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

The pattern of bradykinin (BK; Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9)-inact iva ting peptidases in semen of boar and ram was investigated. The degradation of BK in semen was completely abolished by the metalloprotease inhibitors EDTA and o-phenanthroline. Inhibitors of angiotensin-converting enzyme (ACE; EC 3.4.15.1) and phosphoramidon, an inhibitor of neutral metalloendopeptidase (NEP; EC 3.4.24.11), were only partially effective in preventing BK degradation in semen. An additive effect was seen with simultaneous inhibition of both enzymes, resulting in complete abolition of BK degradation. HPLC analysis demonstrated that exogenous BK in semen is cleaved at Gly4-Phe5, Phe5-Ser6 and Pro7-Phe8. These results indicate that NEP and ACE are the main peptidases responsible for rapid BK inactivation in semen. The involvement of other peptidases known to be responsible for BK cleavage in other tissues and body fluids, namely carboxypeptidase N (EC 3.4.12.7), post proline cleaving enzyme (EC 3.4.21.26) and aminopeptidase P (EC 3.4.11.9) was excluded. NEP and ACE were shown to be localized mainly in seminal plasma and to a lesser extent on sperm cells.
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PMID:Degradation of bradykinin in semen of ram and boar. 839 Feb 57

The two human endothelin-converting enzyme (ECE-1) isoforms, which differ by their N-terminal region, are encoded by a single gene. The gene is composed of 19 exons that span more than 68 kilobases and has been mapped to the 1p36 band of the human genome. The two isoform mRNAs display different tissue distributions. Their precursors are transcribed from two distinct start sites, upstream from exon 1 and exon 3, respectively. Sequence analysis of the two putative promoters revealed the presence of motifs characteristic for several transcription factors. Comparison of the ECE-1 gene structure with those of other zinc metalloproteases, as well as a phylogenetic study, confirm the existence of a metalloprotease subfamily composed of ECE-1, ECE-2, neutral endopeptidase, Kell blood group protein, and two bacterial enzymes.
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PMID:Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). 853 Mar 72

Endothelin-converting enzyme (ECE) is a member of the zinc metalloproteinase family. It is much more specific in its protease activity than the bacterial metalloprotease thermolysin; we aim to construct a model of its active site to help to explain these differences. We aligned the sequence of human ECE with those of human neprilysin (which is 39% identical to ECE) and thermolysin. Residues believed to be important for inhibitor binding were assigned from the alignment and by analogy with structural and functional studies of these enzymes. These included a conserved IGG motif N-terminal to the zinc-binding HExxH motif, and a tyrosine residue that may be analogous to Y157 of thermolysin. We have used the program O to build a model of the active site of ECE based on the crystal structure of thermolysin.
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PMID:Molecular modeling of the active site of endothelin-converting enzyme. 858 73

Endopeptidase 3.4.24.16 belongs to the zinc-containing metalloprotease family and likely participates in the physiological inactivation of neurotensin. The peptidase displays distinct features in pure primary cultured neurons and astrocytes. Neuronal maturation leads to a decrease in the proportion of endopeptidase 3.4.24.16-bearing neurons and to a concomitant increase in endopeptidase 3.4.24.16 activity and mRNA content. By contrast, there is no change with time in endopeptidase 3.4.24.16 activity or content in astrocytes. Primary cultured neurons exhibit both soluble and membrane-associated endopeptidase 3.4.24.16 activity. The latter behaves as an ectopeptidase on intact plated neurons and resists treatments with 0.2% digitonin and Na2CO3. Further evidence for an association of the enzyme with plasma membranes was provided by cryoprotection experiments and electron microscopic analysis. The membrane-associated form of endopeptidase 3.4.24.16 increased during neuronal differentiation and appears to be mainly responsible for the overall augmentation of endopeptidase 3.4.24.16 activity observed during neuronal maturation. Unlike neurons, astrocytes only contain soluble endopeptidase 3.4.24.16. Astrocytes secrete the enzyme through monensin, brefeldin A, and forskolin-independent mechanisms. This indicates that endopeptidase 3.4.24.16 is not released by classical regulated or constitutive secreting processes. However, secretion is blocked at 4 degrees C and by 8 bromo cAMP and is enhanced at 42 degrees C, two properties reminiscent of that of other secreted proteins lacking a classical signal peptide. By contrast, neurons appear unable to secrete endopeptidase 3.4.24.16.
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PMID:Distinct properties of neuronal and astrocytic endopeptidase 3.4.24.16: a study on differentiation, subcellular distribution, and secretion processes. 875 35

Application of gene knockout techniques to endothelin research has led to the revelation of unexpected and interesting roles for endothelin isopeptides and their receptors. Homozygous mice with null endothelin-1 and ETA receptors presented with craniofacial and cardiovascular malformations, indicating that these receptors are essential for the development of the first branchial arch derived from the neural crest. Homozygous mice with null endothelin-3 and ETB receptors presented with megacolon (Hirschsprung's disease) associated with spotted colour coats, indicating that these latter receptors are essential for the development of neural crest-derived cell lineage, enteric neuron and epidermal melanocytes. Isolation and characterization of endothelin-converting enzyme which cleaves big endothelin-1, an intermediate form, into mature endothelin-1 has revealed a type II integral membrane-bound metalloprotease that is structurally homologous to neutral endopeptidase. Development of selective inhibitors for endothelin-converting enzyme isoenzymes will facilitate a greater understanding of the role of endogenous endothelin isopeptides.
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PMID:Endothelin peptides. 883 56

We have purified and characterized human brain endopeptidase 3.4.24.16. The enzyme behaved as a 72 kDa protein and belonged to the metalloprotease family. Human endopeptidase 3.4.24.16 cleaved neurotensin at a unique site at the Pro10-Tyr11 bond, leading to the formation of neurotensin(1-10) and neurotensin(11-13). The kinetic parameters displayed by human endopeptidase 3.4.24.16 towards a series of natural neuropeptides indicated that bradykinin was the most efficiently proteolysed. Angiotensin I, dynorphins 1-8 and 1-9 and substance P also behaved as good substrates while neuromedin N, angiotensin II, leucine and methionine enkephalin and neurokinin A resisted degradation by human endopeptidase 3.4.24.16. We have purified the porcine counterpart of endopeptidase 3.4.24.16 and compared its ability to cleave neurotensin with that of the enzyme from human origin. It appeared that, besides a major production of neurotensin(1-10), an additional formation of neurotensin(1-8) was observed with the pig enzyme, suggesting a cleavage of neurotensin not only at the Pro10-Tyr11 bond but also at the Arg8-Arg9 peptidyl bond. The latter cleavage appeared reminiscent of endopeptidase 3.4.24.15 since this peptidase was reported to cleave neurotensin at the Arg8-Arg9 bond. Our study indicated that neurotensin(1-10) formation by porcine endopeptidase 3.4.24.16 could be potently blocked with the selective endopeptidase 3.4.24.16 dipeptide inhibitor Pro-Ile without interfering with neurotensin(1-8) formation. By contrast, the formation of the latter product was highly potentiated by dithiothreitol and inhibited by the endopeptidase 3.4.24.15 inhibitor Cpp-Ala-Ala-Tyr-pAB, two effects that were not observed for neurotensin(1-10) production. Altogether, our results indicate that porcine endopeptidase 3.4.24.16 cleaves neurotensin at a unique site, leading to the formation of neurotensin(1-10) and that the production of neurotensin(1-8) is due to contaminating endopeptidase 3.4.24.15.
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PMID:Purification and characterization of human endopeptidase 3.4.24.16. Comparison with the porcine counterpart indicates a unique cleavage site on neurotensin. 886 56

In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.
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PMID:Renal and depressor activities of inhibitors of neutral endopeptidase and angiotensin converting enzyme in monkeys infused with angiotensin II. 894 78

The biologically active vasoactive peptides, the endothelins (ETs), are generated from inactive intermediates, the big endothelins, by a unique processing event catalysed by the zinc metalloprotease, endothelin converting enzyme (ECE). In this overview we examine the actions of endothelins in the brain, and focus on the structure and cellular locations of ECE. The heterogeneous distribution in the brain of ET-1, ET-2, and ET-3 is discussed in relation to their hemodynamic, mitogenic and proliferative properties as well as their possible roles as neurotransmitters. The cellular and subcellular localization of ECE in neuronal and in glial cells is compared with that of other brain membrane metalloproteases, neutral endopeptidase-24.11 (neprilysin), angiotensin converting enzyme and aminopeptidase N, which all function in neuropeptide processing and metabolism Unlike these ectoenzymes, ECE exhibits a dual localisation in the cell, being present on the plasma membrane and also, in some instances, being concentrated in a perinuclear region. This differential localization may reflect distinct targeting of different ECE isoforms, ECE-1 alpha, ECE-1 beta, and ECE-2.
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PMID:The endothelin system and endothelin-converting enzyme in the brain: molecular and cellular studies. 923 59

In this study we describe the partial purification and characterization of the HeLa cell oligopeptidase M or endopeptidase 3.4.24.16. The HeLa enzyme was isolated initially by its ability to hydrolyse a nonapeptide substrate (P9) which was cognate to the N-terminal cleavage site of preproTGF alpha. The enzyme was shown to be a metalloprotease as it was inhibited by Zn(2+)-chelating agents and DTT, and had an approximate molecular weight of 55-63 kD determined by gel filtration. Neurotensin, dynorphin A1-17 and GnRH1-9 were rapidly degraded by the enzyme while GnRH1-10 and somatostatin were not. Neurotensin was cleaved at the Pro10-Tyr11 bond, leading to the formation of neurotensin (1-10) and neurotensin (11-13). The K(m) for neurotensin cleavage was 7 microM and the Ki for the specific 24.16 dipeptide inhibitor (Pro-ile) was 140 microM which were similar to those observed from the human brain enzyme [Vincent et al. (1996): Brain Res 709:51-58]. Through the use of specific antibodies, the purified HeLa enzyme was shown to be oligopeptidase M. This enzyme and its closely related family member thimet oligopeptidase were shown to co-elute during the isolation procedure but were finally separated using a MonoQ column. Oligopeptidase M is located mainly in mitochondria though it was detected on the plasma membrane in an inactive form. The results obtained demonstrate the first recorded instance of this enzyme in human tissue cultured cells, and raise the issue of its function therein.
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PMID:Characterization and localization of mitochondrial oligopeptidase (MOP) (EC 3.4.24.16) activity in the human cervical adenocarcinoma cell line HeLa. 925 87

Screening cultures of nonpathogenic microorganisms led us to a glutamic-acid-specific endopeptidase from Bacillus subtilis ATCC 6051, which we purified and named BSase. The nucleotide sequence encoding BSase, with a molecular mass of 23,894 Da, completely agreed with that of the mpr gene, which had been reported by Rufo Jr. and Sloma et al. to encode a metalloprotease [J Bacteriol (1990) 172: 1019-1023 and 1024-1029 respectively]. However, enzymatic characterization revealed it to have the catalytic triad of a serine protease and not the consensus sequence of a metalloprotease, and it was inhibited by diisopropylfluorophosphate. We therefore consider BSase (mpr) to be a serine protease. In the alignment of the acidic-amino-acid-specific proteases, the proteases from bacilli have a highly conserved histidine residue, which is most important in the histidine triad in the proteases from streptomycetes. Furthermore, Ca2+ was necessary for its activity and stability. BSase cleaved the C-terminal glutamic acid with high specificity and was very stable over a wide pH range. On the basis of these properties, we tried to retrieve a bioactive peptide from a fusion protein by sequence-specific digestion, and succeeded in obtaining the bioactive peptide. BSase was found to be very useful as a tool for selective cleavage.
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PMID:Purification and characterization of a glutamic-acid-specific endopeptidase from Bacillus subtilis ATCC 6051; application to the recovery of bioactive peptides from fusion proteins by sequence-specific digestion. 927 45


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