Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phosphonamide peptide, N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid, previously shown to block Clostridium histolyticum collagenases, was examined as a putative inhibitor of endopeptidase 24.16 and endopeptidase 24.15. Hydrolysis of two endopeptidase 24.16 substrates, i.e. 3-carboxy-7-methoxycoumarin (Mcc)-Pro-Leu-Gly-Pro-D-Lys-dinitrophenyl (Dnp) and neurotensin, were completely and dose-dependently inhibited by the phosphonamide inhibitor with KI values of 0.3 and 0.9 nM respectively. In addition, the phosphonamide peptide inhibited the hydrolysis of benzoyl (Bz)-Gly-Ala-Ala-Phe-(pAB) p-aminobenzoate and neurotensin by endopeptidase 24.15 with about a 10-fold lower potency (KI values of 5 and 7.5 nM respectively). The selectivity of this inhibitor towards several exo- and endo-peptidases belonging to the zinc-containing metallopeptidase family established that a 1 microM concentration of this inhibitor was unable to affect leucine aminopeptidase, carboxypeptidase A, angiotensin-converting enzyme and endopeptidase 24.11. The present paper therefore reports on the first hydrophilic highly potent endopeptidase 24.16 inhibitor and describes the most potent inhibitory agent directed towards endopeptidase 24.15 developed to date. These tools should allow one to assess the contribution of endopeptidase 24.16 and endopeptidase 24.15 to the physiological inactivation of neurotensin as well as other neuropeptides.
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PMID:Potent inhibition of endopeptidase 24.16 and endopeptidase 24.15 by the phosphonamide peptide N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid. 133 78

The inhibitory effect of various dipeptides on the neurotensin-degrading metallopeptidase, endopeptidase 24.16, was examined. These dipeptides mimick the Pro10-Tyr11 bond of neurotensin that is hydrolyzed by endopeptidase 24.16. Among a series of Pro-Xaa dipeptides, the most potent inhibitory effect was elicited by Pro-Ile (Ki approximately 90 microM) with Pro-Ile greater than Pro-Met greater than Pro-Phe. All the Xaa-Tyr dipeptides were unable to inhibit endopeptidase 24.16. The effect of Pro-Ile on several purified peptidases was assessed by means of fluorigenic assays and HPLC analysis. A 5 mM concentration of Pro-Ile does not inhibit endopeptidase 24.11, endopeptidase 24.15, angiotensin-converting enzyme, proline endopeptidase, trypsin, leucine aminopeptidase, pyroglutamyl aminopeptidase I and carboxypeptidase B. The only enzyme that was affected by Pro-Ile was carboxypeptidase A, although it was with a 50-fold lower potency (Ki approximately 5 mM) than for endopeptidase 24.16. By means of fluorimetric substrates with a series of hydrolysing activities, we demonstrate that Pro-Ile can be used as a specific inhibitor of endopeptidase 24.16, even in a complex mixture of peptidase activities such as found in whole rat brain homogenate.
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PMID:Specific inhibition of endopeptidase 24.16 by dipeptides. 176 Oct 32

Consensus of the literature points towards a neuropsychogenetic model of alcoholism. Evidence in both animals and humans tends to support the proposed "genotype" theory of alcohol-seeking behavior, whereby a predisposition to alcohol preference may be mediated in part by either innate (genetic) or environmentally (stress and/or alcohol) induced brain opioid peptide dysfunction. Potential therapeutic rationale involving the utilization of novel inhibitors of carboxypeptidase A (enkephalinase) which raise endogenous enkephalin levels and possess anti-alcohol seeking effects is emphasized.
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PMID:Evidence for the importance of the "genotype" theory in alcohol seeking behavior: a commentary. 301 59

cDNA clones encoding rat enkephalinase (neutral endopeptidase, EC 3.4.24.11) have been isolated in lambda gt10 libraries from both brain and kidney mRNAs and the complete 742 amino acid sequence of rat enkephalinase is presented. The enzyme possesses a single transmembrane spanning domain near the N-terminal of the molecule but lacks a signal sequence. Because enkephalinase has it active site located extracellularly and is thus an ectopeptidase, we suggest that the N-terminal transmembrane region of the enzyme anchors the protein in membranes and that the majority of the protein, including the carboxy terminus, is extracellular. Enkephalinase, a zinc-containing metallo enzyme, displays homology with other zinc metallo enzymes such as carboxypeptidase A, B and E, suggesting enzymatic similarities in these enzymes.
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PMID:Molecular cloning and amino acid sequence of rat enkephalinase. 355 89

Thiorphan, N-[(R,S)-3-mercapto-2-benzylpropanoyl]glycine is a highly potent inhibitor (Ki = 3.5 nM) of "enkephalinase," a metalloendopeptidase cleaving the Gly-Phe bond (positions 3 and 4) of enkephalins in brain tissue. In accordance with this property, thiorphan displays antinociceptive activity after systemic administration. However, thiorphan also inhibits to a lesser extent (Ki = 140 nM) the widely distributed angiotensin-converting enzyme, a carboxydipeptidase implicated in blood pressure regulation. Therefore, in view of an eventual clinical use of enkephalinase inhibitors, it was very important to develop fully specific compounds. Such derivatives were obtained taking into account that N-methylation of the ultimate amide bond of dipeptides strongly decreases enkephalinase affinity without affecting angiotension-converting enzyme recognition, whereas retro-inversion of the amide bond leads to the inverse effect. Thus, the retro-inverso dipeptide (R)-H2N-CH(CH2 phi)-NHCO-CH2-CO2H exhibits an inhibitory potency on enkephalinase (IC50 approximately equal to 12 muM) close to that of the natural dipeptide L-Phe-Gly (IC50 approximately equal to 3 muM). This result shows the topological analogy between the crucial components involved in enkephalinase recognition both in active dipeptides and structurally related retro-inverso isomers. Taking into account these observations, retro-thiorphan, (R,S)-HS-CH2-CH-(CH2 phi)-NHCO-CH2-COOH, was prepared. As compared to thiorphan, the retro isomer is 50% as potent (Ki = 6 nM) on enkephalinase but displays a drastic loss of potency on angiotension-converting enzyme (IC50 greater than 10,000 nM). This specificity was interpreted as a consequence of differences in the stereochemical constraints involving enzyme-inhibitor hydrogen bonding. This hypothesis is supported by reported crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. As expected, retro-thiorphan exhibits about the same analgesic potency as thiorphan on the hot plate and writhing tests in mice. Therefore, the topological concept of retro-inverso isomers could be extended to other enkephalinase inhibitors, allowing the design of potent and highly selective compounds occurring as new classes of analgesic and psychoactive agents.
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PMID:Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan. 630 95

Despite the similarities in their mechanism of action, the structural requirements for selective interaction with angiotensin-converting enzyme or enkephalinase are different. Inhibitory potency of a series of new mercaptoalkanoyl amino acids were determined on pure angiotensin-converting enzyme (EC 3.4.15.1) from porcine plasma and on neutral metalloendopeptidase (EC 3.4.24.11) purified from rat brain. This latter enzyme, first designated as enkephalinase, seems to be synaptically involved in the degradation of enkephalins. All tested compounds, whose design was based on the classical active-site model of metallopeptidases, are reversible and competitive inhibitors of both enzymes. Owing to the remarkable similarity in the general topology of metallopeptidases, the differences in optimal binding requirements to enkephalinase and angiotensin-converting enzyme were interpreted from crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. The large size of the S'1 subsite of enkephalinase allows efficient binding (Ki approximately equal to 2-30 nM) of aromatic and bulky hydrophobic residues such as a cyclohexyl ring. In contrast, a methyl group in position P'1 favors inhibitory potency against angiotensin-converting enzyme while a cyclohexyl ring leads to a complete loss of activity. This feature could mean that optimal binding of the Zn atom present in the catalytic site is a more stringent requirement in angiotensin-converting enzyme than in enkephalinase. An increase in the size of the P'2 component of thiol inhibitors potentiates the affinity for angiotensin-converting enzyme without a significant change on enkephalinase. Finally, methylation of the ultimate amide bond of inhibitors produces a 30-fold decrease in potency towards enkephalinase but does not affect the binding of angiotensin-converting enzyme. These findings allow a rational design of selective inhibitors of enkephalinase, an essential prerequisite for their possible clinical use as new analgesic and psycho-active agents.
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PMID:Differences in the structural requirements for selective interaction with neutral metalloendopeptidase (enkephalinase) or angiotensin-converting enzyme. Molecular investigation by use of new thiol inhibitors. 632 Nov 77

A carboxypeptidase A-like enzyme known as cathepsin A was purified from rat brain by extraction with Triton X-100, followed by chromatography on DEAE-Sephadex A-50 and gel-filtration. Purified enzyme was devoid of contamination of tryptic-like enzymes, by dipeptidyl carboxypeptidase (angiotensin converting enzyme) and of enkephalinnases cleaving the Tyr-Gly and Gly-Phe bonds of Met-enkephalin. Incubation of purified enzyme with Met-enkephalin-Arg6-Phe7, a naturally occurring enkephalin surrogate, was accompanied by the release of three products as detected by reverse phase HPLC. Subsequent amino acid analysis identified these as Phe, Met-enkephalin-Arg6, and Met-enkephalin, indicating cleavage at the Arg6-Phe7 and Met5-Phe6 bonds. Breakdown followed a precursor-product-relationship with the hexapeptide appearing as an intermediate and the pentapeptide as the final product. The Km for cleavage of the Arg-Phe site was 0.09 mM. Rates of cleavage of hexa- and heptapeptide accord with those found for synthetic N-protected dipeptide substrates. Cathepsin A does not act as an enkephalinase in the accepted sense, since no breakdown of Met-enkephalin was observed.
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PMID:Conversion of Met-enkephalin-Arg6-Phe7 by a purified brain carboxypeptidase (cathepsin A). 729 Oct 41

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic construction of guinea-pig tracheal smooth muscle. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on constriction induced by the non-immunological mast cell degranulator-compound 48/80. Phosphoramidon produced significant leftward shift of the compound 48/80 concentration-response curve with corresponding decrease in the EC50 value from 51 (28-80) micrograms/ml to 42 (20-72) micrograms/ml. When added during the compound 48/80-induced constriction, phosphoramidon significantly increased the magnitude of this constriction by 69.7% after 30 min, and 78.9% after 45 min. Phosphoramidon was ineffective in tracheal rings from tachykinin-depleted guinea pigs. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) and leukotriene receptor antagonist (ICI 198.615, 5 microM) significantly diminished the contractile response to compound 48/80 and prevented a phosphoramidon-dependent increase of this constriction. These results suggest that compound 48/80 induces the release of tachykinins by the stimulatory activity of histamine and leukotrienes. Anaphylactic release of tachykinins would therefore not depend directly on the antigen-antibody reaction.
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PMID:Inhibition of neutral endopeptidase potentiates compound 48/80-induced constriction of guinea-pig tracheal smooth muscle. 754 50

We compared angiotensin I-converting enzyme (ACE) and carboxypeptidase A (CPA), two zinc metallopeptidases, for the hydrolysis of the usual ACE synthetic substrate benzoylglycyl-histidyl-leucine (HHL) investigating the possible interference by CPA in the determination of ACE activity in biological fluids. Both purified enzymes hydrolyse HHL in a radiochemical assay with the same optimal pH, a characteristic divalent metal requirement, a close similar behavior against inhibitors of other metallopeptidases, such as enkephalinase and kininase I, and the involvement of arginine and lysine residues in their active site. Conversely, CPA does not show the other catalytic properties of ACe, i.e. chloride dependence, low Km for HHL, inhibition by specific synthetic ACE inhibitors and antibody, also hydrolysis of the other ACE substrate furylacryloylphenylalanyl-glycyl-glycine (FAPGG). We advise the use of ACE inhibitors to validate ACE measurement with HHL or, alternatively, FAPGG, which is a more specific substrate for ACE, must be preferred, although the poor sensitivity of the spectrophotometric assay with this substrate limits its use to blood samples.
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PMID:Carboxypeptidase A hydrolyses benzoylglycyl-histidyl-leucine but not furylacryloyl-phenylalanyl-glycyl-glycine, two usual substrates for angiotensin I-converting enzyme. 758 46

This review describes novel aspects of enzymes in the pertinent tissues of the airway and those associated with inflammatory cells. These include neutral endopeptidase, histamine N-methyltransferase, mast cell and neutrophil enzymes which have a potentially important role in the modulation of several airway functions such as bronchoconstriction, gland secretion, plasma extravasation and cough. Thus, regulation of enzyme activities in the airways may have new therapeutic implications in inflammatory diseases of airways.
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PMID:Enzymatic modulation of bronchoconstriction, gland secretion, plasma extravasation and cough. 794 May 21


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