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)

Mutations at the Escherichia coli prlC locus suppress the export defect of certain lamB signal sequence mutations. The Salmonella typhimurium opdA gene encodes an endoprotease that can participate in the catabolism of certain peptides and is required for normal development of phage P22. Plasmids carrying either the wild-type (pTC100 prlC+) or suppressor alleles of prlC complemented all phenotypes associated with an S. typhimurium opdA mutation. A plasmid carrying an amber mutation in prlC [prlC31(AM)] was unable to complement except in an amber suppressor background. Tn1000 insertions which eliminated the ability of pTC100 (prlC+) to complement opdA mapped to the region of the plasmid shown by deletion analysis and subcloning to contain prlC. The nucleotide sequence of a 2.7-kb fragment including this region was determined, revealing an open reading frame encoding a 77-kDa protein. The sequences of this open reading frame and its putative promoter region were very similar (84% nucleotide sequence identity and 95% amino acid identity) to those of S. typhimurium opdA, showing that these genes are homologs. The nucleotide sequence of the prlC1 suppressor allele was determined and predicts an in-frame duplication of seven amino acids, providing further confirmation that the prlC suppressor phenotype results from changes in the endopeptidase OpdA.
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PMID:Escherichia coli prlC encodes an endopeptidase and is homologous to the Salmonella typhimurium opdA gene. 132 67

We have combined gene cloning with an assay for prohormone biosynthesis and processing in Xenopus oocytes to identify the genes that encode mammalian prohormone processing enzymes. The coinjection of RNA encoding murine prohormone convertase 1 (mPC1), a mammalian endoprotease, along with proopiomelanocortin RNA into an oocyte results in the appropriate cleavage after paired basic residues in the proopiomelanocortin polyprotein necessary to generate corticotropin. The ability of mPC1 to generate corticotropin, along with the observation that mPC1 is specifically expressed in endocrine and neuronal cells, suggests that the mPC1 gene encodes the endopeptidase responsible for the pathway of proopiomelanocortin cleavage observed in the anterior pituitary.
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PMID:Isolation and functional expression of a mammalian prohormone processing enzyme, murine prohormone convertase 1. 186 7

Atrial natriuretic factor, the first well defined natriuretic hormone is synthesized in the human heart as 151 aminoacid (AA) preprohormone and stored as 126 AA prohormone in atrial granules. Upon appropriate stimulation, the prohormone is cleaved into a 98 AA N-terminal fragment and a 28 AA C-terminal fragment, the biological active ANF(99-126), both circulating in plasma. Circulating ANF(99-126) is cleared by various organs, such as lung, liver and intestine, kidney and upper and lower limbs. Reported arterial-venous extraction ratios vary greatly, but are not much different between organs, the average extraction ratio being about 35%. Due to marked differences of organ blood flow, the contribution of various organs to total body ANF clearance differs considerably. Major mechanisms for ANF clearance are uptake by clearance receptors and degradation by an endoprotease (EC 3.4.24.11.). Clearance receptors, distinct from the receptors mediating the biological actions of ANF, have been demonstrated in various organs. Characterization of the ANF degrading enzyme activity has been performed in kidney tissue. Whether and how pathophysiological states affect ANF clearance is still poorly understood. Inhibition of clearance by ANF analogues binding to clearance receptors and by inhibitors of degrading peptidase can increase the biological action of circulating ANF. This may prove to be a therapeutic approach in diseases with smooth muscle contraction or volume overload.
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PMID:Degradation and clearance of atrial natriuretic factors (ANF). 217 7

An endopeptidase that converts the opioid peptide dynorphin B (Tyr-Gly-Gly-Phe-Leu-Arg-aRg-Gln-Phe-Lys-Val-Val-Thr) to its bioactive fragment Leu-enkephalin-Arg6 was isolated from bovine spinal cord. The enzyme was purified about 230-fold from a concentrated spinal cord extract. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis, it stained as a protein of Mr 55,000. The purified enzyme is optimally active at around pH7 and has essential thiol groups. It appears to be highly specific for dynorphin B (Km = 11 microM) but not for alpha-neoendorphin or dynorphin A, two other opioids included in the prodynorphin precursor. From its specificity, molecular size, and inhibitory spectrum, this enzyme is different from other known dynorphin-converting or -degrading enzymes and appears to be a unique and novel endoprotease.
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PMID:A novel bovine spinal cord endoprotease with high specificity for dynorphin B. 256 32

Porcine brain natriuretic peptide of 26 amino acid residues (pBNP-26) is inactivated by endoprotease-24.11 (EC 3.4.24.11) of kidney cortical membranes. In contrast to human alpha atrial natriuretic peptide/cardiodilatin (ANP/CDD) showing a single major cleavage within the disulfide-linked loop between Cys and Phe in position 7 and 8, pBNP-26 is cleaved at several sites. Although both pBNP-26 and ANP/CDD exhibit Cys-Phe peptide bonds at the corresponding positions this bond is not cleaved in BNP-26.
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PMID:Degradation of porcine brain natriuretic peptide (pBNP-26) by endoprotease-24.11 from kidney cortical membranes. 274 83

The octacosapeptide sequence [Tyr18] pro-ocytocin/neurophysin (1-18)NH2 [pro-OT/Np(1-18)NH2] was synthesized and used as substrate to detect endoprotease(s) possibly involved in the processing of this precursor in bovine hypothalamo-neurohypophyseal tract. An endopeptidase (58 Kda) was detected in Lysates made from highly purified neurosecretory granules. This protease which cleaves the peptide bond on the carboxyl side of the Lys-Arg doublet, and no single basic residue, generates both OT-Gly10-Lys11-Arg12+Ala13-Val-Leu-Asp-Leu-Tyr18 (NH2) from the octacosapeptide substrate. In addition, a carboxypeptidase B-like activity converting OT-Gly10-Lys11-Arg12 into OT-Gly10 was detected in the same granule Lysates. It is hypothesized that a combination of these endoprotease and carboxypeptidase B-like activities together with the amidating enzyme of secretory granules might participate in the cleavage and processing of pro-OT/Np in vivo.
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PMID:An endopeptidase associated with bovine neurohypophysis secretory granules cleaves pro-ocytocin/neurophysin peptide at paired basic residues. 351 14

Human prohormone convertase PC2 was expressed in Xenopus oocytes and its properties were compared with those of the Type-2 endopeptidase of rat insulin secretory granules, previously identified as PC2 [Bennett, Bailyes, Nielson, Guest, Rutherford, Arden and Hutton (1992) J. Biol. Chem. 267, 15229-15236]. Recombinant PC2 had the same substrate specificity as the Type-2 endopeptidase, cleaving at the CA-junction (Lys64, Arg65) of human des-31,32-proinsulin to generate insulin; little activity was found toward human des-64,65-proinsulin or proinsulin itself. Recombinant PC2 was maximally active in 5-7 mM Ca2+ (K0.5 = 1.6 mM) whereas the Type-2 endopeptidase was maximally active in 0.5-1 mM Ca2+ (K0.5 = 40 microM). Both enzymes had a pH optimum of 5.0-5.5 but the Type-2 endopeptidase was active over a wider pH range. Two molecular forms of recombinant PC2 (71 kDa and 68 kDa) were found, both had an intact C-terminus but differed by the presence of the propeptide. The endogenous PC2 comprised several overlapping forms (size range 64-68 kDa), approximately two-thirds of which lacked C-terminal immunoreactivity. Part of the size difference between recombinant and endogenous PC2 was attributable to differences in N-glycosylation. The different post-translational proteolytic modifications of recombinant and endogenous PC2 did not account for the different pH and Ca2+ sensitivities shown by the enzymes. A modulating effect of carbohydrate on enzyme activity could not be excluded.
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PMID:Differences between the catalytic properties of recombinant human PC2 and endogenous rat PC2. 762 24

Tetanus neurotoxin (TeNT) blocks neuroexocytosis via a zinc-endopeptidase activity highly specific for vescicle-associated membrane protein(VAMP)/synaptobrevin. TeNT is the prototype of clostridial neurotoxins, a new family of metalloproteinases. They consist of three domains and the proteolytic activity is displayed by the 50-kDa light chain (L chain). The L chain was isolated here in the native state from bacterial filtrates of Clostridium tetani and its structure was studied via circular dichroism (CD) and fluorescence spectroscopy. The secondary structure content (27% alpha-helix and 43% beta-sheet), estimated by far-ultraviolet CD measurements, was in reasonable agreement with that obtained by standard predictive methods (25% alpha-helix and 49% beta-sheet). Moreover, the hypothetical zinc-binding motif, encompassing residues His-Glu-Leu-Ile-His, was correctly predicted to be in alpha-helical conformation, as also expected on the basis of the geometrical requirements for a correct coordination of the zinc ion. Both near-ultraviolet CD and fluorescence data strongly suggest that the single Trp43 residue is buried and constrained in a hydrophobic environment, likely distant from the zinc ion located in the active-site cleft. The contribution of the bound zinc ion to the overall conformation of TeNT L chain was investigated by different and complementary techniques, including spectroscopic (far- and near-ultraviolet CD, fluorescence, second derivative absorption spectroscopy) as well as proteolytic probes. The results indicate that the zinc ion plays little, if any, role in determining the structural properties of the L chain molecule. Similarly, the metal-free apo-enzyme and the holo-protein share common stability features evaluated in respect to different physico-chemical parameters (pH, temperature and urea concentration). These results parallel those obtained on thermolysin, a zinc-dependent neutral endoprotease from Bacillus thermoproteolyticus, where both conformational and stability properties are unchanged upon zinc removal.
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PMID:Structural studies on the zinc-endopeptidase light chain of tetanus neurotoxin. 774 50

1. In the anaesthetized, ganglion-blocked rat, intravenous boluses of endothelin-1, endothelin-2 and endothelin-3 induced a transient hypotensive effect followed by a potent long lasting pressor response (ED50 mmHg: 0.72 +/- 0.05, 1.8 +/- 0.2 and 2.7 +/- 0.3 nmol kg-1, respectively). The maximal effect for the three peptides was of a similar order of magnitude (delta MAP: 84 to 89 mmHg). Neither of these effects was influenced by phosphoramidon or thiorphan (10 mg kg-1, i.v.). 2. Intravenously administered big-endothelin-1 and -2 induced a transient (1-2 min) hypotension followed by a potent long lasting (> 25 min) vasopressor effect (ED50 mmHg: 1.8 +/- 0.2 and 6.7 +/- 0.4 nmol kg-1, respectively), with a similar maximal activity (delta MAP: 85 +/- 4 and 81 +/- 2.4 mmHg, respectively). The onset of the big-endothelin-1 vasopressor effect was more rapid (5-6 min) than that of big-endothelin-2 (10-13 min). Big-endothelin-3 was found to induce only a potent, long lasting (> 35 min) hypertension, with a maximal effect of 75 +/- 4.6 mmHg at 10 nmol kg-1 and an ED50 mmHg of 6.5 +/- 0.4 nmol kg-1. The onset of this effect was much slower (20-25 min) than that of the other proendothelins. Pressor responses induced by big-endothelin-1, -2 and -3 (3, 15 and 10 nmol kg-1, respectively) were markedly reduced (60, 80 and 100%) in the presence of phosphoramidon (10 mg kg-1, i.v.). Thiorphan (10 mg kg-1, i.v.) did not inhibit the effects of big-endothelin-1, -2 and -3. 3. In the electrically stimulated rat vas deferens, endothelin-I and -2 were found to be equipotent enhancers of the twitch response (EC100%: 4.0 +/- 0.4 nm and 7.9 +/- 4.8 nm, respectively), both about 3-4 fold as active as endothelin-3 (EC100%: 19 +/- 2.5 nM). Endothelin-1 and -3 showed a comparable maximalstimulatory effect (Emax: 296 +/- 30 and 262 +/- 24%) while endothelin-2 was less active (Emax: 194 +/- 30%).4. Big-endothelin-l and -2 were potent enhancers of the twitch response too (EC 100,%: 10.0 +/- 2.6 nM and 21.6 +/- 3.2 nM, respectively), with a comparable maximal stimulatory effect (Emax: 254 +/- 22 and 264 +/-24%). Big-endothelin-3 was found to be less potent (EC,100%: 275 +/- 21 nM), but retained a marked potentiating effect (Emax: 200 +/- 38%). Phosphoramidon, but not thiorphan, concentration-dependently(10 and 100 microM) reduced big-endothelin-1 (58 and 86% respectively) and big-endothelin-2 (21 and 56%)-mediated responses. Conversely, the big-endothelin-3 effect was reduced by phosphoramidon only at 100 microM (-70%), while thiorphan acts concentration-dependently (31 and 71% at 10 and 100 microM respectively); thus, in the rat vas deferens, big-endothelin-I and -2 were as potent as their corresponding endothelins, while big-endothelin-3 was about 20 times less potent than endothelin-3.5. The increasing effect of endothelin-2 (194 +/- 30% over baseline) was significantly enhanced by either 10 microM phosphoramidon (277 +/- 42%) or thiorphan (318 +/- 15%). The endothelin-I and endothelin-3-mediated twitch enhancement was not affected by the two protease inhibitors (10 microM).6. These results suggest that in vivo big-endothelin-1, -2 and -3, are processed through a similar phosphoramid on-sensitive enzymatic pathway although with different apparent affinity. This enzymatic process is probably attributable to a neutral endoprotease, distinct from neutral-endopeptidase 24.11(NEP). On the other hand, a NEP-like enzymatic activity may be involved, in the rat vas deferens, in the activation of big-endothelin-3 to endothelin-3 and in the metabolism of endothelin-2, but not of endothelin-I or endothelin-3.
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PMID:Comparison of the cardiovascular and neural activity of endothelin-1, -2, -3 and respective proendothelins: effects of phosphoramidon and thiorphan. 810 8

Neutral endopeptidase 24.11 (EC 3.4.24.11; NEP) is a membrane-bound Zn-metalloendopeptidase with a catalytic activity and a specificity very similar to that of thermolysin, a bacterial zinc-endoprotease. NEP can be inactivated by reaction with diethylpyrocarbonate, due to the modification of a histidine residue present in the active site of the enzyme. This histidine residue was proposed to be analogous to His231 in thermolysin, which is involved in the stabilization of the tetrahedral intermediate during the transition state. Using site-directed mutagenesis of the cDNA encoding rabbit NEP, we have created two mutants of NEP where His711 was replaced by either Gln or Phe (NEP-Gln711 and NEP-Phe711). Determination of kinetic parameters showed that both mutants had Km values very similar to that of the non-mutated enzyme but that their kcat values were 25-fold lower. The calculated difference in free energy needed to form the transition state complex was increased by 2.2 kcal/mol for both mutants. These observations strongly suggest that His711 is involved in the stabilization of the transition state by forming an hydrogen bond with the oxyanion of the tetrahedral intermediate.
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PMID:Kinetic evidence that His-711 of neutral endopeptidase 24.11 is involved in stabilization of the transition state. 844 Mar 86


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