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)

The glutathione status of Plasmodium vinckei parasitized erythrocytes of mice was determined in correlation to the intraerythrocytic stage of maturation of the parasite. The different stages of blood schizogony were separated by discontinuous Dextran-density-centrifugation. The changes of protein content, glutathione concentration (reduced/oxidized and bound/free glutathione) and in the specific activities of the following enzymes: gamma-glutamyl-cysteine-synthetase (GC-synthetase), glutathione-reductase (GR), glucose-6-phosphate dehydrogenase (Gl-DH), glutathione-peroxydase (G-POD) and catalase were investigated in dependence of the intraerythrocytic stage of development. The following changes of the investigated metabolic parameters were observed during the schizogony: - the protein content decreased to about one half, - the glutathione concentration increased about 10-fold, while the relations reduced/oxidized and free/bound glutathione remained constant, - Gl-DH activity appeared and increased steeply, - the specific activities of GC-synthetase and of GR increased more than 2-fold, while G-POD remained almost constant, - and the activities of G-6-PDH and catalase showed a significant, strong decrease to about 25% of the original values. It is tried to relate the observed changes to the growing parasite or to the host cell. The significance of the results for the metabolism of malaria parasites and for a possible adaptation to the mosquito by a GSH mediated protection of the malaria parasite against an enzymatic defence-reaction of the mosquito, is discussed.
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PMID:[Glutathionestatus of Plasmodium vinckei parasitized erythrocytes in correlation to the intraerythrocytic development of the parasite (author's transl)]. 121 29

Captopril, an inhibitor of angiotensin converting enzyme is widely used in the treatment of hypertension and congestive heart failure. It contains active sulfhydryl group and shares other structural feature with cysteine, the main substrate of glutathione. Experiments were undertaken to examine the effect of captopril on concentration of endogenous glutathione in the liver and to examine the ability of captopril to protect against paracetamol-induced hepatotoxicity. Single doses of captopril (30 mg/kg) given to male Sprague-Dawley rats produced a significant time dependent depletion of hepatic glutathione: at 3 h--16% (controls--10% as the effect of fasting; p less than 0.02), at 5 h--25% (controls--17%; p less than 0.02). Pretreatment of rats with single doses of captopril (30 mg/kg) 2 hours prior to administration of toxic doses of paracetamol (2500 mg/kg) produced a significant depletion of hepatic glutathione level as compared with animals without pretreatment with captopril (median: 2.95 mumol/g liver and 3.50 mumol/g liver, respectively; p less than 0.01). This was not accompanied by a difference in the hepatotoxic effect of paracetamol as assessed by histological staging of necrosis. Studies on covalent binding of paracetamol showed that neither captopril at the doses 30 mg/kg, nor penicillamine (20 mg/kg) affected covalent binding of paracetamol metabolites to cell protein. The results suggest that captopril despite its structural similarity to cysteine depletes hepatic glutathione level and does not protect against paracetamol hepatotoxicity.
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PMID:[Effect of captopril on glutathione level in the liver and paracetamol-induced liver damage in rats]. 140 91

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.
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PMID:Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exo- and endogenous nitrovasodilators. 172 Aug 43

Thiyl free radicals have been shown to react with polyunsaturated fatty acids via abstraction of bisallylic hydrogen, forming pentadienyl radicals, and via addition to the double bonds. In the absence of oxygen, the latter pathway leads to regeneration of thiyl radicals through beta-elimination or "repair" of the adduct radicals by thiols. In the presence of oxygen, fixation of thiyl-induced damage occurs through reaction of O2 with the pentadienyl radical (yielding conjugated dienyl peroxyl radicals) and also with the thiyl-to-double bond adduct radical. A quantitative reaction scheme evaluated from these data considers abstraction, addition, rearrangement, and repair reactions, and the evaluation of rate constants for the individual steps. Absolute rate constants have been measured, in particular, for reactions of thiyl free radicals from glutathione, cysteine, homocysteine, N-acetylcysteine, cysteine ethyl ester, penicillamine, captopril, mercaptoethanol, and dithiothreitol with polyunsaturated fatty acids (PUFAs) ranging from 18:2 to 22:6, and the lipids trilinolein and trilinolenin. The rate constants for hydrogen abstraction were found to be typically of the order of 10(7) mol-1 dm3 s-1 and to increase with increasing lipophilicity of the attacking thiyl radical. Thioperoxyl radicals, RSOO., were found to be rather unreactive toward PUFAs, in contrast to the isomer sulfonyl radicals, RSO2., which not only abstract hydrogen from the bisallylic methylene groups of the PUFAs (although only at relatively small yield) but also readily add to the PUFA double bonds (major pathway). Specific information was obtained on the optical properties of the thiyl radical derived from the ACE inhibitor captopril, CpS. (lambda max = 340 nm, epsilon = 460 +/- 50 mol-1 dm3 cm-1), and its conjugate disulfide radical anion (CpS:.SCp) (lambda max = 420 nm).
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PMID:Oxidation of polyunsaturated fatty acids and lipids through thiyl and sulfonyl radicals: reaction kinetics, and influence of oxygen and structure of thiyl radicals. 173 11

From the lysosomal cysteine proteinase cathepsin B, isolated from human liver in its two-chain form, monoclinic crystals were obtained which contain two molecules per asymmetric unit. The molecular structure was solved by a combination of Patterson search and heavy atom replacement methods (simultaneously with rat cathepsin B) and refined to a crystallographic R value of 0.164 using X-ray data to 2.15 A resolution. The overall folding pattern of cathepsin B and the arrangement of the active site residues are similar to the related cysteine proteinases papain, actinidin and calotropin DI. 166 alpha-carbon atoms out of 248 defined cathepsin B residues are topologically equivalent (with an r.m.s. deviation of 1.04 A) with alpha-carbon atoms of papain. However, several large insertion loops are accommodated on the molecular surface and modify its properties. The disulphide connectivities recently determined for bovine cathepsin B by chemical means were shown to be correct. Some of the primed subsites are occluded by a novel insertion loop, which seems to favour binding of peptide substrates with two residues carboxy-terminal to the scissile peptide bond; two histidine residues (His110 and His111) in this "occluding loop' provide positively charged anchors for the C-terminal carboxylate group of such polypeptide substrates. These structural features explain the well-known dipeptidyl carboxypeptidase activity of cathepsin B. The other subsites adjacent to the reactive site Cys29 are relatively similar to papain; Glu245 in the S2 subsite favours basic P2-side chains. The above mentioned histidine residues, but also the buried Glu171 might represent the group with a pKa of approximately 5.5 near the active site, which governs endo- and exopeptidase activity. The "occluding loop' does not allow cystatin-like protein inhibitors to bind to cathepsin B as they do to papain, consistent with the reduced affinity of these protein inhibitors for cathepsin B compared with the related plant enzymes.
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PMID:The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. 186 26

The objective of this study was to compare the disposition and metabolism of [14C]1,2-dichloropropane [( 14C]DCP) following oral and inhalation exposure since these two routes are of interest with regards to occupational and accidental exposure. [14C]DCP was administered orally to groups of four rats of each sex as a single dose of 1 or 100 mg/kg and as a multiple 1 mg/kg nonradiolabeled dose for 7 days followed by a single 1 mg [14C]DCP/kg dose on day 8. In addition, four rats of each sex were exposed to [14C]DCP vapors for a 6-h period in a head-only inhalation chamber at target concentrations of 5, 50 and 100 ppm. [14C]DCP was readily absorbed, metabolized and excreted after oral or inhalation exposure. For all treatment groups the principal routes of elimination were via the urine (37-65%) and expired air (18-40%). The tissues, carcass, feces and cage wash contained less than 11, 9.7 and 3.8% of the dose, respectively. The major urinary metabolites, as a group, from the oral and inhalation exposures were identified as three N-acetylcysteine conjugates of DCP, N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine. The majority (61-87%) of the expired volatile organic material was found to be parent DCP in all samples analyzed. Increasing the dose/concentration of [14C]DCP resulted in an increase in the amount of exhaled [14C]-volatile organics. The peak DCP blood concentrations (inhalation exposure) were not proportional to dose, indicating a dose-dependency in the blood clearance of DCP. Nonetheless, upon termination of exposure, DCP was rapidly eliminated from the blood. In all treatment groups, following oral and inhalation exposure the majority of the radioactivity was eliminated by 24 h postdosing and no differences were noted between sexes. Therefore, it can be concluded that in the rat the pharmacokinetics and metabolism of [14C]DCP are similar regardless of route of exposure or sex.
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PMID:Disposition and metabolism of [14C]1,2-dichloropropane following oral and inhalation exposure in Fischer 344 rats. 189

A biological monitoring study was carried out in the Dutch flower-bulb culture to determine the relationship between respiratory occupational exposure to Z- and E-1,3-dichloropropene (Z- and E-DCP) and urinary excretion of two mercapturic acid metabolites, N-acetyl-S-(Z- and E-3-chloropropenyl-2)-L- cysteine (Z- and E-DCP-MA). Urinary excretion of Z- and E-DCP-MA, either based on excretion rates or on creatinine excretion, followed first order elimination kinetics after exposure. Urinary half-lives of elimination were 5.0 +/- 1.2 hr for Z-DCP-MA and 4.7 +/- 1.3 hr for E-DCP-MA and were not statistically significantly different. Calculated coefficients of variation indicated that the half-lives of elimination of Z- and E-DCP-MA were quite consistent inter- and intra-individually. Strong correlations (r greater than or equal to 0.93) were observed between respiratory 8-hr time weighted average (TWA) exposure to Z- and E-DCP and complete cumulative urinary excretion of Z- and E-DCP-MA. Z-DCP yielded three times more mercapturic acid than E-DCP, probably due to differences in metabolism. Z- and E-DCP were excreted 45 and 14% as their respective mercapturic acid metabolites. A respiratory 8-hr TWA exposure to the Dutch occupational exposure limit of 5 mg.m-3 DCP would result in a complete cumulative excretion of 14.4 mg (95% confidence interval: 11.7-17.0 mg) Z-DCP-MA and 3.2 mg (95% confidence interval: 2.3-4.1 mg) E-DCP-MA.
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PMID:Inhalation exposure to 1,3-dichloropropene in the Dutch flower-bulb culture. Part II. Biological monitoring by measurement of urinary excretion of two mercapturic acid metabolites. 199 11

The aceEF-lpd operon of Escherichia coli encodes the pyruvate dehydrogenase (E1p), dihydrolipoamide acetyltransferase (E2p) and dihydrolipoamide dehydrogenase (E3) components of the pyruvate dehydrogenase multienzyme complex (PDH complex). A thermoinducible expression system was developed to amplify a variety of genetically restructured PDH complexes, including those containing three, two, one and no lipoyl domains per E2p chain. Although large quantities of the corresponding complexes were produced, they had only 20-50% of the predicted specific activities. The activities of the E1p components were diminished to the same extent, and this could account for the shortfall in overall complex activity. Thermoinduction was used to express a mutant PDH complex in which the putative active-site histidine residue of the E2p component (His-602) was replaced by cysteine in the H602C E2p component. This substitution abolished dihydrolipoamide acetyltransferase activity of the complex without affecting other E2p functions. The results support the view that His-602 is an active-site residue. The inactivation could mean that the histidine residue performs an essential role in the acetyltransferase reaction mechanism, or that the reaction is blocked by an irreversible modification of the cysteine substituent. Complementation was observed between the H602C PDH complex and a complex that is totally deficient in lipoyl domains, both in vitro, by the restoration of overall complex activity in mixed extracts, and in vivo, from the nutritional independence of strains that co-express the two complexes from different plasmids.
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PMID:Overexpression of restructured pyruvate dehydrogenase complexes and site-directed mutagenesis of a potential active-site histidine residue. 220 Dec 86

The effects of angiotensin converting enzyme inhibitors (ACEIs), CGS 14831 (CAS 86541-78-8) and captopril, on the mechanical function and energy metabolism were studied in isolated rat hearts using global ischemia-reperfusion model. The myocardial tissue levels of ATP, creatine phosphate (CP) and pH were determined with 31P-nuclear magnetic resonance (31P-NMR). Global ischemia was induced by cross-clamping of the inflow line for 40 min. While thiol containing ACEI, captopril, significantly inhibited the ATP depletion and pH fall produced by ischemia, non-thiol compound, CGS 14831, did not have any influence on the ATP degradation and pH fall during ischemia. Both CGS 14831 (20 micrograms/ml) and captopril (80 micrograms/ml) have little influence on the mechanical function during the ischemia-reperfusion period. L-Cysteine (44.6 micrograms/ml) inhibited the pH fall significantly during the ischemia without exerting influence on the ATP degradation. These data suggest that local renin-angiotensin-aldosterone system does not play an important role in maintenance of the myocardial mechanical function during ischemia-reperfusion. The thiol residue of captopril is not responsible for the inhibitory effect of this compound on ischemia-induced ATP degradation. Some specific effect of captopril may play a role in the protective effect.
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PMID:Effects of two angiotensin converting enzyme inhibitors on the mechanical function and energy metabolism of isolated rat hearts. A nuclear magnetic resonance study with an active form of benazeprilat and captopril. 229 44

1. We have investigated the effects of the non-renin-mediated actions of angiotensin converting enzyme inhibitors on the progression of chronic renal failure accelerated by hypertension. For this purpose, we studied the effects of captopril (a thiol-containing angiotensin converting enzyme inhibitor), enalapril (an angiotensin converting enzyme inhibitor without a thiol group) and cysteine (a thiol-containing amino acid which has no angiotensin converting enzyme-inhibitory action) in adriamycin-treated rats with deoxycorticosterone acetate-salt hypertension, in which the renin-angiotensin system was suppressed. 2. There were no significant differences in blood pressure between these groups and the control group [adriamycin-treated group with deoxycorticosterone acetate-salt loading, 206 +/- 7 mmHg (27.4 +/- 0.9 kPa) at week 10]. 3. Massive proteinuria occurred in all groups. At the end of the experiment (at week 10), urinary protein excretion was significantly reduced in the captopril and cysteine groups compared with the control group. No manifest improvements appeared in the enalapril group. 4. Levels of serum creatinine and blood urea nitrogen increased progressively. At week 10, the increases in the serum levels of creatinine were less in the captopril (87 +/- 16 mmol/l) and cysteine (80 +/- 19 mmol/l) groups than in the control group (124 +/- 27 mmol/l) (P less than 0.01). No marked differences were found between the control and enalapril groups. 5. Captopril and cysteine caused more than a three-fold reduction in the focal glomerulosclerosis score when compared with that in the control group, but enalapril did not decrease the score. The extent of tubulointerstitial change was parallel with the focal glomerulosclerosis score. 6. We conclude that the thiol group is possibly involved in the mechanism of the beneficial effects of some angiotensin converting enzyme inhibitors on the progression of chronic renal failure exacerbated by hypertension.
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PMID:Differences in the effects of angiotensin converting enzyme inhibitors with or without a thiol group in chronic renal failure in rats. 254 Sep 31


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