the NEP-phosphoramidon complex. For several of the family members, however, a well-defined physiological function or substrate is lacking. Knowledge of the complete genomes of Caenorhabditis elegans and Drosophila melanogaster allows the full complement of NEP-like activities to be analysed in a single organism. These model organisms also provide convenient systems for examining cell-specific expression, developmental and functional roles of this peptidase family, and reveal the power of functional genomics.

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Section: Endothelin Converting Enzyme (Ece)mentioning

confidence: 90%

Section: Endothelin Converting Enzyme (Ece)mentioning

confidence: 99%

The neprilysin (NEP) family of zinc metalloendopeptidases: Genomics and function

2001

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“…ECE-2 is most abundant in the nervous system. Other mammalian NEP homologues expressed in brain include: (i) the phosphoramidon-and thiorphan-sensitive Ôsoluble secreted endopeptidaseÕ (SEP) (Ikeda et al 1999) or Ôneprilysin-like 1Õ (NL1) (Ghaddar et al 2000) from mouse (of which the human and rat orthologues have been termed MMEL2 and NEP II, respectively) (Tanja et al 2000;Bonvouloir et al 2001), and (ii) the human orphan peptidase ÔECE-like 1Õ (ECEL1) (previously known as X-converting enzyme; XCE), critical for the neural control of respiration (Schweizer et al 1999;Valdenaire et al 2000) and separately identified in rat as Ôdamage-induced neuronal endopeptidaseÕ (DINE) . The recently discovered NEP homologues are all enzymes in search of a function.…”

mentioning

confidence: 99%

β‐Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases?

Carson

Turner

2002

Journal of Neurochemistry

245

153

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The steady-state level of amyloid b-peptide (Ab) represents a balance between its biosynthesis from the amyloid precursor protein (APP) through the action of the b-and c-secretases and its catabolism by a variety of proteolytic enzymes. Recent attention has focused on members of the neprilysin (NEP) family of zinc metalloproteinases in amyloid metabolism. NEP itself degrades both Ab 1)40 and Ab 1)42 in vitro and in vivo, and this metabolism is prevented by NEP inhibitors. Other NEP family members, for example endothelin-converting enzyme, may contribute to amyloid catabolism and may also play a role in neuroprotection. Another metalloproteinase, insulysin (insulin-degrading enzyme) has also been advocated as an amyloid-degrading enzyme and may contribute more generally to metabolism of amyloid-forming peptides. Other candidate enzymes proposed include angiotensin-converting enzyme, some matrix metalloproteinases, plasmin and, indirectly, thimet oligopeptidase (endopeptidase-24.15). This review critically evaluates the evidence relating to proteinases implicated in amyloid catabolism. Therapeutic strategies aimed at promoting Ab degradation may provide a novel approach to the therapy of Alzheimer's disease.

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“…The NEP homologues, ECE-1 and ECE-2, appear to have a more restricted role in the proteolytic processing of some prohormones, particularly the endothelin precursor 'big endothelin' [1]. Previously, it has been shown that one of the NEP family members, known as either SEP (secreted endopeptidase) or NL1 (neprilysin-like 1) in mouse [6,7], NEP2 in rat [8] and MMEL2 (membrane metallo-endopeptidase-like 2) in human [9], can exist both as a membranebound form and as a soluble secreted protein. SEP and its homologues are strongly expressed in mammalian testes [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, it has been shown that one of the NEP family members, known as either SEP (secreted endopeptidase) or NL1 (neprilysin-like 1) in mouse [6,7], NEP2 in rat [8] and MMEL2 (membrane metallo-endopeptidase-like 2) in human [9], can exist both as a membranebound form and as a soluble secreted protein. SEP and its homologues are strongly expressed in mammalian testes [6][7][8][9]. The fact that all other mammalian NEP/ECE proteins are strictly Abbreviations used: ECE, endothelin-converting enzyme; EST, expressed sequence tag; LomTK, locustatachykinin; MMEL2, membrane metalloendopeptidase-like 2; NEP, neprilysin; NL1, neprilysin-like 1; PTr, 0.5 % Triton X-100 in PBS; PTrN, 5 % normal goat serum in 0.5 % Triton X-100/PBS; PTw, 0.1 % Tween 20 in PBS; ECE-i, 4-chloro-N-[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl benzene sulphonamide, monosodium salt; SEP, secreted endopeptidase.…”

Section: Introductionmentioning

confidence: 99%

Drosophila melanogaster NEP2 is a new soluble member of the neprilysin family of endopeptidases with implications for reproduction and renal function

Thomas

Rylett

Çarhan

et al. 2005

Biochemical Journal

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The mammalian neprilysin (NEP) family members are typically type II membrane endopeptidases responsible for the activation/inactivation of neuropeptides and peptide hormones. Differences in substrate specificity and subcellular localization of the seven mammalian NEPs contribute to their functional diversity. The sequencing of the Drosophila melanogaster genome has revealed a large expansion of this gene family, resulting in over 20 fly NEP-like genes, suggesting even greater diversity in structure and function than seen in mammals. We now report that one of these genes (Nep2) codes for a secreted endopeptidase with a highly restricted pattern of expression. D. melanogaster NEP2 is expressed in the specialized stellate cells of the renal tubules and in the cyst cells that surround the elongating spermatid bundles in adult testis, suggesting roles for the peptidase in renal function and in spermatogenesis. D. melanogaster NEP2 was found in vesicle-like structures in the syncytial cytoplasm of the spermatid bundles, suggesting that the protein was acquired by endocytosis of protein secreted from the cyst cells. Expression of NEP2 cDNA in D. melanogaster S2 cells confirmed that the peptidase is secreted and is only weakly inhibited by thiorphan, a potent inhibitor of human NEP. D. melanogaster NEP2 also differs from human NEP in the manner in which the peptidase cleaves the tachykinin, GPSGFYGVR-amide. Molecular modelling suggests that there are important structural differences between D. melanogaster NEP2 and human NEP in the S1' and S2' ligand-binding subsites, which might explain the observed differences in inhibitor and substrate specificities. A soluble isoform of a mouse NEP-like peptidase is strongly expressed in spermatids, suggesting an evolutionarily conserved role for a soluble endopeptidase in spermatogenesis.

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Neprilysin II: A Putative Novel Metalloprotease and Its Isoforms in CNS and Testis

Cited by 4 publications

References 0 publications

The neprilysin (NEP) family of zinc metalloendopeptidases: Genomics and function

The neprilysin (NEP) family of zinc metalloendopeptidases: Genomics and function

β‐Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases?

Drosophila melanogaster NEP2 is a new soluble member of the neprilysin family of endopeptidases with implications for reproduction and renal function

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