[17] Inhibitors of neprilysin: Design, pharmacological and clinical applications

Roques, Bernárd P.; Noble, Florence; Crine, Philippe; Fournié‐Zaluski, Marie‐Claude

doi:10.1016/0076-6879(95)48019-6

Cited by 24 publications

(14 citation statements)

References 90 publications

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“…11 In NEP, His584, His588, and Glu647 are coordinating ligands for zinc. 5,7 In Kell, Glu634 is expected to play a similar role. A Kell Glu634Asp mutant, which has a shorter side chain than the wild-type, retained nearly 60% of its enzyme activity indicating structural flexibility in this region, but activity was completely lost when glutamic acid was substituted with glycine ( Figure 3).…”

Section: Site-directed Mutagenesis Of Essential Amino Acid Residuesmentioning

confidence: 99%

“…Three motifs are conserved in all zinc endopeptidases including bacterial thermolysin and are part of the active site of the M13 family (for reviews, see Roques et al 5,7 ). A ClustalX sequence alignment of NEP and Kell matches the M13 consensus motifs, HExxH, ExxxD, and NAararS where "x" is any amino acid and "ar" indicates aromatic amino acids.…”

Section: Alignment Of Catalytic Active Sitesmentioning

confidence: 99%

“…3 As a group the mammalian M13 peptidases are involved in the activation of bioactive peptides by specific cleavages of larger inactive peptides and in the proteolysis of bioactive peptides. [4][5][6] The substrate specificities of the M13 family members vary with neutral endopeptidase (NEP; EC 3.4.24.11) 7 and secreted endopeptidase (SEP) 8 having a wide range of substrates and endothelinconverting enzyme 1 (ECE-1; EC 3.4.24.71), endothelin-converting enzyme 2 (ECE-2), 9,10 Kell, 11 and phosphate-regulating protein (PHEX) 12,13 with a restricted number of substrates. ECE-1 and ECE-2 preferentially cleave big endothelin-1-releasing endothelin-1 (ET-1) but can also cleave big endothelin-2 and big endothelin-3.…”

Section: Introductionmentioning

confidence: 99%

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Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11

Lee

Debnath

Redman

2003

Blood

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In addition to its importance in transfusion, Kell protein is a member of the M13 family of zinc endopeptidases and functions as an endothelin-3-converting enzyme. To obtain information on the structure of Kell protein we built a model based on the crystal structure of the ectodomain of neutral endopeptidase 24.11 (NEP). Similar to NEP, the Kell protein has 2 globular domains consisting mostly of ␣-helical segments. The domain situated closest to the membrane contains both the N-and C-terminal sequences and the enzyme-active site. The outer domain contains all of the amino acids whose substitutions lead to different Kell blood group phenotypes. In the model, the zinc peptidase inhibitor, phosphoramidon, was docked in the active site. Site-directed mutagenesis of amino acids in the active site was performed and the enzymatic activities of expressed mutant Kell proteins analyzed and compared with NEP. IntroductionThe Kell blood group protein is a type II membrane glycoprotein that is important in transfusion medicine due to the immunogenicity of its many polymorphic forms. The primary structure of Kell protein and its enzyme function as an endothelin-converting enzyme, classifies it as a member of the neprilysin (M13) subfamily of zinc endopeptidases. Kell differs from other M13 members in that it is linked by a single disulfide bond to another protein, XK, which traverses the membrane 10 times (for reviews, see Lee et al 1,2 ). XK has the structural characteristics of a membrane transporter, but its function has not yet been determined. 3 As a group the mammalian M13 peptidases are involved in the activation of bioactive peptides by specific cleavages of larger inactive peptides and in the proteolysis of bioactive peptides. [4][5][6] The substrate specificities of the M13 family members vary with neutral endopeptidase (NEP; EC 3.4.24.11) 7 and secreted endopeptidase (SEP) 8 having a wide range of substrates and endothelinconverting enzyme 1 (ECE-1; EC 3.4.24.71), endothelin-converting enzyme 2 (ECE-2), 9,10 Kell, 11 and phosphate-regulating protein (PHEX) 12,13 with a restricted number of substrates. ECE-1 and ECE-2 preferentially cleave big endothelin-1-releasing endothelin-1 (ET-1) but can also cleave big endothelin-2 and big endothelin-3. 14 ECE-1 also hydrolyzes other bioactive peptides such as bradykinin, neurotensin, and substance P. 9 Kell, like ECE-1 and ECE-2, is also an endothelin-converting enzyme but, in contrast to ECE-1 and ECE-2, Kell preferentially cleaves big endothelin-3, releasing the active peptide endothelin-3 (ET-3) although it also, to a lesser degree, activates ET-1 and endothelin-2 (ET-2). 11 Thus far the parathyroid hormone-related fragment 107-139 and fibroblast growth factor 23 (FGF-23), which is involved in phosphate transport in the kidney, are the only known substrates for PHEX. 12,13 Substrates for XCE, which is mostly expressed in the central nervous system, have not yet been identified. 15,16 Site-directed mutagenesis of conserved amino acid residues in NEP have yielded valuab...

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Section: Site-directed Mutagenesis Of Essential Amino Acid Residuesmentioning

confidence: 99%

Section: Alignment Of Catalytic Active Sitesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11

Lee

Debnath

Redman

2003

Blood

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“…endogenous levels of atrial natriuretic peptide (for reviews, see [13,14]). The identification of novel inhibitors of NEP is evidently of great interest for their eventual application in clinical treatments.…”

Section: Introductionmentioning

confidence: 99%

Interaction of mammalian neprilysin with binding protein and calnexin in Schizosaccharomyces pombe

Beaulieu

Elagöz

Crine

et al. 1999

Biochemical Journal

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Neutral endopeptidase (neprilysin or NEP, EC 3.4.24.11) is a zinc metallo-endopeptidase expressed in many eukaryotic cell types and displaying several important physiological roles. In the brain (and central nervous system), this enzyme is involved in the molecular mechanism of pain by its action in the degradation of enkephalin molecules. In the kidney, NEP is implicated in the degradation of regulatory factors involved in the control of arterial pressure, including atrial natriuretic peptide and bradykinin. In this study we assessed the potential of the fission yeast Schizosaccharomyces pombe to overproduce rabbit NEP and secreted NEP (sNEP, a soluble derivative of this integral membrane protein). Both recombinant NEP and sNEP were produced at high levels (5 mg\l) in this system. Enzymic studies revealed that these recombinant proteins were fully active and exhibit kinetic parameters similar to those of the bona fide enzyme.

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“…To confirm that potentiation of BK-induced contractile responses at 5 h in HUA is mediated by NEP inhibition, a chemically unrelated NEP inhibitor, thiorphan, was tested (Roques et al, 1995). Although thiorphan failed to modify BK-induced responses in HUA rings after a 2-h in vitro incubation, it significantly potentiated responses elicited by BK at 5 h. Moreover, potentiation of BK-elicited responses produced by thiorphan was quantitatively equivalent to that observed with phosphoramidon.…”

Section: Discussionmentioning

confidence: 99%

Neutral Endopeptidase Up-Regulation in Isolated Human Umbilical Artery: Involvement in Desensitization of Bradykinin-Induced Vasoconstrictor Effects

Pelorosso¹,

Halperin²,

Palma³

et al. 2006

J Pharmacol Exp Ther

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[17] Inhibitors of neprilysin: Design, pharmacological and clinical applications

Cited by 24 publications

References 90 publications

Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11

Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11

Interaction of mammalian neprilysin with binding protein and calnexin in Schizosaccharomyces pombe

Neutral Endopeptidase Up-Regulation in Isolated Human Umbilical Artery: Involvement in Desensitization of Bradykinin-Induced Vasoconstrictor Effects

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