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)

A novel angiotensin I-converting enzyme (ACE) inhibitory peptide (RMLGQTPTK; 9mer) from porcine skeletal troponin C was investigated for its inhibitory profile. This peptide was noncompetitive and as hydrophobic as the known ACE inhibitory peptides. Aminopeptidase M quickly hydrolyzed 9mer, resulting in production of MLGQTPTK and LGQTPTK with inhibitory activities similar to those of 9mer. The main hydrolysis product of 9mer with carboxypeptidase A and B was RMLGQTPT showing very weak activity. Most products derived from 9mer hydrolysis by ACE, aminopeptidase, or carboxypeptidase showed weak but definite ACE inhibitory activities. Thus, 9mer was estimated to be a wholly efficient inhibitor with these fragment peptides.
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PMID:Inhibitory profile of nonapeptide derived from porcine troponin C against angiotensin I-converting enzyme. 1496 29

The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague-Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17beta-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1-7) [Ang-(1-7)] and on aminopeptidase (AMP), which degrades Ang-(1-7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31+/-0.03 nmol/min/mg versus 0.18+/-0.04 nmol/min/mg of protein, p<0.05) and Tg(+) (0.26+/-0.04 nmol/min/mg versus 0.13+/-0.02 nmol/min/mg of protein, p<0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p<0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1-7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.
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PMID:Effect of estrogen on neprilysin expression in uterus and kidney of Sprague-Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats. 1689 Mar 25

Incubation of [3H]-tyrosine methionine5-enkephalin (MET) with human brain preparations (100,000g supernatant; sections of the limbic system, thalamus, basal ganglia, cerebellum, and cortex) results in its rapid and complete degradation; over 95% of the initial labeled tyrosine is recovered as the free aminoacid within 10 min. Results show a considerable range in the peptide initial velocity (Iv) and half-life (t1/2) degradation values obtained from different brain sections of individual brains, either from the same or from different main brain areas. This relatively wide range of values was scattered, failing to identify consistent differences between the various brains areas studied. Differences in brain tissue storage time or repeated sample freezing and thawing failed to alter significantly either of these kinetic parameters of MET metabolism. Peptide degradation rate (optimum pH and temperature of 7.4 and 37 degrees C, respectively) was concentration-dependent inhibited by known aminopeptidase inhibitors (puromycin, bacitracin, and bestatin, and to a lesser extent by thioridazine). However, it was not significantly affected by either N-carboxymethyl phenyl leucine, captopril or thiorphan [dipeptidyl peptidase(s) or peptidyl dipeptidase(s) inhibitors, respectively]. A better understanding of the mechanisms regulating brain MET metabolism may contribute to the rational design of pharmacological strategies based in the modulation of its bioavailability.
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PMID:In vitro methionine5-enkephalin degradation kinetics by human brain preparations. 1767 90

The contractile effects of angiotensinogen (Aogen) and its metabolization pathways were studied on rat renal vein (RRV), rat pulmonary artery (RPA) and human umbilical vein (HUV) rings. Experiments were made in the presence or in the absence of pepstatin A (a renin inhibitor, 10 microM), captopril (an ACE inhibitor, 10 microM), chymostatin (a chymase inhibitor, 10 microM), amastatin (an aminopeptidase-A and -M inhibitor) or losartan (a specific AT1 blocker, 10 microM). On all rings, Aogen-induced contractions were reduced by pepstatin A or captopril, amplified by amastatin and blocked by losartan. Chymostatin had a stronger inhibitory effect than captopril on HUV and simultaneous administering of chymostatin and captopril prevented Aogen contractile effects on HUV. It is suggested that all studied vessels possess a local renin-angiotensin system and possibility of angiotensin II production within the vessel walls using various and species-dependent enzymatic pathways.
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PMID:Contractile effects of angiotensinogen and its multiple metabolization pathways on vessel walls. 1829 6

After 10-minute incubation of [3H]-tyrosine methionine-enkephalin (MET) with 100,000 x g supernatant from select brain regions of patients with chronic schizophrenia (n = 3), essentially all of the labeled tyrosine was recovered as the free amino acid. Initial velocity and half-life of MET degradation obtained from different brain areas (limbic system, thalamus, basal ganglia, cerebellum, and cortex) of individual brains or from equivalent sections from different brains were scattered and considerable spread out (brains A, B, and C: 21.7-60.2 and 2.1-14.3, 25.6-88.7 and 1.6-14.1, 24.5-56.1 and 2.6-14.3 pg MET/mg brain tissue/min and min, respectively; brains A-C range, 21.7-88.7 pg MET/mg brain tissue/min and 1.6-14.3 min, respectively). These results failed to identify consistent differences in peptide degradation kinetics between the various brains areas studied from the same individual or from equivalent section from different subjects. MET metabolic rate was pH and temperature-dependent (optimum 7.4 degrees C and 37 degrees C), reduced by the aminopeptidase inhibitors puromycin, bacitracin, and bestatin, and to a lesser extent by thioridazine. However, peptide metabolism was not significantly affected by differences in tissue storage time or repeated freezing and thawing; by preincubation with N-carboxymethyl phenyl leucine, captopril, or thiorphan (dipeptidyl peptidase[s] or peptidyl dipeptidase[s] inhibitors, respectively); or by the many different drugs used by the patients with chronic schizophrenia. Our findings, although of a preliminary nature and generally similar to those recently reported for comparable studies on nonneuropsychiatric patients, provide a much needed understanding of the mechanisms regulating brain MET metabolism. Whether these results may contribute to the rational design of pharmacologic strategies for the treatment of pathologies associated with alterations in the enkephalinergic system needs further research.
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PMID:Degradation kinetics of methionine5-enkephalin by select brain areas from patients with chronic schizophrenia. 1835 32

Select phenothiazine drugs significantly decrease, in a dose-dependent manner, the rate of methione-enkephalin (MET) degradation by discrete human brain areas, for example, putamen and hippocampus. This pentapeptide is rapidly, and essentially completely, hydrolyzed at the tyrosine-glycine bond by bacitracin-sensitive aminopeptidase(s) (AP); neither dipeptidyl peptidase(s) (N-carboxyphenylmethyl leucine and captopril) nor peptidyl dipeptidase(s) (thiorphan) inhibitors altered the kinetics of MET degradation. Half-life (t1/2) and initial velocity (Iv) of this reaction were significantly increased and decreased, respectively, by fluphenazine > prochlorpherazine > chlorpromazine > thioridazine > promethazine > ethopropazine; brain A hippocampus (t1/2, control 2.8 and 60.2, 22.9, 15.4, 10.0, 9.9, and 4.8 minutes; and Iv, control 59.0 and 3.1, 10.7, 21.3, 22.8, 23.8, and 36.9 pg MET/mg brain tissue/minute) and putamen (t1/2, control 2.5 and 52.4, 19.9, 12.4, 8.2, 8.4, and 4.1 minutes; and Iv, control 53.1 and 2.7, 9.3, 17.1, 18.6, 20.1, and 31.7 pg MET/mg brain tissue/minute). Bacitracin was used for comparison purposes; hippocampus (t1/2 and Iv of 64.2 minutes and 4.3 pg MET/mg brain tissue/minute, respectively). Results using brain B tissue followed a comparable pattern, providing similar results. Hippocampus and putamen samples from both brains showed similar Km (mean 25.2, muM; range, 23.3-27.2 mum), Vmax (mean 108 nmol/mg protein/minute; range, 103-115 nmol/mg), and IC50 values (bacitracin, mean 14.4 muM; range, 13.8-14.7 mum) for MET AP degradation. Neither the phenothiazines methotrimeprazine or trifluoperazine nor other commonly used nonphenothiazine antipsychotic tested, for example, clozapine, haloperidol, loxapine, molindone, sulpiride and thiothixine, significantly altered the kinetics of this reaction. The presence of the phenothiazine molecule appears to be necessary for AP inhibition; however, our results failed to show s correlation among chemical structure, pharmacologic profile, and tested compound ability to inhibit MET degradation. This research provides initial information that could lead to the rational design of agents capable of modulate the bioavailability of enkephalins and other AP-metabolized biologically active compounds. Whether their development could find useful pharmacologic applications remains to be explored.
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PMID:Bacitracin-sensitive aminopeptidase(s) degradation of methionine(5)-enkephalin by human brain putamen and hippocampus preparations: inhibition by phenothiazine drugs. 1979 41

Metabolism of Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) was studied using synaptosomal plasma membranes prepared from rat corpus striatum and whole brain. Cleavage of the pentapeptide was mediated largely by an aminopeptidase leading to the release of Tyr and Gly-Gly-Phe-Leu. Bestatin, an aminopeptidase inhibitor, prevented the release of Tyr and the tetrapeptide, but not secondary cleavage at the Gly Phe site leading to the release of Tyr-Gly-Gly and Phe-Leu. Cleavage at the latter site was inhibited by low concentrations of Thiorphan, an inhibitor of a non-aminopeptidase enkephalinase. MK-421, an inhibitor of the angiotensin converting enzyme, acted only at high substrate concentrations of Leu-enkephalin, indicating that the converting enzyme has a relatively low affinity for the pentapeptide. In contrast to the pentapeptide the major products found upon incubation of heptapeptide with synaptosomal plasma membrane were Arg-Phe and Met-enkephalin. Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. This pathway may represent a mechanism for the formation of Met-enkephalin from larger precursors present in striatum and other regions of the central nervous system.
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PMID:Separate metabolic pathways for Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) degradation by rat striatal synaptosomal membranes. 2048 92

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.
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PMID:Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers. 2119 57

In the classical renin angiotensin system (RAS), angiotensin II Ang IIplays many important roles in cardiovascular disease and in kidney, brain, and other organs via the Ang II type 1 receptor (AT1). The RAS consists of many angiotensin peptides, including Ang (1-7), Ang (1-9), Ang (2-8), and Ang IV. Ang (1-7), produced by angiotensin-converting enzyme 2 (ACE2), has received attention because ACE2-deficient mice have heart failure. In addition, the proto-oncogene mas and insulin regulatory aminopeptidase (IRAP) have been identified as receptors for Ang (1-7) and Ang IV, respectively, accelerating investigations into both peptides. Many groups have suggested that the ACE2/Ang (1-7)/mas axis results in beneficial effects in cardiovascular disease, renal damage, and glucose intolerance and plays an independent role in kidney disease and glucose metabolism. On the other hand, Ang IV/IRAP strongly influences memory disturbance and protects against brain ischemia. Finally, the classical RAS-ACE/Ang II/AT1 axis blockade yields beneficial effects in the context of organ damage, and additional modulation of ACE2/Ang (1-7)/mas or angiotensin IV/IRAP with this blockade results in even greater improvement. In the near future, new treatments targeting RAS and using new angiotensin peptide players might be developed for managing lifestyle-related diseases.
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PMID:Angiotensin (1-7) and other angiotensin peptides. 2317 20

In mammalian species, except humans, N-terminal processing of the precursor peptide angiotensin I (ANG-1-10) into ANG-2-10 or ANG-3-10 was reported. Here we hypothesize that aminopeptidase-generated angiotensins bearing the same C-terminus as ANG-1-10 are also present in humans. We demonstrate the time dependent generation of ANG-2-10, ANG-3-10, ANG-4-10, ANG-5-10 and ANG-6-10 from the precursor ANG-1-10 by human plasma proteins. The endogenous presence of ANG-4-10, ANG-5-10 and ANG-6-10 in human plasma was confirmed by an immuno-fluorescence assay. Generation of ANG-2-10, ANG-3-10 and ANG-4-10 from ANG-1-10 by immobilized human plasma proteins was sensitive to the cysteine/serine protease inhibitor antipain. The metal ion chelator EDTA inhibited Ang-6-10-generation. Incubation of the substrates ANG-3-10, ANG-4-10 and ANG-5-10 with recombinant aminopeptidase N (APN) resulted in a successive N-terminal processing, finally releasing ANG-6-10 as a stable end product, demonstrating a high similarity concerning the processing pattern of the angiotensin peptides compared to the angiotensin generating activity in plasma. Recombinant ACE-1 hydrolyzed the peptides ANG-2-10, ANG-3-10, ANG-4-10 and ANG-5-10 into ANG-2-8, ANG-3-8, ANG-4-8 and ANG-5-8. Since ANG-2-10 was processed into ANG-2-8, ANG-4-8 and ANG-5-8 by plasma proteases the angiotensin peptides bearing the same C-terminus as ANG-1-10 likely have a precursor function in human plasma. Our results confirm the hypothesis of aminopeptidase mediated processing of ANG-1-10 in humans. We show the existence of an aminopeptidase mediated pathway in humans that bypasses the known ANG-1-8-carboxypeptidase pathway. This expands the knowledge about the known human renin angiotensin system, showing how efficiently the precursor ANG-1-10 is used by nature.
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PMID:Proteolytic processing of angiotensin-I in human blood plasma. 2372 17


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