Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human angiotensin-I converting enzyme (ACE) is a central component of the renin-angiotensin system and a major target for cardiovascular therapies. The somatic form of the enzyme (sACE) comprises two homologous metallopeptidase domains (N and C), each bearing a zinc active site with similar but distinct substrate and inhibitor specificities. On the basis of the recently determined crystal structures of both ACE domains, we have studied their complexes with gonadotropin-releasing hormone (GnRH), which is cleaved releasing both the protected NH2- and COOH-terminal tripeptides. This is the first molecular modeling study of an ACE-peptide substrate complex that examines the structural basis of ACE's endopeptidase activity and offers novel insights into subsites that are distant from the obligatory binding site and were not identified in the crystal structures. Our data indicate that a bridging interaction between Arg500 of the N-domain and Arg8 of GnRH that involves a buried chloride ion may account for its role in the specificity of the N-domain for endoproteolytic cleavage of the substrate at the NH2-terminus in vitro. In support of this, the protected NH2-terminal dipeptide of GnRH exhibits stronger interactions than the protected COOH-terminal dipeptide with the N-domain of ACE. Further comparison of the models of ACE-substrate complexes promotes our understanding of how the two domains differ in their function and specificity and provides an extension of the pharmacophore model used for structure-based drug design up to the S7 subsite of the enzyme.
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PMID:Simulated interactions between angiotensin-converting enzyme and substrate gonadotropin-releasing hormone: novel insights into domain selectivity. 1760 72

Healed partial thickness wounds including burns and donor sites cause hypertrophic scar formation and patient discomfort. For many patients with hypertrophic scars, pruritus is the most distressing symptom, which leads to wound excoriation and chronic wound formation. In spite of the clinical significance of abnormal innervation in scars, the nervous system has been largely ignored in the pathophysiology of hypertrophic scars. Evidence that neuropeptides contribute to inflammatory responses to injury include inflammatory cell chemotaxis, cytokine and growth factor production. The neuropeptide substance P, which is released from nerve endings after injury, induces inflammation and mediates angiogenesis, keratinocyte proliferation, and fibrogenesis. Substance P activity is tightly regulated by neutral endopeptidase (NEP), a membrane bound metallopeptidase that degrades substance P at the cell membrane. Altered substance P levels may contribute to impaired cutaneous healing responses associated with diabetes mellitus or hypertrophic scar formation. Topical application of exogenous substance P or an NEP inhibitor enhances wound closure kinetics in diabetic murine wounds suggesting that diabetic wounds have insufficient substance P levels to promote a neuroinflammatory response necessary for normal wound repair. Conversely, increased nerve numbers and neuropeptide levels with reduced NEP levels in human and porcine hypertrophic scar samples suggest that excessive neuropeptide activity induces exuberant inflammation in hypertrophic scars. Given these observations about the role of neuropeptides in cutaneous repair, neuronal modulation of repair processes at two extremes of abnormal wound healing, chronic non-healing ulcers in type II diabetes mellitus and hypertrophic scars in deep partial thickness wounds, may provide therapeutic targets.
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PMID:Making sense of hypertrophic scar: a role for nerves. 1772 64

Neprilysin-2 (NEP2) is a novel metallopeptidase homologous to neprilysin (NEP), an enzyme involved in regulation of neuropeptide signalling. NEP2 exists as two alternatively spliced isoforms, NEP2 and NEP2(Delta). In this study, we cloned and expressed both human isoforms. Human NEP2 exists as a membrane-bound and soluble enzyme, whereas human NEP2(Delta) exists as two membrane-bound glycoforms, localised to the ER and plasma membrane. Surprisingly, NEP2 substrate specificity and inhibitor binding was distinct from that of human NEP, suggesting that NEP and NEP2 play distinct physiological roles in humans, and human NEP2 differs markedly from its rodent homologues.
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PMID:Human neprilysin-2 (NEP2) and NEP display distinct subcellular localisations and substrate preferences. 1853 50

The PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome) identified as a mutated gene in patients with X-linked hypophosphatemia (XLH), encodes a protein (PHEX) that shows striking homologies to members of the M13 family of zinc metallopeptidases. In the present work the interaction of glycosaminoglycans with PHEX has been investigated by affinity chromatography, circular dichroism, protein intrinsic fluorescence analysis, hydrolysis of FRET substrates flow cytometry and confocal microscopy. PHEX was eluted from a heparin-Sepharose chromatography column at 0.8 M NaCl showing a strong interaction with heparin. Circular dichroism spectra and intrinsic fluorescence analysis showed that PHEX is protected by glycosaminoglycans against thermal denaturation. Heparin, heparan sulfate and chondroitin sulfate inhibited PHEX catalytic activity, however among them, heparin presented the highest inhibitory activity (Ki=2.5+/-0.2 nM). Flow cytometry analysis showed that PHEX conjugated to Alexa Fluor 488 binds to the cell surface of CHO-K1, but did not bind to glycosaminoglycans defective cells CHO-745. Endogenous PHEX was detected at the cell surface of CHO-K1 colocalized with heparan sulfate proteoglycans, but was not found at the cell surface of glycosaminoglycans defective cells CHO-745. In permeabilized cells, PHEX was detected in endoplasmic reticulum of both cells. In addition, we observed that PHEX colocalizes with heparan sulfate at the cell surface of osteoblasts. This is the first report that the metallopeptidase PHEX is a heparin binding protein and that the interaction with GAGs modulates its enzymatic activity, protein stability and cellular trafficking.
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PMID:The critical interaction of the metallopeptidase PHEX with heparan sulfate proteoglycans. 1858 73

In this study, for the first time, we used the in vitro metallopeptidase model for the identification of a potential novel activity of defatted evening primrose seed extracts. Prepared extracts of different polarity (aqueous, 60% ethanolic, isopropanolic, and 30% isopropanolic) at concentrations of 1.5-100 microg/mL exhibited a significant and dose dependent inhibition of three tested enzymes. The 50% inhibition of enzymes activity showed that aminopeptidase N (APN) was the enzyme affected to the greatest extent with IC50 at the level of 2.8 microg/mL and 2.9 microg/mL for aqueous and 30% isopropanolic extracts, respectively. The activity of neutral endopeptidase (NEP) was quite strongly inhibited by the extracts as well. The HPLC-DAD analysis and bioguided fractionation led to the identification of four active compounds: (-)-epicatechin gallate, proanthocyanidin B3, oenothein B, and penta-O-galloyl-beta-D-glucose (PGG). Oenothein B has been shown previously to inhibit metallopeptidases. The three other compounds are known to inhibit angiotensin-converting enzyme (ACE), but they have not been previously reported to inhibit the NEP and APN activity. PGG and procyanidins with different degrees of polymerization, as the dominating compounds in O. paradoxa seeds, seemed to play a role in the crude extract activity.
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PMID:Novel biological properties of Oenothera paradoxa defatted seed extracts: effects on metallopeptidase activity. 1870 16

Background : CD10 is a zinc-dependent metallopeptidase known as common acute lymphoblastic leukemia antigen (CALLA). Although CD10 expression has been investigated in some cutaneous tumors, to our knowledge, data regarding its expression in cutaneous epithelial neoplasms are very limited. We aimed to determine the immunohistochemical expression of CD10 in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and to associate it with the available clinicopathological parameters in both tumors. Patients and Methods : This study included 16 SCC and 21 BCC cases (17 solid type, 2 morphea type and 2 adenoid basal types). BCC cases were divided into 12 cases with microscopic infiltrative base and 9 cases with well-circumscribed base. The localization of anti-CD10 to the tumor and/or stromal cells was determined in each case. Results : Positive CD10 staining was identified as brown cytoplasmic, with or without cell membrane staining. In all the 16 SCC cases, tumor cells failed to stain with CD10 in contrast to the stromal cells that showed CD10 expression in 13 cases (81%). In BCC cases, the expression of CD10 was noted in tumor cells in 10 cases (47.6%) and in stromal cells of 20 cases (95.24%). Most of CD10+ (7/10) BCC showed well-circumscribed deep margin, however, most of CD10- cases (9/11) showed infiltrating base (p=0.030). BCCs with infiltrating deep margins (12 cases) tended to show CD10 negative basaloid cells (9/12) and CD10 positive stromal cells (12/12) (p=0.0003). Conclusion : From our results we suggest that CD10 might be a useful immunohistochemical marker to differentiate between BCC and SCC. At least, if tumor cells were CD10 positive, this would favor BCC over SCC. Absence of CD10 in all the SCC and in infiltrating BCC together with its overexpression in the surrounding stromal cells might confer invasive properties to such tumors. However, its relation to other poor prognostic factors needs larger studies to be confirmed. Key Words : CD 10 -Immunostaining -Skin.
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PMID:Immunohistochemical Expression of CD10 in Cutaneous Basal and Squamous Cell Carcinomas. 1919 Jun 92

Bacterial virus entry and cell wall depolymerization require the breakdown of peptidoglycan (PG), the peptide-cross-linked polysaccharide matrix that surrounds bacterial cells. Structural studies of lysostaphin, a PG lytic enzyme (autolysin), have suggested that residues in the active site facilitate hydrolysis, but a clear mechanism for this reaction has remained unsolved. The active-site residues and a structural pattern of beta-sheets are conserved among lysostaphin homologs (such as LytM of Staphylococcus aureus) and the C-terminal domain of gene product 13 (gp13), a protein at the tail tip of the Bacillus subtilis bacteriophage varphi29. gp13 activity on PG and muropeptides was assayed using high-performance liquid chromatography, and gp13 was found to be a d,d-endopeptidase that cleaved the peptide cross-link. Computational modeling of the B. subtilis cross-linked peptide into the gp13 active site suggested that Asp195 may facilitate scissile-bond activation and that His247 is oriented to mediate nucleophile generation. To our knowledge, this is the first model of a Zn(2)(+) metallopeptidase and its substrate. Residue Asp195 of gp13 was found to be critical for Zn(2)(+) binding and catalysis by substitution mutagenesis with Ala or Cys. Circular dichroism and particle-induced X-ray emission spectroscopy showed that the general protein folding and Zn(2)(+) binding were maintained in the Cys mutant but reduced in the Ala mutant. These findings together support a model in which the Asp195 and His247 in gp13 and homologous residues in the LytM and lysostaphin active sites facilitate hydrolysis of the peptide substrate that cross-links PG. Thus, these autolysins and phage-entry enzymes have a shared chemical mechanism of action.
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PMID:Shared catalysis in virus entry and bacterial cell wall depolymerization. 1936 22

Neprilysin (NEP, CD10, CALLA - common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is involved in the metabolism of a number of regulatory peptides and plays an important role in turning off peptide signalling at the cell surface. NEP gene is located on chromosome 3q 25.1-q25.2 and is composed of 24 exons. Four types of NEP cDNAs have been identified resulting from alternative splicing of exons 1, 1bis, 2a or 2b to the common exon 3. Neprilysin is expressed in normal and malignant hematopoietic cells and in epithelial cells of many organs. In kidneys, it is expressed in podocytes, renal proximal tubular epithelium and in smooth muscles of the vessels.
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PMID:[Neprilysin--structure of the gene and protein product and the localization of expression]. 1965 Apr 30

Neprilysin (NEP, CD10, CALLA-common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is involved in the metabolism of a number of regulatory peptides and plays an important role in turning off peptide signalling at the cell surface. Neprilysin is involved in many physiological and pathological processes in organism. It regulates blood pressure and inflammatory response, takes part in the pathogenesis of Alzheimer disease, influences cellular proliferation and differentiation, as well as neoplastic progression.
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PMID:[The relevance of neprilysin for systemic homeostasis and its involvement in the pathological processes]. 1965 Apr 31

Neprilysin (NEP, CD10, CALLA-common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is the first podocytic antigen, which has been shown to induce human membranous glomerulonephritis (GN). Debiec et al. in a case of antenatal membranous GN identified NEP as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. However, NEP is expressed on normal podocytes and renal proximal tubular epithelial cells. Moreover, decreased podocyte expression of NEP has been found in a variety of glomerular diseases. Recent studies show that in patients with GN the podocyte expression of NEP correlates with that of other podocyte proteins, i.e.: synaptopodin and CR1 and reflects the severity of glomerular damage.
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PMID:[The involvement of neprilysin in the pathogenesis of glomerulopathies]. 1982 39


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