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)

Determination of the X-ray structure of thermolysin-inhibitor complexes has proven useful in aiding our understanding of the mode of binding of inhibitors of related, physiologically important, mammalian zinc peptidases including neutral endopeptidase EC 3.4.24.11 and angiotensin-converting enzyme. Here we describe the mode of binding to crystalline thermolysin of N-[1-(2(R,S)-carboxy-4-phenylbutyl)-cyclopentylcarbonyl]-(S) -tryptophan (CCT). CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure. CCT differs from the previously studied N-carboxyalkyl dipeptide CLT [N-(S)-(1-carboxy-3-phenylpropyl)-(S)-leucyl-(S)-tryptophan] in several important respects. It has a highly constrained gem-cyclopentyl P1' substituent and lacks the characteristic imino nitrogen substituent of CLT. The structure determination shows that, notwithstanding the conformational influence of the gem-cyclopentyl substituent, CCT binds within the active site of thermolysin in a similar manner to CLT. Although the characteristic hydrogen bond between the imino nitrogen of CLT and thermolysin is absent in CCT, the affinities of the two inhibitors for the enzyme are virtually identical. These results illustrate the importance of considering not only those hydrogen bonds that are formed in an enzyme-ligand complex but also the other hydrogen bonds that may be lost due to desolvation of the enzyme and ligand on formation of the complex. In addition, the overall conformational demands placed upon a ligand in order to achieve receptor interaction may be critically important.
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PMID:Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex. 828 62

Proteolytic, aminopeptidase, endopeptidase and carboxypeptidase activities of seven strains of rumen anaerobic fungi, selected to represent the fungal population commonly found in the rumen, were investigated in vitro. Whatever the nitrogen source included in the culture medium, a proteolytic activity against the 14C-labelled casein was detected in only one fungal strain. This strain belonged to the genus Piromyces. The activity was extracellular and was found both in the culture supernatant and bound to the mycelium. No carboxypeptidase activity was detected in the seven strains. In contrast, all the strains exhibited aminopeptidase activity. Two strains had an endopeptidase activity.
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PMID:In vitro study of the proteolytic activity of rumen anaerobic fungi. 831 94

The function of the Rhizobium meliloti bacA gene, which is a homolog of the Escherichia coli sbmA gene, is required for an intermediate step in nodule development. A strain carrying the bacA386::TnphoA fusion was mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine, and three mutants that had higher levels of alkaline phosphatase activity were identified. The mutations in these strains were recessive and mapped to the same genetic locus. The gene affected by these mutations was identified and sequenced and was found to be a homolog of the E. coli degP gene, which encodes a periplasmic endopeptidase. Although degP function is important for the virulence of certain intracellular pathogens of mammals, it is not required for the R. meliloti-alfalfa symbiosis. The genetic analyses involving degP were complicated by the presence of a locus immediately upstream of depP that was lethal when present in multiple copies in a DegP- background. R. meliloti derivatives carrying insertion mutations in this locus displayed an N,N,N',N'-tetramethyl-p-phenylenediamine oxidase-negative phenotype, elicited the formation of white cylindrical nodules that did not fix nitrogen, and grew slowly in rich medium, suggesting that the locus was a cyc gene encoding a protein involved in the biosynthesis of a component or components of a respiratory chain. The previously identified fix-382::TnphoA, which similarly causes the formation of white cylindrical nodules that do not fix nitrogen, was shown to affect a gene that is separate from this cyc gene but extremely closely linked to it.
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PMID:Genetic analysis of Rhizobium meliloti bacA-phoA fusion results in identification of degP: two loci required for symbiosis are closely linked to degP. 855 May 9

The utilization of exogenous peptides was studied in mutants of Lactococcus lactis in which combinations of the peptidase genes pepN, pepC, pepO, pepX and pepT were deleted. Multiple mutants lacking PepN, PepC, PepT plus PepX could not grow on peptides such as Leu-Gly-Gly, Gly-Phe-Leu, Leu-Gly-Pro, Ala-Pro-Leu and Gly-Leu-Gly-Leu, respectively, indicating that no other peptidases are present to release the essential amino acid Leu. In these mutants, peptides accumulate intracellularly, demonstrating that peptides are translocated as whole entities prior to degradation. The mutant lacking all five peptidases could still grow on Gly-Leu and Tyr-Gly-Gly-Phe-Leu, which confirmed the presence of a dipeptidase and led to the identification of an unknown PepO-like endopeptidase. These studies have also shown that the general aminopeptidases PepN, PepC and PepT have overlapping but not identical specificities and differ in their overall activity towards individual peptides. In contrast, PepX has an unique specificity, because it is the only enzyme which can efficiently degrade Ala-Pro-Leu. The concerted action of peptidases in the breakdown of particular peptides revealed how these substrates are utilized as sources of nitrogen.
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PMID:Fate of peptides in peptidase mutants of Lactococcus lactis. 884 39

The aims of this work were (1) to determine the dose-response relationship between ex vivo exposure to oxidizing pollutants such as nitrogen dioxide (NO2), the aldehyde acrolein, and ozone (O3), and the reactivity to agonists in isolated human bronchial smooth muscle; and (2) to investigate the alterations in the cellular mechanisms of human airway smooth muscle contraction induced by such exposures. Experiments were performed in isolated human bronchi obtained at thoracotomy. Isometric contraction in response to a variety of agonists was compared between pollutant-exposed preparations and paired controls. Short exposures to NO2, acrolein, or O3 altered the subsequent airway smooth muscle responsiveness in a dose-dependent manner. The cellular mechanisms producing the airway hyperresponsiveness observed in vitro are shared by the three pollutants and include alterations in airway smooth muscle excitation-contraction coupling as well as indirect effects on neutral endopeptidase activity.
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PMID:Human bronchial smooth muscle responsiveness after in vitro exposure to oxidizing pollutants. 903 16

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl) propionic acid, prevents deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related organ damage, such as cardiovascular hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with candoxatril and enalapril, which are a selective NEP and ACE inhibitor, respectively. During DOCA-salt treatment for 4 weeks, the rats were given SA7060, candoxatril, enalapril or vehicle, once daily by gavage. The 4-weeks treatment with DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and increases in urinary excretion of protein and blood urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of atrial natriuretic peptide and cyclic GMP in SA7060- or candoxatril-treated animals. Histopathological examination of the kidney in DOCA-salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or candoxatril. When the vascular hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with the sham rats. The development of vascular hypertrophy was suppressed by the treatment with SA7060, candoxatril or enalapril. Our findings indicate that SA7060 efficiently prevents DOCA-salt-induced hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both renin-dependent and renin-independent hypertensive subjects, although further studies examining efficiency in a renin-dependent hypertensive model are needed.
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PMID:Effects of SA7060, a novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, on deoxycorticosterone acetate-salt-induced hypertension in rats. 1091 59

Porphyromonas gingivalis is an asaccharolytic bacterium that requires nitrogen substrates as carbon and energy sources. The aims of this study were to investigate the aminopeptidase activities of P. gingivalis and to evaluate the effect of aminopeptidase inhibitors on bacterial growth. Only arginine aminopeptidase and dipeptidyl aminopeptidase IV activities were detected. Experimental evidence was obtained suggesting that the Arg-gingipains of P. gingivalis can function as both an endopeptidase and an aminopeptidase. Firstly, the arginine aminopeptidase activity was found to be inhibited by leupeptin, a well-known inhibitor of Arg-gingipain activity. Secondly, a preparation of Arg-gingipain activity could hydrolyze the chromogenic substrate for arginine aminopeptidase. Lastly, a mutant of P. gingivalis constructed via gene disruption by use of suicide plasmids and deficient in both Arg-gingipain A and B was also devoid of arginine aminopeptidase activity. To investigate the key role of aminopeptidase activities in growth of P. gingivalis, aminopeptidase inhibitors were incorporated in the culture medium prior to inoculation. Bestatin and actinonin were the only ones to inhibit growth of P. gingivalis. Their mechanism of growth inhibition appears to be different but does not involve inhibition of the two major aminopeptidase activities (arginine aminopeptidase and dipeptidyl aminopeptidase IV).
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PMID:Studies on the aminopeptidase activities of Porphyromonas gingivalis. 1144 45

In order to study the effects of a small difference in starch and nitrogen availability on proteolysis, two different diets were supplied to four ewes fitted with rumen fistulae. They differed in the ratio of fermentable nitrogen over fermentable energy. with 144 g of fermentable nitrogen (FN) per kg of fermentable energy (FE) for diet I and 126 g FN x kg(-1) FE for diet II. The diets were constituted of 700 g hay grass, 200 g ground pea and either 100 g ground wheat (diet I) or 100 g corn starch (diet II). After two weeks of an adapting period to the diets, rumen content was sampled after feeding over time. The rate of disappearance of soluble proteins was 2.5 times higher with diet II and ammonia concentrations were significantly lower (from -28 to -43%) with diet II. Total proteolytic activity, by considering all the bacterial compartments, was significantly higher with diet II (+40 EU/mL x h(-1)): changes in the total proteolytic activity in the particulate and the liquid phases of the rumen could explain the difference observed between the two diets. Moreover, with diet II, exopeptidase activities increased more in the liquid phase, especially leucine aminopeptidase and Dipeptidyl peptidase I (DPP-I), and the diversity of endopeptidase activities increased in the particulate phase. These two facts could account for the higher total proteolytic activity in the rumen content with diet II.
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PMID:Variation of proteolytic activity in ewe during in vivo digestion of two pea-based diets differing by their fermentability characteristics. 1178 87

One of the mechanisms of the skin blistering effect (vesication) of sulfur mustard (bis-(2-chloroethyl)sulfide, HD) is believed to be via the stimulation of specific protease(s) at the dermal-epidermal junction. Cultured normal human epidermal keratinocytes (NHEK) were used as a model to study and characterize protease stimulated by the mustards 2-chloroethyl ethyl sulfide (CEES), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (nitrogen mustard, HN(2)) and HD. The results obtained using a chromozym (TRY) peptide substrate protease assay revealed the optimum mustard concentrations and time for protease stimulation to be about 200 microM (CEES), 100 microM (HN(2)) and 100 microM (HD) and 16 h. The mustard-stimulated protease was membrane bound and was inhibited by adding a Ca(2+) chelator (either 2 mM EGTA (ethylene glycol-bis(amino ethyl ether) N,N,N',N' tetraacetic acid) or 50 microM BAPTA AM (1,2-bis(z-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetraacetoxy methyl ester) alone or in combination), a serine protease inhibitor diisopropyl fluoro-phosphate (DFP, 1 mM), or a protein synthesis inhibitor cycloheximide (35 microM) in the extracellular medium. These results suggest that mustard toxicity may involve the stimulation of trypsin/chymotrypsin-like serine protease, dependent on Ca(2+) and new protein synthesis. Protein purification by gel exclusion and hydrophobic chromatography produced a 70-80 kDa protease, which had an amino acid sequence homologous with a mammalian-type bacterial serine endopeptidase. Based on this information, research is in progress to identify the protease stimulated by HD in NHEK and to determine whether its inhibitors are useful as prospective antivesicant drugs.
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PMID:Sulfur mustard-stimulated protease: a target for antivesicant drugs. 1192 Sep 39

A keratinolytic Xanthomonas maltophilia strain (POA-1), cultured on feather meal broth, using keratin as its sole source of carbon and nitrogen, secretes several extracellular peptidases. The major serine peptidase was purified to homogeneity by a five-step procedure. Its purity was evaluated by capillary zone electrophoresis. This enzyme has a molecular mass of 36 kDa, an optimum pH of 9.0, and an optimum temperature of 60 degrees C. The inhibitory profile using protease inhibitors shows that this enzyme is a serine endopeptidase. Besides keratin, the enzyme is active upon the substrates azokeratin, azocasein, and the following fluorogenic peptide substrates: Abz-Leu-Gly-Met-Ile-Ser-Leu-Met-Lys-Arg-Pro-Gln-EDDnp, Abz-Lys-Leu-Cys(SBzl)-Gly-Pro-Lys-Gln-EDDnp, and Abz-Lys-Pro-Cys(SBzl)-Phe-Ser-Lys-Gln-EDDnp.
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PMID:Purification and characterization of an alkaline serine endopeptidase from a feather-degrading Xanthomonas maltophilia strain. 1203 Jul 7


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