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)

Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of acetorphan against placebo. The significant antidiarrhoeal activity of acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example, abdominal pain or distension, nausea and anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of acetorphan in man. The efficacy and tolerance of acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.
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PMID:Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea. 847 99

Thiorphan and acetorphan, two potent inhibitors of enkephalinase (EC 3.4.24.11 membrane-metalloendopeptidase) significantly reduced the castor oil-induced diarrhea in rats when administered intravenously (or orally, for acetorphan) but not when administered intracerebroventricularly. These effects were more marked during the 90 min period following the castor oil challenge but were still significant up to 4-8 h after the latter. Acetorphan was about 6 times more potent than thiorphan. The antidiarrheal activity of both compounds was completely prevented in rats receiving naloxone subcutaneously but not intracerebroventricularly (in the case of thiorphan). In contrast to loperamide, a peripherally acting opiate receptor agonist, the enkephalinase inhibitors did not significantly reduce gastrointestinal transit as measured in the charcoal meal test. The antidiarrheal activity of enkephalinase inhibitors therefore seems attributable to protection of endogenous opioids, presumably outside the brain, and to reduction of intestinal secretion rather than transit.
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PMID:Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors. 348 37

Acetorphan, i.e. N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]-glycine, benzyl ester, is a lipophilic derivative of Thiorphan, a potent inhibitor of "enkephalinase" (EC 3.4.24.11). On purified enkephalinase its inhibitory potency was approximately 1000 fold less than that of Thiorphan but became close to the latter (nanomolar) when it was incubated previously with cerebral membranes. After parenteral administration to mice and rats (1-10 mg/kg) extensive inhibition of cerebral enkephalinase was shown by the depressed enzyme activity in brain membranes from treated animals and the long-lasting potentiation of analgesia elicited by (D-Ala2,Met5)enkephalin (i.c.v.). This suggests that acetorphan easily enters the brain where the active Thiorphan is released. Parenteral acetorphan elicited a series of naloxone-reversible, opioid-like effects, most of which were described previously with intracerebral Thiorphan or other enkephalinase inhibitors. Antinociceptive effects were found in some tests (hot plate jump and phenylbenzoquinone-induced writhing) but not in others (hot plate licking and tail withdrawal). "Antidepressant" effect was found in the "mouse despair" test and antidiarrhoeal effect in the rat castor oil test. Acetorphan also elicited significant increases and decreases in turnover indexes of serotonin and noradrenaline, respectively, in mouse cerebral cortex. In mice chronically treated with acetorphan, the antinociceptive activity of the compound was not modified markedly and no overt withdrawal symptom could be observed after either treatment interruption or administration of naloxone.
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PMID:Pharmacological properties of acetorphan, a parenterally active "enkephalinase" inhibitor. 351 39

Proteinase B, an asparagine-specific endopeptidase, has been purified from germinating vetch (Vicia sativa L.) seeds. The final preparation consists of two enzymically active proteins with molecular masses of approximately 39 kDa and 37 kDa. Synthetic substrates were used to confirm cleavage specificity of the proteinase B preparation. As expected, the enzyme cleaves the substrates at the C-terminal side of Asn residues. The octapeptide ETRNGVEE was digested most efficiently. When Gly was replaced by Ile or Glu, cleavage took place with lower efficiency. Polyclonal antibodies displayed both proteins in cotyledon extracts of germinated vetch seeds. In addition, a strong cross-reacting protein band was found in cotyledon extracts of developing seeds, indicating the presence of a very similar enzyme during seed development. cDNA clones encoding proteinase B precursor have been obtained on the basis of the N-terminal amino acid sequence DDDFEGTRWAILLAGS, by means of the polymerase chain reaction. The cDNA clones contain an open reading frame of 1479 bp encoding a polypeptide of 493 amino acids. The precursor displayed 59% sequence identity to the cDNA-derived amino acid sequence of a vacuolar Asn-specific enzyme from the developing castor beam endosperm which is thought to catalyze the post-translational processing of pro-proteins into the mature forms. Proteinase B is synthesized de novo during seed germination. The results of Southern-blot analyses suggested that there are at least two genes for proteinase B.
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PMID:Purification, cDNA cloning and characterization of proteinase B, an asparagine-specific endopeptidase from germinating vetch (Vicia sativa L.) seeds. 770 62

A plant cysteine endopeptidase with a molecular mass of 35 kD was purified from microbodies of germinating castor bean (Ricinus communis) endosperm by virtue of its capacity to specifically process the glyoxysomal malate dehydrogenase precursor protein to the mature subunit in vitro. Processing of the glyoxysomal malate dehydrogenase precursor occurs sequentially in three steps, the first intermediate resulting from cleavage after arginine-13 within the presequence and the second from cleavage after arginine-33. The endopeptidase is unable to remove the presequences of prethiolases from rape (Brassica napus) glyoxysomes and rat peroxisomes at the expected cleavage site. Protein sequence analysis of N-terminal and internal peptides revealed high identity to the mature papain-type cysteine endopeptidases from cotyledons of germinating mung bean (Vigna mungo) and French bean (Phaseolus vulgaris) seeds. These endopeptidases are synthesized with an extended pre-/prosequence at the N terminus and have been considered to be processed in the endoplasmic reticulum and targeted to protein-storing vacuoles.
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PMID:A cysteine endopeptidase isolated from castor bean endosperm microbodies processes the glyoxysomal malate dehydrogenase precursor protein. 908 76

To understand the mechanism of the maturation of various proteins in protein-storage vacuoles, we purified a 48-kDa aspartic endopeptidase composed of 32-kDa and 16-kDa subunits from castor bean. Immunocytochemical and cell fractionation analyses of the endosperm of maturing castor bean seed showed that the aspartic endopeptidase was localized in the matrix of the protein-storage vacuoles, where a variety of seed storage proteins were also present. The amount of the aspartic endopeptidase increased at the mid-maturation stage of the seeds before accumulation of the storage proteins. To determine how the aspartic endopeptidase is responsible for maturation of seed proteins in concert with the vacuolar processing enzyme, we prepared 35S-labeled proproteins of seed proteins from the endoplasmic reticulum fraction of pulse-labeled maturing endosperm and used the authentic proproteins as substrates for in vitro processing experiments. The purified aspartic endopeptidase was unable to convert any of three endosperm proproteins, pro2S albumin, proglobulin, and proricin, into their mature sizes, while the purified vacuolar processing enzyme could convert all three proproteins. We further examined the activity of aspartic endopeptidase on the cleavage of an internal propeptide of Arabidopsis pro2S albumin, which is known to be removed post-translationally. The aspartic endopeptidase cleaved the propeptide at three sites under acidic conditions. These results suggest that aspartic endopeptidase cannot directly convert pro2S albumin into the mature form, but it may play a role in trimming the C-terminal propeptides from the subunits that are produced by the action of the vacuolar processing enzyme.
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PMID:An aspartic endopeptidase is involved in the breakdown of propeptides of storage proteins in protein-storage vacuoles of plants. 921 Apr 75

This review describes aspects of programmed cell death (PCD). Present research maps the enzymes involved and explores the signal transduction pathways involved in their synthesis. A special organelle (the ricinosome) has been discovered in the senescing endosperm of germinating castor beans (Ricinus communis) that develops at the beginning of PCD and delivers large amounts of a papain-type cysteine endopeptidase (CysEP) in the final stages of cellular disintegration. Castor beans store oil and proteins in a living endosperm surrounding the cotyledons. These stores are mobilized during germination and transferred into the cotyledons. PCD is initiated after this transfer is complete. The CysEP is synthesized in the lumen of the endoplasmic reticulum (ER) where it is retained by its C-terminal KDEL peptide as a rather inactive pro-enzyme. Large number of ricinosomes bud from the ER at the same time as the nuclear DNA is characteristically fragmented during PCD. The mitochondria, glyoxysomes and ribosomes are degraded in autophagic vacuoles, while the endopeptidase is activated by removal of the propeptide and the KDEL tail and enters the cytosol. The endosperm dries and detaches from the cotyledons. A homologous KDEL-tailed cysteine endopeptidase has been found in several senescing tissues; it has been localized in ricinosomes of withering day-lily petals and dying seed coats. Three genes for a KDEL-tailed cysteine endopeptidase have been identified in Arabidopsis. One is expressed in senescing ovules, the second in the vascular vessels and the third in maturing siliques. These genes open the way to exploring PCD in plants.
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PMID:Ricinosomes: an organelle for developmentally regulated programmed cell death in senescing plant tissues. 1132 Aug 88

We have investigated the pro- and anti-inflammatory effects of ricinoleic acid (RA), the main active principle of castor oil, in an experimental model of blepharitis induced by intradermal injection of carrageenan in the guinea-pig eyelid and its possible capsaicin-like mode of action on acutely dissociated rat dorsal root ganglia (DRG) neurons in vitro. Topical treatment with RA (10-100 mg/guinea-pig) or capsaicin (1-10 mg/guinea-pig) caused eyelid reddening and oedema. At lower doses (0.3-3 mg/guinea-pig and 0.009-0.09 mg/guinea-pig for RA and capsaicin, respectively) both drugs significantly potentiated the eyelid oedema induced by carrageenan. The tachykinin NK1 receptor antagonist FK 888 (0.59 mg/kg s.c.) abolished the potentiation of carrageenan-induced eyelid oedema induced by either RA or capsaicin. The neutral endopeptidase inhibitor, thiorphan (1.3 mg/kg i.v.) significantly enhanced the potentiation of carrageenan-induced eyelid oedema produced by RA. This potentiating effect was abolished by FK 888. Repeated (8 days) topical application of RA (0.9 mg/guinea-pig) or capsaicin (0.09 mg/guinea-pig) inhibited the carrageenan-induced eyelid oedema. This anti-inflammatory effect was accompanied by a reduction (75%-80% of SP and 46%-51% of NKA) in tachykinin content of the eyelids, as determined by radioimmunoassay. In dissociated rat DRG neurons, RA (0.1 mM for 5 min) significantly inhibited the inward currents induced by application of capsaicin (1 microM) and/or low pH (5.8), without inducing any currents by itself or changing voltage-dependent currents. Moreover, after 24-h incubation, RA (0.1 mM) significantly decreased the capsaicin (1 microM)-induced calcitonin gene-related peptide (CGRP) release from rat DRG neurons, whereas acute drug superfusion did not evoke CGRP release by itself. Summarizing, RA possesses capsaicin-like dual pro-inflammatory and anti-inflammatory properties which are observed upon acute and repeated application, respectively. However, unlike capsaicin, RA does not induce inward current in DRG neurons and it is devoid of algesic properties in vivo.
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PMID:Pro- and anti-inflammatory actions of ricinoleic acid: similarities and differences with capsaicin. 1153 59

In the senescing endosperm of germinating castor bean (Ricinus communis) a special organelle (the ricinosome) releases a papain-type cysteine endopeptidase (CysEP) during the final stages of cellular disintegration. Protein cleavage sites for the Ricinus CysEP were determined with fluorogenic peptides (Abz-Xaa-Arg-/-Gln-Gln-Tyr(NO2)-Asp). The highest kcat/Km values were obtained with neutral amino acid residues with large aliphatic and non-polar (Leu, Val, Ile, Met) or aromatic (Phe, Tyr, Trp) side-chains. A second series (Abz-Leu-Xaa-/Gln-Pro-Tyr(NO2)-Asp) was evaluated. Based on these results, the covalent binding inhibitor H-D-Val-Leu-Lys-chloromethylketone (CMK) was chosen as substrate analogue for replacement in the catalytic site. Unusually, CysEP cleaved beta-casein N and C-terminal to the amino acid proline. CysEP was crystallized, its structure was solved by molecular replacement at 2.0 A resolution and refined to a R-factor of 18.1% (Rfree=22.6%). The polypeptide chain folds as in papain into two domains divided by the active site cleft, an elongated surface depression harboring the active site. The non-primed specificity subsites of the proteinase are clearly defined by the H-D-Val-Leu-Lys-CMK-inhibitor covalently bound to the active site. The absence of the occluding loop, which blocks the active site of exopeptidases at the C-terminal side of the scissile bond, identifies CysEP as an endopeptidase. The more open pocket of the Ricinus CysEP correlates with the extended variety of substrate amino acid residues accommodated by this enzyme, including even proline at the P1 and P1' positions. This may allow the enzyme to attack a greater variety of proteins during programmed cell death.
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PMID:The 2.0 A crystal structure and substrate specificity of the KDEL-tailed cysteine endopeptidase functioning in programmed cell death of Ricinus communis endosperm. 1503 72

Leupeptin, a tripeptide inhibitor of some proteinases, was shown previously to maintain the stability of several enzymes (isocitrate lyase, fumarase, and catalase) in crude extracts of castor bean endosperm. This reagent is now shown to inhibit the breakdown of water-soluble and crystalloidstorage proteins of the protein bodies isolated from castor beans by the SH-proteinase and it also inhibits the endopeptidase from mung beans. When suitably introduced into the endosperm of dry castor beans it strongly inhibits germination and seedling development. Application of leupeptin to endosperm halves removed from the seed prevents the normal development of enzymes concerned with gluconeogenesis from fat and drastically curtails sugar production. The results suggest that the SH-proteinase is intimately involved in the mobilization of storage proteins.
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PMID:Effects of leupeptin on proteinase and germination of castor beans. 1666 11


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