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Results for “3-Mercaptopropionic Acid”

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PubMed1992

Bradykinin degrading activity in cultured human endothelial cells.

The role of angiotensin-converting enzyme (ACE), neutral endopeptidase 24.11 (NEP), and other peptidases in the endothelial degradation of bradykinin was investigated in cultured human umbilical vein endothelial cells (HUVEC). The major part of the kininase II activity on intact cells was attributed to ACE activity, the minor part to NEP activity. Amastatin, as aminopeptidase inhibitor, and DL-2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid (MGTA), an inhibitor of kininase I, did not affect endothelial kininase activity. The decline of the bradykinin concentrations in the supernatant of intact endothelial monolayer indicated a total kininase activity of 289 +/- 27 fmol/min/dish. The calculated activity of ACE was 223 fmol/min/dish and the neutral endopeptidase activity was 51 fmol/min/dish. Thus, ACE and neutral endopeptidase are the main kininases in the degradation of bradykinin by intact endothelial cells. In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA.

3-Mercaptopropionic Acid↗
PubMed1992

Effects of peptidase inhibition on angiotensin receptor agonist and antagonist potency in rabbit isolated thoracic aorta.

1. Experiments were performed with peptidase inhibitors on rabbit aortic strip preparations, to determine whether endogenous peptidase activity can influence the potency estimates for angiotensin receptor agonists and antagonists in this tissue. 2. Angiotensin II (A II) and angiotensin III (A III) both induced concentration-related contractions of rabbit aortic strip preparations. A III was approximately 38 fold less potent than A II, and the gradient of the A III concentration-response curve (1.00 +/- 0.04) was significantly more shallow than that (1.76 +/- 0.05) of the A II curve. 3. Neither the aminopeptidase-A and -M inhibitor, amastatin, nor the aminopeptidase-B and -M inhibitor, bestatin, affected the potency of, or the maximum response to, A II. In contrast, the potency of A III was increased by both amastatin and bestatin. Amastatin had the most marked effect and at 10 microM caused approximately a 12 fold increase in the potency of A III (EC50 values, 102 nM and 8.6 nM in the absence and presence of amastatin, respectively), and also significantly steepened the gradient of the A III concentration-response curve. Amastatin did not affect the position or shape of the concentration-response curve to the alpha 1-adrenoceptor agonist, phenylephrine. Finally, the carboxypeptidase-N inhibitor, D-L-mercaptomethyl-3-guanidine-ethylpropanoic acid (MERGETPA) did not change the position or shape of the concentration-response curves to either A II or A III.4. In the presence of amastatin, the potency of the peptide angiotensin receptor antagonist, Ile7-A III (100nM-l microM ), was increased approximately 13 fold (pA2, with A II as the agonist, 7.0 +/- 0.1 and 8.1 +/- 0.1, in the absence and presence of amastatin, respectively). However, the potency of the nonpeptide angiotensin receptor antagonist, DuP 753 (30-300 nM), was little affected by amastatin (pA2, 8.2 +/- 0.1 and 8.1 +/- 0.1 in the absence and presence of amastatin, respectively).5. The results of this study suggest that endogenous aminopeptidase activity in the rabbit thoracic aorta can profoundly affect estimates of the potency of peptide angiotensin receptor agonists and antagonists.A suitable aminopeptidase inhibitor should therefore be included in studies, using this tissue, which aim to classify angiotensin receptor subtype(s) based on the rank order of peptide angiotensin receptor agonist and/or antagonist potencies.

3-Mercaptopropionic Acid↗
PubMed1992

Carboxypeptidase M-like enzyme modulates the noncholinergic bronchoconstrictor response in guinea pig.

We studied the effects of aerosolized DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA) (10(-4) M, 90 breaths), a specific inhibitor of carboxypeptidase B-type enzymes, on changes in total pulmonary resistance (RL) induced by aerosolized capsaicin (10(-7) to 10(-4) M; 10 breaths at each concentration) and vagus nerve stimulation (5 V, 5 ms, for 20 s at frequencies varying from 2 to 10 Hz) in anesthetized, atropinized, and ventilated guinea pigs. We also studied the effect of aerosolized MGTA on the bronchoconstrictor response to either aerosolized substance P, neurokinin A (10(-7) to 10(-4) M; 10 breaths at each concentration), and carbachol (10(-5) to 2 x 10(-4) M; 10 breaths at each concentration) or to i.v. administration of neurokinin A (10(-11) to 10(-8) mol/kg), bradykinin (10(-10) to 10(-7) mol/kg), and histamine (10(-8) to 10(-6) mol/kg). Although aerosolized MGTA caused no change in basal RL (P > 0.5), it did potentiate the noncholinergic bronchoconstrictor response to capsaicin (n = 5; P < 0.001) as well as to vagus nerve stimulation (n = 5; P = 0.001). In contrast, MGTA did not potentiate the bronchoconstrictor response to either aerosolized substance P, neurokinin A, and carbachol or to i.v. administration of neurokinin A, histamine, and bradykinin. Carboxypeptidase activity cleaving C-terminal arginine or lysine was found in the membrane preparations of trachea and lung from guinea pigs. The membrane-bound carboxypeptidase activity was maximal at pH 7.0 and was enhanced by the presence of CoCl2 (1 mM) in both the tracheal and lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Mercaptopropionic Acid↗
PubMed1992

Carboxypeptidase M in brain and peripheral nerves.

Carboxypeptidase M (CPM), a plasma membrane-bound enzyme, cleaves C-terminal basic amino acids with a neutral pH optimum. We studied its distribution in human, baboon, and dog brain and in dog peripheral nerves. Areas were dissected, homogenized, centrifuged, and assayed for activity with dansyl-Ala-Arg. The corpus callosum and the pyramidal and optic tract were especially rich in CPM, whereas basal ganglia and cortex had low activity. The identity of the basic carboxypeptidase activity with CPM was shown by similarities in subcellular localization, membrane attachment, substrate hydrolysis, inhibition by a specific basic carboxypeptidase inhibitor, and cross-reaction with anti-human CPM antiserum. This antiserum immunoprecipitated an average of 85% of the activity in human and baboon brain and approximately 66% in dog brain. CPM co-purified with myelin extracted from the brain. Consistent with results obtained in placenta and cultured kidney cells, CPM in the brain appears to be membrane-bound via a phosphatidylinositol glycan anchor. In the peripheral nerves, the specific activity in dog sciatic nerve and in vagus was high (98 and 149 nmol/h/mg of protein, respectively). In immunohistochemical studies, glia in the brain, which appear to be oligodendrocytes or astrocytes, and the outer aspects of myelin sheaths and Schwann cells in sciatic and vagus nerves were stained. We conclude that in some areas of the CNS and the PNS, CPM is closely associated with myelin and myelin-forming cells. Northern blot analysis revealed the presence of mRNA coding for CPM in the brain, showing that the enzyme is indeed synthesized there.

3-Mercaptopropionic Acid↗
PubMed1979

The convulsant drugs 3-mercaptopropionate and methionine sulfoximine inhibit L-glutamate and L-aspartate binding to a hydrophobic protein fraction from rat cerebral cortex.

The action of the convulsant drugs, methionine sulfoximine (MSO), 3-mercaptopropionate (3-MP), megimide (MG), and allylglycine on the binding of L-[14C]aspartate, L-[14C]glutamate and [14C]GABA to a hydrophobic protein fraction isolated from rat cerebral cortex was studied. Using the convulsant at 10(-4) M concentration and the radioactive ligands as 10(-6) M the binding of L-[14C]glutamate was inhibited 60% by 3-MP and 40% by MSO, while MG and allylglycine had no effect. The binding of L-[14C]aspartate was inhibited 55%, and 10--20% by 3-MP and MSO, respectively, while MG and allylglycine had not effect. None of the drugs mentioned, except for a minimal inhibition by MG, altered the binding of [14C]GABA. Neither MSO nor 3-MP affected the high-affinity sites for L-[14C]glutamate of L-[14C]aspartate, but they had a strong inhibitory action on the medium affinity site. These results are discussed in relation to the possible mechanism of action of these drugs on L-glutamate and L-aspartate receptors.

3-Mercaptopropionic Acid↗
PubMed1992

Inhibition of baroreflex bradycardia by ethanol involves both GABAA and GABAB receptors in the brainstem of the rat.

The effects of ethanol on baroreceptor reflex bradycardia and its interactions with cardiovascular effects mediated by GABA receptors in the dorsal vagal complex were studied in urethane-anaesthetised rats. Ethanol, 1 g kg-1 administered i.v. or 25-200 nmol microinjected bilaterally into the dorsal vagal complex, inhibited the reflex bradycardic response to bolus i.v. doses of phenylephrine both in spontaneously breathing and in paralysed, artificially ventilated animals, and this effect could be prevented by pretreatment with the GABA-depleting agent, 3-mercaptopropionate in both groups of rats. Ethanol, 1 g kg-1 i.v., did not influence the bradycardic response to electrical stimulation of the cervical vagus. Microinjection of muscimol into the dorsal vagal complex caused a dose-dependent pressor response and inhibited baroreflex bradycardia. The pressor response was potentiated and a tachycardic response to muscimol emerged following microinjection of ethanol into the dorsal vagal complex. Similar administration of baclofen caused dose-dependent increases in blood pressure and heart rate and inhibited baroreflex bradycardia. Injection of ethanol into the dorsal vagal complex potentiated the pressor response to a low dose of baclofen but did not affect the tachycardic response. Bicuculline, 10 pmol/side into the dorsal vagal complex, blocked the effects of muscimol but not those of baclofen and reduced the baroreflex inhibitory action of ethanol. 2-Hydroxysaclofen, microinjected at 400 pmol to 1 nmol/side, blocked the effects of baclofen but not those of muscimol. 2-Hydroxysaclofen or phaclofen, 2 mg kg-1 s.c., prevented the baroreflex inhibitory action of ethanol and also prevented ethanol potentiation of the pressor and, less effectively, the tachycardic effects of muscimol. It is concluded that ethanol inhibits baroreflex bradycardia through potentiation of the actions of endogenous GABA in the dorsal vagal complex. Both GABAA and GABAB receptors appear to be involved in this action of ethanol.

3-Mercaptopropionic Acid↗
PubMed1979

A novel orally active converting-enzyme inhibitor YS 980: effects on blood pressure in spontaneously hypertensive rats.

1. The effects of long-term treatment with the angiotensin I converting-enzyme inhibitor YS 980 were examined in stroke-prone spontaneously hypertensive (sp-SH) rats. Development of hypertension was markedly blunted in the YS 980-treated animals. 2. Effective converting-enzyme inhibition was confirmed by significant increases in plasma angiotensin I (ANG I) and plasma renin concentration, inhibition of the pressor responses to intravenous ANG I and potentiation of the depressor responses to intravenous bradykinin. 3. Urinary free aldosterone excretion was decreased but no changes in urinary sodium and potassium excretion were observed. 4. The pressor responses to intravenous leucine-enkephalin were reduced. 5. The pressor responses to injection of ANG I and bradykinin into the lateral brain ventricle were unaltered. 6. We conclude that the antihypertensive action of YS 980 in sp-SH rats cannot be explained by the inhibition of the plasma renin-angiotensin system alone. Effects on other peptide systems must be considered.

3-Mercaptopropionic Acid↗
PubMed1977

Allergic contact dermatitis to a photopolymerizable resin used in printing.

Organic photopolymerizable resins increasingly used in printing make it possible to produce flexible, lighter plates. A certain number of skin lesions and general symptoms appeared upon manipulation of plates made by the Letterflex process. In the workshop where this study was carried out, 12 out of 15 people suffered various degrees of skin lesions. The epicutaneous tests and biopsies performed indicate an allergic type reaction to one of the resin's constituents, polythiol. Experiments with animals confirm the strong allergenicity of this compound.

3-Mercaptopropionic Acid↗
PubMed1992

Preparation of acetylmercapto-3-carboxypropanoyl insulins using preparative high-performance liquid chromatography on an anion-exchange column.

A method for the preparation of insulin derivatives which have protected sulfhydryl group(s) at definite site(s) on the molecule is described. Porcine insulin reacts with S-acetylmercaptosuccinic anhydride to afford four species of insulin derivatives that have 2 (or 3)-acetylmercapto-3-carboxypropanoyl group(s) at i) Gly(A1), ii) Gly(A1) and Phe(B1), iii) Gly(A1) and Lys(B29), and iv) Gly(A1), Phe(B1) and Lys(B29) positions. The derivatives are efficiently separated in a preparative scale by anion-exchange high-performance liquid chromatography on a TSKgel DEAE-2SW column. The four derivatives are all readily deacetylated with hydroxylamine to give the corresponding sulfhydryl insulin derivatives.

3-Mercaptopropionic Acid↗
PubMed1979

Formation of stable anhydrides from CoA transferase and hydroxamic acids.

Acetohydroxamic acid reacts with the enzyme-CoA form of succinyl-CoA:3-ketoacid coenzyme A transferase to give an inactive product with a rate constant of 860 M-1 min-1 at pH 8.1, 25 degrees C. The reaction is reversible in the presence of coenzyme A and has an equilibrium constant of 0.040. The product is an anhydride that is an analog of the intermediate that has been postulated in the normal catalytic pathway; it is inactive because coenzyme A does not react with the acyl group of the hydroxamic acid. The equilibrium constant for formation of the anhydride from the thil ester of enzyme and methyl 3-mercaptopropionate is 75 times larger than the equilibrium constant of 2.2 for the formation of N,O-diacetylhydroxylamine from acetohydroxamic acid and acetyl-CoA. This shows that the enzyme stabilizes the anhydride at the active site by at least -2.6 kcal mol-1. Succinomonohydroxamic acid reacts with enzyme-CoA as both a substrate and an inactivator, with relative rate constants of 25:1. The inactivation is irreversible, indicating that the enzyme provides a larger stabilization of at least -5.9 kcal mol-1 for the anhydride of an analog of the specific substrate, succinate. The results are consistent with the hypothesis that the enzyme stabilizes an anhydride that is formed at the active site during turnover of normal substrates through a stepwise reaction mechanism.

Acetoacetates↗
PubMed1992

Structure-activity relationships for inhibition of papain by peptide Michael acceptors.

Two series of peptidyl Michael acceptors, N-Ac-L-Phe-NHCH2CH = CH-E with different electron withdrawing groups (E = CO2CH3, 1a; SO2CH3, 1b; CO2H, 1c; CN, 1d; CONH2, 1e; and C6H4-p-NO2, 1f) and R-NHCH2CH = CHCOOCH3 with different recognition and binding groups (R = N-Ac-D-Phe, 2a; N-Ac-L-Leu, 3a; N-Ac-L-Met, 4a; PhCH2CH2CO, 5a; PhCO, 6a), were synthesized and evaluated as inactivators against papain. It was found that the inhibition of papain by peptidyl Michael acceptors is a general phenomenon and that the intrinsic chemical reactivity of the E group in the Michael acceptors has a direct effect on the kinetics of the inactivation process as reflected in k2/Ki. At pH 6.2, the reactivity of papain toward the Michael acceptors is about 283,000-fold higher than the reactivity of the model thiol 3-mercaptopropionate. This large increase in reactivity is attributable to at least 2 factors; one is the low apparent pKa of Cys-25 of papain, and the other is the recruitment of catalytic power by specific enzyme-substrate interactions. The unexpectedly high reactivity of 1c (E = COOH) was rationalized by proposing a direct interaction of the acid group with His-159 in the active site of papain. The unexpected inactivity of 1f (E = C6H4-p-NO2) as a Michael acceptor and its very powerful competitive inhibition of papain were rationalized by molecular graphics which showed the nitrophenyl moiety rotated out of conjugation with the olefin and interacting instead with the hydrophobic S1' region of papain. A plot of log (k2/Ki) for 1a-6a vs log (kcat/Km) for analogous R-Gly-p-NA substrates was linear (r = 0.98) with slope of 0.83, suggesting that binding energy from specific enzyme-ligand interactions can be used to drive the self-inactivation reaction to almost the same extent as it is used to drive catalysis.

Amino Acid Chloromethyl Ketones↗