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 activity in rat cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE) was determined in control animals and in rats with monoarthritis. Enzymatic activities were measured with specific radioimmunoassays toward the N-terminal products Leu-enkephalin-Arg6 and substance P1-7, respectively. A monoarthritis stable during weeks 2-6 post-injection was induced by injection (0.05 ml) into one joint with Freund's adjuvant. Both SPE and DCE were significantly decreased 15 days after the intraarticular injection. Despite the degree of arthritis that was sustained equally at four weeks after inoculation, both DCE and SPE were back to control levels at that time. It can therefore be concluded that arthritis from a single joint is sufficient to elicit changes in CSF convertase activities, and that these effects disappear between 2 and 4 weeks after injection, although the arthritis persists.
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PMID:Decreased cerebrospinal fluid neuropeptide-converting enzyme activity in monoarthritic rats. 127 76

Whereas endopeptidase 24.11 cleaves the Gly-Phe bond in both Met- and Leu-enkephalin, endopeptidase 24.15 rapidly converts dynorphin A1-8, alpha and beta-neoendorphin into Leu-enkephalin, and Met-enkephalin-Arg6-Gly7-Leu8 (MERGL) into Met-enkephalin. Inhibitors of both endopeptidase 24.11 and endopeptidase 24.15 each produce antinociception, and inhibitors of endopeptidase 24.11 increase the magnitude of enkephalin antinociception. The present study compared the central antinociceptive effect of an inhibitor of endopeptidase 24.15, N-[1-(R-S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB) with one of endopeptidase 24.11 N-[1-(RS)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (cFP-F-pAB) upon central opioid antinociception induced by MERGL, metenkephalin and dynorphin A1-8. cFP-AAF-pAB, but not cFP-F-pAB increased MERGL antinociception on the tail-flick and jump tests. In contrast, cFP-F-pAB, but not cFP-AAF-pAB increased met-enkephalin antinociception. Whereas central dynorphin A1-8 failed to induce antinociception itself, co-administration of cFP-AAF-pAB and dynorphin A1-8 increased nociceptive thresholds. This effect was not accompanied by motor dysfunction, but was blocked by systemic pretreatment with naloxone or central pretreatment with naltrexone or nor-binaltorphamine, but not beta-funaltrexamine. These data indicate that endopeptidase 24.15 may be responsible for the degradation of specific opioid peptides (e.g., MERGL, dynorphin), and that this process may prevent the full expression of their antinociceptive properties.
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PMID:Endopeptidase 24.15 inhibition and opioid antinociception. 134 91

The cleavage of dynorphin and three analogs containing paired basic residues by several proteases was investigated. The cysteine protease of neuroblastoma cells cleaved only the bond between Arg-Arg residues. Submandibular arginyl-endopeptidase, however, cleaved bonds between both Arg-Arg and Arg-Lys residues, and pancreatic trypsin at the carboxyl sides of both arginine and lysine residues. This shows that the cysteine protease is highly specific for paired arginine residues.
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PMID:Dynorphin-degrading cysteine protease is highly specific for paired arginine residues. 134 63

The main somatostatin-degrading proteases were purified from rat and pig brain homogenates and characterized as thiol- and metal-dependent endoproteases. Two types of proteases with apparent native and subunit molecular masses of 70 kDa and 68 kDa could be differentiated in both species. Beside somatostatin, both hydrolyzed several other neuropeptides with chain lengths between 8 and 30 amino acid residues. Cleavage sites were generally similar or identical, but some clear exceptions were observed for enzymes from both species which could be used to differentiate between the two proteases. The 68-kDa protease cleaved somatostatin at three bonds (Asn5-Phe6, Phe6-Phe7 and Thr10-Phe11) and neurotensin only at the Arg8-Arg9 bond, whereas the 70-kDa protease digested somatostatin at only two bonds (Phe6-Phe7 and Thr10-Phe11) and neurotensin as well as acetylneurotensin-(8-13) additionally (pig protease) or almost exclusively (rat protease) at the Pro10-Tyr11 bond. Relative rates for the digestions of various peptides were, however, more dependent on the species than on the type of protease. Cleavage sites for angiotensin II, bradykinin, dynorphin, gonadoliberin and substance P were, apart from different rates, identical for both proteases. In both species the 68-kDa protease was found to be mainly, but not exclusively, soluble and not membrane-associated, whereas the inverse was detected for the 70-kDa protease. Based on distinct molecular and catalytic properties, the 68-kDa protease is supposed to be congruent with the endopeptidase 24.15 (EC 3.4.24.15), the 70-kDa protease with endopeptidase 24.16 (EC 3.4.24.16, neurotensin-degrading endopeptidase). This investigation demonstrates that both proteases hydrolyze various neuropeptides with similar cleavage sites, but with species-dependent activity. Species-independent distinctions are the exclusive action of endopeptidase 24.16 on acetylneurotensin-(8-13) and liberation of free Phe from somatostatin only by endopeptidase 24.15.
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PMID:Purification of the main somatostatin-degrading proteases from rat and pig brains, their action on other neuropeptides, and their identification as endopeptidases 24.15 and 24.16. 135 47

We investigated the effects of collagen II-induced arthritis on two cerebrospinal fluid (CSF) enzymes converting dynorphin A and substance P (SP), namely dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE). The products generated by these enzymes are the bioactive fragments Leu-enkephalin-Arg6 and substance P, respectively. The strain used (DA rats) is very sensitive towards induction of arthritis. The collagen arthritis is a chronic autoimmune arthritis induced by native rat collagen type II (CII). Following intradermal injection of CII into the tailbase. CSF was sampled on day 21 (acute arthritis) and day 38 (chronic arthritis). Control rats were untreated because the strain used developed an acute and self-limited arthritis (adjuvant arthritis) when administered vehicle (i.e. incomplete Freund's adjuvant). The DCE activity was significantly lowered in the acute phase of arthritis (P less than 0.05) when analysed with two-factor analysis of variance (ANOVA). The enzyme converting SP (SPE) also showed a significant decrease in the acute phase of arthritis (P less than 0.05). These results demonstrate that both DCE and SPE are affected in the acute phase of arthritis. A functional role of these enzymes in processing pain-related neuropeptides is therefore implicated.
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PMID:Decreased neuropeptide-converting enzyme activities in cerebrospinal fluid during acute but not chronic phases of collagen induced arthritis in rats. 138

The duration of action and potency of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidases 24.11 and 24.15. Whereas endopeptidase 24.11 cleaves enkephalin pentapeptides, endopeptidase 24.15 degrades longer-chained opioids including dynorphin A1-8 and met-enkephalin-Arg6-Gly7-Leu8 (MERGL). Inhibitors of endopeptidase 24.11 and 24.15 both increase basal nociceptive thresholds and respective forms of opioid antinociception. Acute exposure to certain environmental stressors can produce antinociception which is opioid mediated; inhibitors of endopeptidase 24.11 potentiate this effect. The present study evaluated whether central administration of a selective inhibitor of endopeptidase 24.15, N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB) increased antinociception following intermittent cold-water swims (ICWS) in rats. cFP-AAF-pAB (0.25-25 nmol, ICV) dose-dependently increased ICWS antinociception on the tail-flick and jump tests without affecting basal nociceptive thresholds. The opioid mediation of ICWS antinociception was confirmed by significant reductions in this response following naloxone. These data indicate that longer-chained endogenous opioid peptides participate in the antinociception induced by ICWS.
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PMID:Increases in opioid-mediated swim antinociception following endopeptidase 24.15 inhibition. 166 30

Fast atom bombardment mass spectrometry (FAB-MS) and high-performance liquid chromatography using a photodiode-array ultraviolet detector were applied to study a dynorphin-converting endopeptidase from the human pituitary gland. The specificity of the enzyme was tested towards various opioid peptides derived from the prodynorphin precursor, i.e. dynorphin A, dynorphin B and alpha-neoendorphin. Peptide fragments were analysed directly by continuous-flow FAB-MS and those containing aromatic amino acids were detected independently by the photodiode-array ultraviolet detector. The results obtained suggest a similar processing of these structure-related substrates and it appears that the enzyme recognizes the dibasic stretch in their sequence. It is also clear from this study that the combination of the above techniques provides a powerful tool for studies of enzymatic conversion among the prodynorphin-derived peptides and it should be applicable to studies of similar mechanisms in other peptide systems.
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PMID:Approach to studying proteinase specificity by continuous-flow fast atom bombardment mass spectrometry and high-performance liquid chromatography combined with photodiode-array ultraviolet detection. 168 13

Neurotensin (NT) endopeptidase (EC 3.4.24.16) has been purified about 800-fold from pig brain by four sequential chromatographic steps depending on ion-exchange and hydrophobic interactions. Two types of preparation were studied: one from a Triton X-100-solubilized membrane fraction, and the other from the soluble fraction containing 90% or more of the total activity in the homogenate. NT endopeptidase activity was monitored by high-precision liquid chromatography of the two peptide products, characterized as NT-(1-10) and NT-(1-8), resulting from cleavage of the Pro10-Tyr11 and Arg8-Arg9 bonds respectively. As purification proceeded, from both membranes and cytosol, the yield of the two products achieved a constant ratio of 5:1 and this ratio was reproduced in repeated purifications. However, a distinct peptidase which hydrolysed exclusively at the Arg8-Arg9 bond was partially resolved from NT endopeptidase by chromatography on hydroxyapatite, and this activity was further purified and assigned to endopeptidase-24.15 (EC 3.4.24.15). SDS/PAGE of both preparations of neurotensin endopeptidase revealed a major band of apparent Mr 75000, and treatment of the membrane-associated form with N-Glycanase gave no evidence that the enzyme was a glycoprotein. The membrane-associated and cytosol forms of NT endopeptidase activities, monitored for both NT-(1-10) and NT-(1-8) products, were compared in their responses to 1,10-phenanthroline, EDTA, dithiothreitol (DTT) and some synthetic site-directed inhibitors of endopeptidase-24.15 or peptidyl dipeptidase A. The effects revealed no significant differences between the two preparations, nor did the reagents discriminate between the activities generating the two NT fragments. The partially purified form of endopeptidase-24.15 was also included in this comparison: while some responses were similar, this peptidase was distinguishable in its activation by DTT and its relative resistance to inhibition by EDTA. Both forms of NT endopeptidase were found to hydrolyse other substrates, including Boc-Phe-Ala-Ala-Phe-4-aminobenzoate, bradykinin and substance P (these at faster rates than neurotensin), as well as dynorphin A-(1-8) and luliberin. The bonds hydrolysed in these neuropeptides, as well as in angiotensins I and II and alpha-neoendorphin, were defined. These studies confirm that NT endopeptidase is distinct from endopeptidase-24.15. They further show that the former is a soluble enzyme, not an integral membrane protein, that it is not peptide-specific and that it might be more appropriately named. enzyme, not an integral membrane protein, that it is not peptide-specific and
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PMID:Purification and properties of a neurotensin-degrading endopeptidase from pig brain. 190 21

Endopeptidase 24.15, a metalloendopeptidase active in brain, rapidly converts prodynorphin-derived peptides into leu-enkephalin. Inhibitors of this enzyme slow the degradation of these peptides in vivo and in vitro. The present study evaluated two inhibitors of endopeptidase 24.15, N-[1-(RS)-carboxy-3-phenyl-propyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-D-Ala-Phe-p-aminobenzoate (cFP-A(D)AF-pAB), for antinociception on the tail-flick and jump tests in rats following intracerebroventricular administration relative to an inhibitor of endopeptidase 24.11, N-(1-(RS)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (cFP-F-pAB). cFP-AAF-pAB, cFP-A(D)AF-pAB and cFP-F-pAB produced equipotent dose-dependent (25-250 nmol) and time-dependent (5-7 h) antinociception with larger effects on the jump (49-51% increase) relative to the tail-flick (28-41% increase) test. Naloxone (1 mg/kg, SC) significantly reduced antinociception elicited by all inhibitors on the jump test. Motor performance failed to be affected by inhibitor administration. The gradual appearance of antinociception and its naloxone sensitivity suggest that these effects are mediated through inhibition of opioid peptide degradation.
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PMID:Antinociceptive properties of inhibitors of endopeptidase 24.15. 193 29

Conversion of the octapeptide dynorphin (Dyn) A-(1-8) to Leu5-enkephalin (LE) by endopeptidase EC 3.4.24.15 (EP-24.15) in vivo was examined using the technique of ventriculocisternal perfusion. Peptides were administered intracerebroventricularly in the presence or absence of the EP-24.15 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFPAAF-pAB) via cannulae placed into the lateral ventricle of urethane-anesthetized rats. The concentration of Dyn-like peptides and LE within the CSF was monitored by radioimmunoassay in samples of CSF taken from a second cannula placed in the cisterna magna. In the absence of inhibitor, less than 5% of the Dyn A-(1-8) administered was recovered in CSF. Immunoreactive LE, which is normally not found in CSF, increased rapidly in content following Dyn A-(1-8) infusion, an observation suggesting that the larger peptide is converted to LE. When the inhibitor cFPAAF-pAB was coadministered with Dyn A-(1-8), the concentration of immunoreactive Dyn A-(1-8) after 5 min was 40 times higher than that found in the absence of inhibitor. The angiotensin converting enzyme inhibitor captopril reduced the degradation of Dyn A-(1-8) to a much lesser degree. The inhibitor of EP-24.15 also afforded some protection of other Dyn-like peptides. No EP-24.15 activity was found in rat CSF, whereas high activity was found in the choroid plexus. Taken together, these data clearly indicate that an ectoenzyme form of EP-24.15 rapidly converts intracerebroventricularly administered Dyn-like peptides to LE.
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PMID:An inhibitor of endopeptidase-24.15 blocks the degradation of intraventricularly administered dynorphins. 197 55


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