Hydrolysis of bradykinin and its higher homologues by angiotensin-converting enzyme.
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ABSTRACT:
SUBMITTER: Dorer F
PROVIDER: S-EPMC1168198 | biostudies-other | 1974 Sep
REPOSITORIES: biostudies-other
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Project description:Endothelin-converting enzyme (ECE) is the key enzyme in the production of the potent vasoconstrictor endothelin from its inactive precursor big endothelin. To date, no other physiological peptide substrate has been identified for ECE. Here, by using Chinese hamster ovary (CHO) cells transfected with rat ECE-1 cDNA, we have established that ECE can hydrolyse the vasodilator bradykinin. The hydrolysis of bradykinin by ECE is exclusively at the Pro7-Phe8 bond, producing bradykinin-(1-7) and bradykinin-(8-9). Hydrolysis is completely inhibited by 100 microM phosphoramidon and 200 microM EDTA, but only slightly by the specific neprilysin inhibitor thiorphan (100 microM). The ability of ECE to act as a peptidyl dipeptidase rather than an endopeptidase in hydrolysing bradykinin suggests a much broader specificity for the enzyme than previously recognized, which may lead to the design of new and specific inhibitors of ECE and to the identification of other potential physiological substrates.
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Project description:Angiotensin-I converting enzyme (ACE) is a zinc dipeptidylcarboxypeptidase with two active domains and plays a key role in the regulation of blood pressure and electrolyte homeostasis, making it the principal target in the treatment of cardiovascular disease. More recently, the tetrapetide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) has emerged as a potent antifibrotic agent and negative regulator of haematopoietic stem cell differentiation which is processed exclusively by ACE. Here we provide a detailed biochemical and structural basis for the domain preference of Ac-SDKP. The high resolution crystal structures of N-domain ACE in complex with the dipeptide products of Ac-SDKP cleavage were obtained and offered a template to model the mechanism of substrate recognition of the enzyme. A comprehensive kinetic study of Ac-SDKP and domain co-operation was performed and indicated domain interactions affecting processing of the tetrapeptide substrate. Our results further illustrate the molecular basis for N-domain selectivity and should help design novel ACE inhibitors and Ac-SDKP analogues that could be used in the treatment of fibrosis disorders.
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Project description:Angiotensin converting enzyme (ACE) is well known for its dual actions to convert inactive Ang I to active Ang II, and degrades active bradykinin (BK), which plays an important role in controlling blood pressure. Because it is the bottleneck step for the production of pressor Ang II, it was targeted pharmacologically in the 1970s. Successful ACE inhibitors such as captopril were produced to treat hypertension. Studies on domain-specific ACE inhibitors are continuing to produce effective hypertension-controlling drugs with fewer side effects. ACE2 was discovered in 2000 and it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus, causing the infamous severe acute respiratory syndrome (SARS) in 2003.
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Project description:The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 850 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 100 is Angiotensin-Converting Enzyme-2. Keywords: Angiotensin, angiotensin-converting enzyme 2 (ACE2), apelin, bradykinin, carboxypeptidase, cardiovascular, collectrin, renin-angiotensin system, SARS virus, shedding, transmembrane, vasoactive, zinc-binding motif.
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Project description:UnlabelledAngiotensin-1-converting enzyme (ACE), a zinc metallopeptidase, consists of two homologous catalytic domains (N and C) with different substrate specificities. Here we report kinetic parameters of five different forms of human ACE with various amyloid beta (Aβ) substrates together with high resolution crystal structures of the N-domain in complex with Aβ fragments. For the physiological Aβ(1-16) peptide, a novel ACE cleavage site was found at His14-Gln15. Furthermore, Aβ(1-16) was preferentially cleaved by the individual N-domain; however, the presence of an inactive C-domain in full-length somatic ACE (sACE) greatly reduced enzyme activity and affected apparent selectivity. Two fluorogenic substrates, Aβ(4-10)Q and Aβ(4-10)Y, underwent endoproteolytic cleavage at the Asp7-Ser8 bond with all ACE constructs showing greater catalytic efficiency for Aβ(4-10)Y. Surprisingly, in contrast to Aβ(1-16) and Aβ(4-10)Q, sACE showed positive domain cooperativity and the double C-domain (CC-sACE) construct no cooperativity towards Aβ(4-10)Y. The structures of the Aβ peptide-ACE complexes revealed a common mode of peptide binding for both domains which principally targets the C-terminal P2' position to the S2' pocket and recognizes the main chain of the P1' peptide. It is likely that N-domain selectivity for the amyloid peptide is conferred through the N-domain specific S2' residue Thr358. Additionally, the N-domain can accommodate larger substrates through movement of the N-terminal helices, as suggested by the disorder of the hinge region in the crystal structures. Our findings are important for the design of domain selective inhibitors as the differences in domain selectivity are more pronounced with the truncated domains compared to the more physiological full-length forms.DatabaseThe atomic coordinates and structure factors for N-domain ACE with Aβ peptides 4-10 (5AM8), 10-16 (5AM9), 1-16 (5AMA), 35-42 (5AMB) and (4-10)Y (5AMC) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (http://www.rcsb.org/).
| S-EPMC4950319 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.
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Project description:Angiotensin-converting enzyme inhibitors (ACE-I) are widely used in diseases, such as hypertension, congestive heart failure, and myocardial infarction. Although these drugs are well tolerated, one out of five patients discontinues ACE-I due to drug side effects, mainly chronic cough. However, the pathogenesis of ACE-I-induced cough remains controversial and requires further study. In this review, the mechanisms that are suggested in ACE-I-induced cough pathophysiology will be discussed in detail in light of the current literature.
| S-EPMC6340691 | biostudies-literature
Project description:Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female; 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality (p < 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis (p < 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63-0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62-0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continued treatment, and those taking ARB.
| S-EPMC8232748 | biostudies-literature
Project description:ObjectiveTo assess the polymorphism of angiotensin converting enzyme (ACE) in ischemic stroke in an Egyptian sample.MethodsOne hundred subjects (70 ischemic stroke patients, and 30 healthy controls) were included in case control cross sectional study during the period from January 2017 to January 2018, at Neurology Department, Menufia University Hospital, Shibin EL-Kom, Egypt. Patients underwent complete neurological assessment, national institute health stroke scale (NIHSS), and Toast classification. All subjects underwent genotyping of ACE gene polymorphism.ResultsThere are 42.9% from the patients versus 33.3% from controls showed geno typing of Insertion/Deletion (I/D) and Allele D is more frequent regarding I allele in ischemic stroke patients but this difference did not reach significant level to be risk factor. The I/D polymorphism was the predominant type in SVS and LVS while DD was the predominant type in cardio-embolic one. There were no significant differences between NIHSS in different ACE gene polymorphism.ConclusionIn spite of ACE genotyping differences among Egyptian ischemic stroke patients, we cannot consider it a predisposing factor to stroke occurrence or severity.
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Project description:Angiotensin III is formed from des-Asp1 -angiotensin I by angiotensin-converting enzyme. The Km (11 muM) of the reaction is one-third of that for the conversion of angiotensin I into angiotensin II. As suggested by the Km values, bradykinin, peptide BPP9a and angiotensins II and III are better inhibitors of the formation of angiotensin II than of the formation of angiotensin III.
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