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)

Markers of immediate-type hypersensitivity such as histamine and tryptase were measured in the plasma of nonallergic volunteers and patients with a history of hymenoptera venom anaphylaxis. No significant differences in histamine or tryptase were found between patients and controls. Norepinephrine, an important compound involved in the control of cardiovascular functions and blood pressure, was the same in patients and nonallergic volunteers. In addition, components of the renin-angiotensin system were determined. Patients with hymenoptera venom anaphylaxis showed significantly lower plasma angiotensinogen concentrations as compared to healthy nonallergic controls (p < 0.007), whereas plasma ACE activity was the same. Likewise, the plasma levels of angiotensin I and angiotensin II were significantly reduced in patients as compared to controls (p < 0.04 and p < 0.003, respectively). These findings suggest that the renin-angiotensin system may play an important role as a counteracting factor in hymenoptera venom anaphylaxis.
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PMID:Histamine, tryptase, norepinephrine, angiotensinogen, angiotensin-converting enzyme, angiotensin I and II in plasma of patients with hymenoptera venom anaphylaxis. 791 43

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) dilates resistance arterioles in the in situ systemic circulation and whether inhibitors of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE), two membrane-bound metalloenzymes that are widely distributed in the microcirculation and cleave and inactive VIP, potentiate this response. Using intravital microscopy, we found that VIP (0.05 and 0.1 nmol) induced significant vasodilation in the hamster cheek pouch (13 +/- 1 and 20 +/- 2% increase from baseline, respectively; mean +/- SE; P < 0.05). These responses were significantly potentiated by topical application of phosphoramidon and thiorphan, two relatively selective NEP inhibitors, but not by captopril, a relatively selective ACE inhibitor. Furthermore, suffusion of a mixture of proteinase inhibitors consisting of leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid to inhibit serine proteinases, including mast cell tryptase, aminopeptidases, and carboxypeptidase N, respectively, had no significant effects on VIP-induced responses. These data indicate that VIP elicits vasodilation in the in situ systemic microcirculation and that NEP modulates this response.
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PMID:Neutral endopeptidase modulates VIP-induced vasodilation in hamster cheek pouch vessels in situ. 877 Jan 40

Human chymase (HC) is a chymotrypsin-like serine proteinase expressed by mast cells. The 2.2 A crystal structure of HC complexed to the peptidyl inhibitor, succinyl-Ala-Ala-Pro-Phe-chloromethylketone (CMK), was solved and refined to a crystallographic R-factor of 18.4 %. The HC structure exhibits the typical folding pattern of a chymotrypsin-like serine proteinase, and shows particularly similarity to rat chymase 2 (rat mast cell proteinase II) and human cathepsin G. The peptidyl-CMK inhibitor is covalently bound to the active-site residues Ser195 and His57; the peptidyl moiety juxtaposes the S1 entrance frame segment 214-217 by forming a short antiparallel beta-sheet. HC is a highly efficient angiotensin-converting enzyme. Modeling of the chymase-angiotensin I interaction guided by the geometry of the bound chloromethylketone inhibitor indicates that the extended substrate binding site contains features that may generate the dipeptidyl carboxypeptidase-like activity needed for efficient cleavage and activation of the hormone. The C-terminal carboxylate group of angiotensin I docked into the active-site cleft, with the last two residues extending beyond the active site, is perfectly localized to make a favorable hydrogen bond and salt bridge with the amide nitrogen of the Lys40-Phe41 peptide bond and with the epsilon-ammonium group of the Lys40 side-chain. This amide positioning is unique to the chymase-related proteinases, and only chymases from primates possess a Lys residue at position 40. Thus, the structure conveniently explains the preferred conversion of angiotensin I to angiotensin II by human chymase.
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PMID:The 2.2 A crystal structure of human chymase in complex with succinyl-Ala-Ala-Pro-Phe-chloromethylketone: structural explanation for its dipeptidyl carboxypeptidase specificity. 993 Dec 57

We investigated whether daphnodorin A, daphnodorin B and daphnodorin C inhibited human chymase-dependent angiotensin II-forming activity. Although the structures of these compounds are very similar, daphnodorin A completely inhibited angiotensin II formation generated by chymase, while daphnodorin B partially inhibited and daphnodorin C did not. On the other hand, these daphnodorins did not affect angiotensin converting enzyme-dependent angiotensin II formation. Furthermore, these daphnodorins did not inhibit purified human tryptase, which, like chymase, is contained in mast cells. Therefore, daphnodorin A, but not daphnodorin B and daphnodorin C, may specifically inhibit the chymase-dependent angiotensin II formation, and such differences between inhibitory effects of these compounds to human chymase may be useful for the development of human chymase inhibitor.
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PMID:Effects of daphnodorin A, daphnodorin B and daphnodorin C on human chymase-dependent angiotensin II formation. 1035 87

Possible involvement of mast cells in pulmonary sarcoidosis has been suggested, however whether mast cells are involved in cutaneous sarcoidosis remains unknown. We undertook a morphological study of mast cells in the lesional skin from 17 patients with cutaneous sarcoidosis using immunohistochemical methods. Mast cells were present in non-parenchymal fibrous areas, but not in granulomatous areas, in the biopsy specimens from the cutaneous lesions. However, there were no significant differences between the number of mast cells in the lesional skin and that in non-lesional skin from the patients. Mast cells containing substantial quantities of both tryptase and chymase (MC(TC) cells) were present in 41% of the patients, and cells containing tryptase but not chymase (MC(T) cells) were present in 59% of patients. All patients of the former group showed systemic manifestations of the disease concomitantly. Serum angiotensin I-converting enzyme levels were elevated in 71.4% of the former group, and in 30% of the latter group. This study for the first time demonstrated that mast cells were present in non-parenchymal fibrous areas of the cutaneous lesions of sarcoidosis, and the mast cell subtypes may be related to systemic manifestations.
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PMID:Mast cells in the cutaneous lesions of sarcoidosis: their subtypes and the relationship to systemic manifestations. 1096 Jul 79

The imaginal discs of Drosophila melanogaster give rise to the adult epidermis during metamorphosis. During this developmental period several peptidase genes are expressed in disc cells, but there is a paucity of biochemical information regarding substrate specificity. We have used peptides and peptidyl 7-amino-4-methylcoumarin (AMC) substrates to detect several peptidases either positioned on the surface of wing discs or secreted by the imaginal cells. Using [Leu(5)]enkephalin as a substrate, a captopril sensitive dipeptidyl carboxypeptidase (angiotensin I-converting enzyme) and an amastatin-sensitive aminopeptidase were detected as prominent activities associated with intact discs. The formation of [Leu(5)]enkephalin-derived Phe was attributed to the concerted action of the D. melanogaster angiotensin I-converting enzyme (Ance) and a dipeptidase. The disc Ance also showed endopeptidic activity towards locust tachykinin-1 (LomTK-I) by cleaving the Gly-Val peptide bond, but this enzyme was not the sole endopeptidase activity associated with discs. Complete inhibition of the endopeptidic hydrolysis of the LomTK-1 by a disc homogenate required a combination of captopril and the neprilysin inhibitor, phosphoramidon, providing biochemical evidence for a neprilysin-like peptidase, in addition to Ance, in imaginal discs of D. melanogaster. Peptidyl AMC substrates for furin, prohormone convertase and tryptase provided evidence for trypsin-like serine endopeptidases in addition to the metalloendopeptidases. We conclude that imaginal discs are endowed with a variety of peptidases from different families that together are capable of hydrolyzing a broad range of peptides and proteins. Some of these peptidases might be responsible for the metabolic activation/inactivation of signaling peptides, as well as being involved in the production of dipeptides and free amino acids required for protein synthesis and osmotic balance during adult morphogenesis.
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PMID:Extracellular peptidases of imaginal discs of Drosophila melanogaster. 1243 39

NK3201 is an orally active chymase inhibitor. Its inhibitory activity leads to formation of acyl-intermediate between active serine residue of the enzyme and di-ketone structure of NK3201. NK3201 inhibits human, dog and hamster chymases with IC(50) of 2.5, 1.2, and 28 nM, respectively. On the other hand, NK3201 does not inhibit other types of serine proteases, tryptase, thrombin, elastase, plasmin, and plasminogen activator. In dogs, at 8 h after oral administration of NK3201, 1 mg/kg, the drug levels in plasma, heart, and aorta reached 470, 195, and 78 nM, respectively. In a dog model NK3201, 5 mg/kg/day, increased chymase activity in grafted veins, and suppressed vascular proliferation. After balloon injury in dog vessels, chymase activity was increased locally, in the injured artery, and NK3201, 1 mg/kg/day was effective in preventing vascular proliferation. On the other hand, NK3201, unlike angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, did not affect blood pressure. These findings indicate that local angiotensin II production by chymase is involved only in vascular proliferation, as seen in the injured vessels. Therefore, NK3201 may be useful for preventing vascular proliferation without affecting blood pressure.
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PMID:Application of a chymase inhibitor, NK3201, for prevention of vascular proliferation. 1293 Dec 53

Mast cell tryptase plays an important role in fibrosis. Tryptase levels in bronchial alveolar lavage fluid (BALF) from patients with interstitial lung diseases are frequently increased, but little is known of the clinical significance. The study population consisted of 93 patients [38 with sarcoidosis, 23 with collagen vascular disease (CVD), and 32 with idiopathic pulmonary fibrosis (IPF)]. BALF tryptase levels were measured with a newly developed B12 antibody-fluoroimmunocap method (UniCAP method), which can detect an activated form of tryptase. We examined the relationship between BALF tryptase levels and clinical parameters of the diseases. BALF tryptase was detected in 7 (18.4%) patients with sarcoidosis, 7 (30.4%) with CVD, and 14 (45.8%) with IPF. In tryptase-positive group, serum ACE levels and the numbers of BALF-mast cells and lymphocytes were higher than the tryptase-negative group in sarcoidosis, serum LDH levels were higher in CVD, and the number of BALF-lymphocyte and Hugh-Jones grade were higher in IPF. Furthermore, tryptase-positive IPF cases had a poorer outcome than the tryptase-negative group by Kaplan-Meier analysis. Tryptase in BALF detected with the UniCAP method may be associated with disease activity in sarcoidosis and CVD, and with severity and poor prognosis in IPF. BALF tryptase measurement may be useful in the assessment of disease activity and severity in various interstitial lung diseases.
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PMID:[The clinical significance of mast cell tryptase in bronchial alveolar lavage fluid in interstitial lung diseases]. 1805 86

Angioedema (AE) is the end result of deep dermal, subcutaneous and/or submucosal swelling, and represents a major criterion in the definition of anaphylaxis. Drug-induced AE, like other cutaneous drug reactions, is most frequently elicited by betalactam antibiotics and nonsteroidal antiinflammatory drugs. However, differences exist in their underlying pathophysiology (IgE mediated vs. pseudoallergic). Blockers of the renin-angiotensin-aldosterone system are the most common class of medications associated with isolated AE and are most probably related to elevated bradykinin levels. Typically, ACE inhibitor-associated AE can occur up to several years after initiating treatment, and may sporadically recur even after discontinuation. A comprehensive investigation of AE must include analysis of complement factors, tryptase levels as well as specific allergy tests. Furthermore, other possible causative agents ought to be excluded. Every patient with drug-induced AE must receive an allergy pass as well as emergency medication including epinephrine. In some cases, inhibitors of the bradykinin system may be considered for treatment.
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PMID:Drug-induced angioedema. 2261 56

We report two probable cases of delayed presentation of ACE inhibitor (ACEi)-induced angio-oedema. The first patient was on ACEi for more than 10 years while the second one was on it for 7 years. Both the patients presented with initial unilateral swelling of the tongue which progressed further to involve the soft tissues of the oropharynx, head and neck leading to a compromised airway needing awake fibreoptic intubation and were managed successfully in the intensive care unit (ICU). C1 esterase inhibitor and mast cell tryptase level was normal for both patients. Both were treated with intravenous antihistamines and corticosteroids in the ICU. Both patients were successfully extubated within 72 h and transferred to a medical ward. Age above 65 years, atopy and non-steroidal anti-inflammatory drug use may have been the predisposing factors. Both patients made a full recovery with no complications and the ACEi was ceased.
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PMID:Delayed presentation of ACE inhibitor-induced angio-oedema. 2389 86


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