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)

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

N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. The present investigation describes its ACE and other enzymes inhibitory properties and compares it to those of captopril, MK-421 and MK-422 in vitro. MK-0521 inhibited rat pulmonary ACE by 50% (IC50) at a concentration of 3 nM and was 6.13 times more potent than captopril. The IC50 values of MK-421 and MK-422 against ACE were 2,000 nM and 3.5 nM, respectively. MK-0521 had practically no inhibitory activities against carboxypeptidase A, carboxypeptidase B, leucine aminopeptidase, papain, pepsin and trypsin. The kinetic study on the inhibitory activity of M-0521 against ACE using Lineweaver-Burk plots indicated that MK-0521 exerted competitive ACE inhibition. The dialysis study conducted on the ACE-MK-0521 complex revealed that the inhibitory effect of MK-0521 against ACE was reversible. In the guinea pig ileum, MK-0521 potentiated the contractile effect of bradykinin and depressed the contractile effect of angiotensin I. These effects on bradykinin and angiotensin I were 33.11 and 2.63 times more potent than that of captopril, respectively. The present results suggest that MK-0521 may show a potent hypotensive effect in vivo.
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PMID:[Inhibitory effect of N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) on angiotensin converting enzyme in vitro]. 254 78

An inhibitor of sodium-potassium-ATPase has been partially purified from the culture medium obtained from hypothalamic cells maintained in a capillary membrane perfusion system, and some of the properties of this inhibitory factor have been investigated. Gel filtration (Sephadex G-25 Superfine) of heat-treated medium (80 degrees C for 10 min) resulted in elution of inhibitory activity in the post-salt fraction. These fractions inhibited active (i.e. sodium-potassium-ATPase-mediated) sodium transport in intact human erythrocytes, displaced [3H]ouabain from its binding site, and directly inhibited canine kidney sodium-potassium-ATPase as measured by NADH oxidation. High-performance liquid chromatography (on Hypersil ODS) of these fractions after desalting yielded one region which showed inhibitory activity on all three assays. Inhibition of sodium-potassium-ATPase was dose-related and filtered through an Amicon UM10 membrane. Incubation of this material with dispase, carboxypeptidase A, chymotrypsin, and prolidase destroyed inhibitory activity, whereas trypsin and leucine aminopeptidase were ineffective. These studies show that hypothalamic neurones release a low molecular weight heat-stable peptide which inhibits active sodium transport, ouabain binding, and sodium-potassium-ATPase.
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PMID:Characterization and partial purification of the sodium-potassium-ATPase inhibitor released from cultured rat hypothalamic cells. 299 73

Effects of condensed tannins isolated from Rhei Rhizoma on the activities of angiotensin converting enzyme (ACE) and various proteases were examined in vitro. Among the various condensed tannins tested, procyanidin B-5 3,3'-di-O-gallate and procyanidin C-1 3,3',3"-tri-O-gallate strongly inhibited the activity of ACE. The concentration of procyanidin B-5 3,3'-di-O-gallate required for 50% inhibition of ACE was 1.3 X 10(-6) M. The inhibition of ACE by condensed tannins was reversible and non-competitive, according to dialysis and to Dixon plots. However, over one hundred times the concentration was required to inhibit activities of other proteases such as trypsin, chymotrypsin, leucine aminopeptidase, carboxypeptidase A and urinary kallikrein. These results suggest that the inhibitory effects of condensed tannins on the activities of ACE are specific.
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PMID:Inhibitory effects of condensed tannins on angiotensin converting enzyme. 303 68

A novel inhibitor of angiotensin I converting enzyme (ACE), designated K-13, was isolated from the culture broth of Micromonospora halophytica subsp. exilisia K-13. K-13 inhibited ACE non-competitively when hippuryl-L-histidyl-L-leucine was used as a substrate. The inhibition constant (Ki) was 0.349 microM. K-13 hardly inhibited carboxypeptidase A, trypsin, alpha-chymotrypsin, leucine aminopeptidase, and aminopeptidase B even at a level of 61 microM. When K-13 was administered intravenously to rats, it inhibited the pressor response to angiotensin I.
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PMID:K-13, a novel inhibitor of angiotensin I converting enzyme produced by Micromonospora halophytica subsp. exilisia. I. Fermentation, isolation and biological properties. 303 44

The origin of the fluorescence changes observed in stopped-flow experiments of the hydrolysis of three 5-(dimethylamino)naphthalene-1-sulfonyl-(dansyl) peptide substrates by porcine kidney cytosol leucine aminopeptidase has been investigated. The substrates used all have the potential to accept energy from aromatic residues of the enzyme via resonance energy transfer when they are bound as enzyme-substrate complexes, indicating that fluorescence changes due to the buildup and decay of such intermediates are possible. However, the fluorescence of these substrates differs from that of the products, and direct excitation of their dansyl groups during hydrolysis can also be responsible for the observed fluorescence changes due to changes in the concentrations of free substrate and product. The dansyl fluorescence changes observed with excitation wavelengths near 280 nm are not accompanied by quenching of the enzyme fluorescence, as would be expected if there were enzyme-to-substrate energy transfer. The magnitude of the maximal fluorescence change at a fixed concentration of substrate is also independent of the enzyme concentration. Furthermore, the excitation profile for the fluorescence changes shows that they arise from direct excitation of the dansyl group. Thus, there is no energy transfer in these reactions, and the fluorescence changes observed arise from direct excitation of the dansyl group and reflect the instantaneous concentration of substrate. This behavior contrasts sharply with that for the reaction of carboxypeptidase A with dansyl-Gly-Tyr, which has been studied as a positive control for an energy-transfer system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydrolysis of dansyl-peptide substrates by leucine aminopeptidase: origin of dansyl fluorescence changes during hydrolysis. 316 28

The use of competitive spectrophotometry to measure kinetic constants for enzyme-catalyzed reactions is described. The equation for the progress curve characterizing the kinetic behavior of an enzyme acting simultaneously on two alternative substrates is derived. By the addition of a competition term to the integrated Michaelis-Menten equation, the kinetic constants of an alternative substrate can be evaluated by measuring the competition with a substrate of known kinetic constants in a single experiment. Studies are presented involving the enzymes leucine aminopeptidase (LAP) and carboxypeptidase A (CPA). The results obtained with LAP and CPA showed that the kinetic constants determined using competitive spectrophotometry were in agreement with values cited in the literature or with values determined by single substrate enzyme kinetics.
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PMID:Rapid determination of kinetic constants by competitive spectrophotometry. 338 8

1. Using a previously established method of isolating an active-sodium-transport inhibitor (ASTI) from hypothalamic cell culture medium, the inhibitor was isolated and partially purified from sequential passages through Sephadex G-25 and h.p.l.c., and its effects on de-endothelialized rabbit aortic strips were investigated. 2. ASTI caused a cumulative concentration-dependent increase in tension which reversed slowly after wash, and the wash showed an identical effect on fresh strips. 3. Ouabain, used as a control, also caused a concentration-dependent increase in tension which reached a plateau at a concentration of 10 mmol/l. Both ouabain and ASTI caused a significant potentiation of the vasoconstrictor effect of noradrenaline at concentrations of 1 nmol/l-0.1 mmol/l. 4. Both ASTI and ouabain caused a significantly greater (P less than 0.01) calcium retention than control medium in aortic strips. 5. Incubation of ASTI with prolidase, chymotrypsin and carboxypeptidase A destroyed the vasoconstrictor effects as well as its inhibitory effects on sodium, potassium-dependent adenosine triphosphatase and sodium efflux from erythrocytes, but leucine aminopeptidase was ineffective. 6. These studies suggest that hypothalamic cells in culture release a peptidic inhibitor of active sodium transport which increases vascular reactivity, potentiates vasoconstrictor effects of noradrenaline and causes calcium retention.
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PMID:Calcium retention and increased vascular reactivity caused by a hypothalamic sodium transport inhibitor. 340 35

Thionoleucine S-anilide (Leut-anilide), Leut-Gly-OEt and Leut-Phe-OMe were synthesized and shown to be competitive inhibitors of leucine aminopeptidase from pig kidney. The kinetics of inhibition were determined in the presence of leucine 4-methylcoumarin-7-amide as substrate. Although the compounds showed only moderate inhibitory potency, it was found that all were resistant to hydrolysis by the enzyme, in contrast with the reported behaviour of some thionopeptide analogues of substrates for other Zn2+-peptidases such as carboxypeptidase A and angiotensin-converting enzyme.
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PMID:The behaviour of leucine aminopeptidase towards thionopeptides. 366 53

The mechanism-based inactivations of a number of serine proteases, including human leukocyte (HL) elastase, cathepsin G, rat mast cell proteases I and II, several human and bovine blood coagulation proteases, and human factor D by substituted isocoumarins and phthalides which contain masked acyl chloride or anhydride moieties, are reported. 3,4-Dichloroisocoumarin, the most potent inhibitor investigated here, inactivated all the serine proteases tested but did not inhibit papain, leucine aminopeptidase, or beta-lactamase. 3,4-Dichloroisocoumarin was fairly selective toward HL elastase (kobsd/[I] = 8920 M-1 s-1); the inhibited enzyme was quite stable to reactivation (kdeacyl = 2 X 10(-5) s-1), while enzymes inhibited by 3-acetoxyisocoumarin and 3,3-dichlorophthalide regained full activity upon standing. The rate of inactivation was decreased dramatically in the presence of reversible inhibitors or substrates, and ultraviolet spectral measurements indicate that the isocoumarin ring structure is lost upon inactivation. Chymotrypsin A gamma is totally inactivated by 1.2 equiv of 3-chloroisocoumarin or 3,4-dichloroisocoumarin, and approximately 1 equiv of protons is released upon inactivation. These results indicate that these compounds react with serine proteases to release a reactive acyl chloride moiety which can acylate another active site residue. These are the first mechanism-based inhibitors reported for many of the enzymes tested, and 3,4-dichloroisocoumarin should find wide applicability as a general serine protease inhibitor.
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PMID:Reaction of serine proteases with substituted isocoumarins: discovery of 3,4-dichloroisocoumarin, a new general mechanism based serine protease inhibitor. 389 37


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