Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carboxypeptidase N (CPN, kininase I) and kininase II (angiotensin converting enzyme) activities were measured simultaneously in blood plasma and synovial fluid in patients suffering from rheumatoid arthritis (RA), psoriatic arthritis (PA) and osteoarthritis (OA) and in the plasma of normal volunteers. CPN levels (defined as the rate of hydrolysis of furylacryloyl-Ala-Lys) in blood were modestly increased and correlated with erythrocyte sedimentation rate in RA and PA. Based on the hydrolysis of synthetic substrates, CPN activity was much higher than kininase II activity in synovial fluid (SF). SF kininase activities were always inferior to the blood levels in all patients and were correlated with the logarithm of SF leukocyte counts, an indicator of the intensity of inflammation. In addition, CPN and albumin levels in SF were highly correlated when expressed as a percent of the plasma concentrations. Biochemical properties of CPN in crude SF confirmed its similarity to blood CPN. Polymorphonuclear leukocytes derived from inflammatory SF did not release CPN. It is concluded that kininases diffuse from the blood into SF through increased vascular permeability and that CPN could be a major metabolic pathway for kinins in this form of exudate. CPN leads to the formation of des-Arg kinins, selective agonists of the B1 receptors for kinins.
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PMID:Carboxypeptidase N (kininase I) activity in blood and synovial fluid from patients with arthritis. 304 Nov 37

Partially purified kinin potentiating peptide (KPP) obtained from kininogen-depleted human plasma inhibited lung angiotensin converting enzyme in vitro and potentiated guinea-pig ileum contractions induced by bradykinin (BK), Lys-BK, Met-Lys-BK, Ile-Ser-BK, and Lys-Lys-BK. Contractions evoked by angiotensin II, histamine, acetylcholine, and barium chloride were not potentiated. KPP also potentiated kinin-induced contractions of rat uterus and of guinea-pig ileum pre-incubated with 1,10-phenanthroline. It is suggested that KPP potentiation is due, at least in part, to a direct effect on kinin receptor(s).
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PMID:Characterization of a new kinin potentiating peptide obtained from human plasma proteins. 322 25

Cathepsin B from brain exhibited both endopeptidase and dipeptidyl carboxypeptidase activity. Recently the factors, contributing to dipeptidyl carboxypeptidase properties of brain cathepsin B, were identified: I. occupation of the enzyme S3 subsite, 2. free C-terminal group of the substrate, 3. specific interaction between the split off dipeptide and the enzyme active site. The identification was carried out using angiotensin I, its C-end tripeptide and chromophore oligopeptides containing p-nitrophenylalanine residue. C-terminal dipeptide was split off in the proopioid peptides dynorphins 1-7 and 1-8, Met-enkephalin-Arg6-Phe7, Met-enkephalin-Arg6-Gly7-Leu8; the enzyme hydrolyzed also the C-terminal dipeptide bond in Leu- and Met-enkephalins without the subsequent hydrolysis of the remaining tripeptide. D-Ala2, D-Leu5-enkephalin were not hydrolyzed; the bond Arg9-Pro10 was resistant to proteolysis in dynorphin 1-11. Cathepsin B split off the C-terminal dipeptide in synthetic substrates Leu-Trp-Met-Arg-Phe-Ala and Trp-Met-Arg-Phe-Ala but not in Met-Arg-Phe-Ala. These results 06.08 M-15 demonstrated the essential role of branched-chain amino acid residue at the position of P2 and/or P3 of substrates for the enzyme dipeptidyl carboxypeptidase activity. The data obtained suggest that Arg residue at the position P2 (dynorphin 1-7) slowed down, D-amino acid at the position P2 (D-Ala2, D-Leu5-enkephalin) and Pro-Lys bond at the position P1-P2 (dynorphin 1-11) inhibited the cathepsin B dipeptidyl carboxypeptidase activity.
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PMID:[Brain cathepsin as dipeptidylcarboxypeptidase transforming provasopressor, pro-opioid and model peptides]. 331 15

The acute hemodynamic and hormonal effects of the oral angiotensin converting enzyme (ACE) inhibitor MK-521 were assessed over a period of 96 hours in 6 patients with heart failure. This compound is the lysine analogue of enalapril diacid (MK-422) and is biologically active following absorption. Dosages ranging from 1.25 mg to 5.0 mg were administered on days 1 and 3, followed by 48 hours intensive hemodynamic observation. Marked reduction in mean arterial pressure (25.2%), pulmonary capillary wedge pressure (47.3%), and systemic vascular resistance (34.5%) was observed. Arterial blood was sampled at frequent intervals for angiotensin I (AI), angiotensin II (AII), plasma renin activity, renin substrate, plasma aldosterone, urinary aldosterone, ACE activity, and serum drug levels. Right atrial blood was sampled simultaneously for AI and AII thus permitting reliable assessment of the degree of pulmonary conversion to angiotensin II. Prolonged inhibition of the renin-angiotensin-aldosterone system was confirmed and corresponded to drug concentration. The results indicate hemodynamic efficacy and potent ACE inhibition over a period exceeding 24 hours.
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PMID:Acute hemodynamic and hormonal effects of MK-521 in congestive heart failure. 608 11

The interaction of angiotensin converting enzyme with six metal-coordinating [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), N-(phenylphosphoryl)-L-Phe-L-Phe, N alpha-(3-mercaptopropanoyl)-L-Arg, N alpha-[1(S)-carboxy-3-phenylpropyl]-Ala-L-Lys, and N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly] and three dipeptide inhibitors (Gly-L-Trp, L-Phe-L-Arg, and L-Ala-L-Pro) was examined at pH 7.5 in the presence of 300 mM NaCl. Inhibition modes, apparent Ki [Ki(app)] values, and shapes of 1/v vs. [I] plots were found to vary with the substrate employed. All inhibitors except Phe-Arg were competitive with the substrate furanacryloyl (Fa)-Phe-Gly-Gly, while five of seven tested with Fa-Phe-Phe-Arg as substrate produced mixed patterns. Ki-(app) values for N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-Trp, and MK-422 were 8.3-, 5.5-, 4.7-, and 2.6-fold lower, respectively, when Fa-Phe-Gly-Gly was substrate, compared with values measured with Fa-Phe-Phe-Arg. In contrast, Ki(app) values for Phe-Arg and (3-mercaptopropanoyl)-Arg were lower (2.8- and 2.2-fold, respectively) when Fa-Phe-Phe-Arg was the substrate. Plots of 1/v vs. [I] for most of the inhibitors were nonlinear, to an extent which was also substrate dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of angiotensin converting enzyme: mechanism and substrate dependence. 609 93

In a previous report [Shapiro, R., Holmquist, B., & Riordan, J. F. (1983) Biochemistry 22, 3850], it was demonstrated that activation of angiotensin converting enzyme (ACE) by chloride is strongly dependent on substrate structure, and three substrate classes were identified on the basis of activation behavior. The present study examines the chloride dependence of the inhibition of ACE by nine inhibitors [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), L-Ala-L-Pro, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-L-Trp, N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, L-Phe-L-Arg, N alpha-(3-mercaptopropanoyl)-L-Arg, and N alpha-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Lys] containing structural features characteristic of the three classes of substrates. Apparent Ki values for all inhibitors are markedly (70-250-fold) decreased by 300 mM chloride. However, the enhancement of inhibition is achieved at significantly lower chloride concentrations with those inhibitors having an ultimate arginine or lysine than with the remainder. This variability parallels that previously found for activation of substrate hydrolysis. The effect of chloride on the individual steps in the formation and dissociation of the steady-state enzyme-inhibitor complexes was determined with the slow-binding inhibitor MK-422. Pre-steady-state analysis indicates that binding of both MK-422 and captopril follows a (minimally) two-step mechanism: (formula; see text) in which rapid formation of an enzyme-inhibitor complex is followed by a slow isomerization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of angiotensin converting enzyme: dependence on chloride. 609 94

A set of chemical reactions was used to show that one glutamic acid residue at the active site of bovine lung angiotensin I-converting enzyme is esterified with the alkylating agent p-[N,N-bis(chloroethyl)amino] phenylbutyryl-L-Pro (chlorambucyl-L-Pro), an affinity label for this enzyme (Harris, R. B., and Wilson, I. B. (1982) J. Biol. Chem. 257, 811-815). The same procedure was used to confirm that a glutamic acid residue of carboxypeptidase A alpha is esterified by reaction with bromoacetyl-N-methyl-L-phenylalanine (Haas, G. M., and Neurath, H. (1971) Biochemistry 10, 3535-3546). In the procedure described in this paper, the esterified residue at the active site is converted to the hydroxamic acid by reaction with hydroxylamine and the hydroxamic acid is subject to the Lossen rearrangement. If a glutamic acid residue was esterified, 1 eq of 2,4-diaminobutyric acid will be formed. Aspartyl esters will give 2,3-diaminopropionic acid. The diamino acids can be quantitatively measured using the short column of an amino acid analyzer if the amount of lysine and histidine is largely decreased by modification with suitable side chain protecting groups. With carboxypeptidase A, the reactions were done on the whole undigested enzyme. With the converting enzyme, we first cleaved the esterified enzyme with cyanogen bromide. Twenty-nine cleavage peptides were separated on high performance liquid chromatography and one of these contained all of the bound radioactive inhibitor. This active site peptide was then subjected to the derivatization and Lossen procedures, and 1 eq of 2,4-diaminobutyric acid was obtained.
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PMID:Glutamic acid is an active site residue of angiotensin I-converting enzyme. Use of the Lossen rearrangement for identification of dicarboxylic acid residues. 613 87

Synaptosomal membrane (SPM) bound exo- and endopeptidases cleave the dynorphins and Met-enkephalin-Arg-Gly-Leu at several sites to produce shorter fragments; among these are dynorphin 1-8 from 1-17, and Met-enkephalin from Met-enkephalin-Arg-Gly-Leu. The most vulnerable site is the Tyr-Gly bond cleaved by membrane-bound aminopeptidase(s), with the shorter peptides degraded more rapidly than the longer ones. A purified metalloendopeptidase sensitive to phosphoramidon inactivates the shorter peptide sequences at the Gly3-Phe4 bond, and the 1-13 and 1-17 sequences also at the Arg7-Ile8 bond. The kcat/Km ratios for purified metalloendopeptidase were 20-30 times higher for Leu-enkephalin and the proenkephalin octapeptide than for dynorphins 1-8, 1-13, and 1-17. Dynorphins 1-13 and 1-17 may serve as precursors for the widely distributed CNS neuropeptide dynorphin 1-8 since they were cleaved by a separate SPM endopeptidase insensitive to phosphoramidon. SPM monocarboxypeptidase converted dynorphin 1-13 to 1-12 (release of Lys) and dipeptidyl carboxypeptidase converted dynorphin 1-8 to 1-6; enkephalin octapeptide served as a precursor of Met-enkephalin by sequential action (release of Leu and Arg-Gly) of both carboxypeptidases.
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PMID:Membrane-bound enzymes and their role in processing of the dynorphins and of the proenkephalin octapeptide Metenkephalin-Arg-Gly-Leu. 614 75

The angiotensin substrate analog Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 +/- 4 to 79 +/- 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 +/- 3 to 131 +/- 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 +/- 4 mm Hg--a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.
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PMID:Specific inhibition of renin by an angiotensinogen analog: studies in sodium depletion and renin-dependent hypertension. 615 48

Angiotensin I (A I) and angiotensin II (A II) when injected through the pulmonary artery caused an increase in perfusion pressure (PP) of the isolated perfused rat lung and a contraction when the venous outflow was superfused over rat ascending colon (RC). Nicotine (N) when added to the perfusion medium caused a significant increase in PP to A II without altering that to A I. Further addition of ZK 36374, a stable analog of prostacyclin (PGI2), to the medium prevented the potentiating effect of N on the A II pressor response. Neither N nor ZK 36374 altered the superfused RC responses to A I and A II-injected venous effluent. Lysine acetylsalicylate (ASA), however, caused a potentiation in the pressor response to A I. The response of venous effluent superfused RC to A I was also found to be potentiated by ASA. ASA failed to alter the responses to A II. These results were taken as evidence that A II is a potent activator for the biosynthesis of PGI2 in the pulmonary vascular bed. Moreover, PGI2 does not affect angiotensin converting enzyme activity in the lung circulation while other stable metabolites of arachidonic acid can inhibit the conversion of A I to A II.
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PMID:Possible prostacyclin-mediated vascular effect of angiotensin II in the isolated perfused rat lung. 619 76


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