Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex.
Ontology highlight
ABSTRACT:
SUBMITTER: Bartolome A
PROVIDER: S-EPMC8105332 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC8361046 | biostudies-literature
Project description:ACE2 is a monocarboxypeptidase which generates Angiotensin (1-7) from Angiotensin II (1-8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent tubular uptake. Here, we show that both urine and kidney lysates are capable of digesting native ACE2 into shorter proteins of ~60-75 kDa and then demonstrate that they are enzymatically very active. We then truncated the native ACE2 by design from the C-terminus to generate two short recombinant (r)ACE2 variants (1-605 and 1-619AA). These two truncates have a molecular size of ~70 kDa, as expected from the amino acid sequence and as shown by Western blot. ACE2 enzyme activity, measured using a specific substrate, was higher than that of the native rACE2 (1-740 AA). When infused to mice with genetic ACE2 deficiency, a single i.v. injection of 1-619 resulted in detectable ACE2 activity in urine, whereas infusion of the native ACE2 did not. Moreover, ACE2 activity was recovered in harvested kidneys from ACE2-deficient mice infused with 1-619, but not in controls (23.1 ± 4.3 RFU/µg creatinine/h and 1.96 ± 0.73 RFU/µg protein/hr, respectively). In addition, the kidneys of ACE2-null mice infused with 1-619 studied ex vivo formed more Ang (1-7) from exogenous Ang II than those infused with vehicle (AUC 8555 ± 1933 vs. 3439 ± 753 ng/mL, respectively, p < 0.05) further demonstrating the functional effect of increasing kidney ACE2 activity after the infusion of our short ACE2 1-619 variant. We conclude that our novel short recombinant ACE2 variants undergo glomerular filtration, which is associated with kidney uptake of enzymatically active proteins that can enhance the formation of Ang (1-7) from Ang II. These small ACE2 variants may offer a potentially useful approach to target kidney RAS overactivity to combat kidney injury.
| S-EPMC6995632 | biostudies-literature
Project description:The pandemic of coronavirus disease 2019 (COVID-19) is a global health emergency that poses a significant threat to world people's health. This outbreak causes major challenges to healthcare systems. Given the lack of effective treatments or vaccine for it, the identification of novel and safe drugs against COVID-19 infection is an urgent need. Angiotensin-converting enzyme 2 (ACE2) is not only an entry receptor of the SARS-CoV-2 virus, the virus that causes COVID-19, but also can protect from lung injury. In this view, we highlighted potential approaches to address ACE2-mediated SARS-CoV-2 virus, including 1) delivering an excessive soluble form of ACE2 (recombinant human ACE2: rhACE2) and 2) inhibition of the interaction between SARS-CoV-2 virus and ACE2 by some compounds with competitive effects (morphine and codeine). Further clinical trials in this regard can reveal a more definite conclusion against the COVID-19 disaster.
| S-EPMC7214324 | biostudies-literature
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.
| S-EPMC7150073 | biostudies-literature
Project description:?-Secretase is essential for the generation of the neurotoxic 42-amino acid amyloid ?-peptide (A?(42)). The aggregation-prone hydrophobic peptide, which is deposited in Alzheimer disease (AD) patient brain, is generated from a C-terminal fragment of the ?-amyloid precursor protein by an intramembrane cleavage of ?-secretase. Because A?(42) is widely believed to trigger AD pathogenesis, ?-secretase is a key AD drug target. Unlike inhibitors of the enzyme, ?-secretase modulators (GSMs) selectively lower A?(42) without interfering with the physiological function of ?-secretase. The molecular target(s) of GSMs and hence the mechanism of GSM action are not established. Here we demonstrate by using a biotinylated photocross-linkable derivative of highly potent novel second generation GSMs that ?-secretase is a direct target of GSMs. The GSM photoprobe specifically bound to the N-terminal fragment of presenilin, the catalytic subunit of ?-secretase, but not to other ?-secretase subunits. Binding was differentially competed by GSMs of diverse structural classes, indicating the existence of overlapping/multiple GSM binding sites or allosteric alteration of the photoprobe binding site. The ?-amyloid precursor protein C-terminal fragment previously implicated as the GSM binding site was not targeted by the compound. The identification of presenilin as the molecular target of GSMs directly establishes allosteric modulation of enzyme activity as a mechanism of GSM action and may contribute to the development of therapeutically active GSMs for the treatment of AD.
| S-EPMC3199465 | biostudies-literature
Project description:Angiotensin-converting enzyme (ACE; EC 3.4.1.15.1) exists in both membrane-bound and soluble forms. Phase separation in Triton X-114 and a competitive e.l.i.s.a. have been employed to characterize the activity which post-translationally converts the amphipathic, membrane-bound form of ACE in pig kidney microvilli into a hydrophilic, soluble form. This secretase activity was enriched to a similar extent as other microvillar membrane proteins, was tightly membrane-associated, being resistant to extensive washing of the microvillar membranes with 0.5 M NaCl, and displayed a pH optimum of 8.4. The ACE secretase was not affected by inhibitors of serine-, thiol- or aspartic-proteases, nor by reducing agents or alpha 2-macroglobulin. The metal chelators, EDTA and 1,10-phenanthroline, inhibited the secretase activity, with, in the case of EDTA, an inhibitor concentration of 2.5 mM causing 50% inhibition. In contrast, EGTA inhibited the secretase by a maximum of 15% at a concentration of 10 mM. The inhibition of EDTA was reactivated substantially (83%) by Mg2+ ions, and partially (34% and 29%) by Zn2+ and Mn2+ ions respectively. This EDTA-sensitive secretase activity was also present in microsomal membranes prepared from pig lung and testis, and from human lung and placenta, but was absent from human kidney and human and pig intestinal brush-border membranes. The form of ACE released from the microvillar membrane by the secretase co-migrated on SDS/PAGE with ACE purified from pig plasma, thus the action and location of the secretase would be consistent with it possibly having a role in the post-translational proteolytic cleavage of membrane-bound ACE to generate the soluble form found in blood, amniotic fluid, seminal plasma and other body fluids.
| S-EPMC1134252 | biostudies-other
Project description:BackgroundBeneficial effects of angiotensin-converting enzyme (ACE) inhibitors seem to be mediated by mechanisms that are partly independent of blood pressure lowering. The present study evaluates effects of an ACE inhibitor (ie, fosinopril) intervention on novel cardiovascular risk factors.MethodsData are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial enrolling subjects > or =55 years old with high cardiovascular disease risk profile. Biomarkers of hemostasis (ie, plasminogen activator inhibitor 1, D-dimer), inflammation (ie, C-reactive protein, interleukin-6), and endothelial function (ie, endothelin 1, vascular cell adhesion molecule 1) were measured at the baseline, at the midterm, and at end of follow-up (after 1 year) clinic visits. Paired t test analyses (after Sidak's adjustment, P < .009) were performed to compare biomarkers modifications after fosinopril/placebo interventions.ResultsMean age of the sample (n = 290, women 43.4%) was 66.0 years old. No significant differences were reported for C-reactive protein, interleukin 6, plasminogen activator inhibitor 1, vascular cell adhesion molecule 1, and endothelin 1 levels in the comparisons between fosinopril and placebo interventions. D-dimer was the only biomarker showing a significant difference between fosinopril intervention (median 0.32 microg/mL, interquartile range 0.22-0.52 microg/mL) and placebo (median 0.29 microg/mL, interquartile range 0.20-0.47 microg/mL, P = .007) when analyses were restricted to participants with higher compliance to treatment and receiving the maximum ACE inhibitor dosage.ConclusionsAngiotensin-converting enzyme inhibition does not significantly modify major biomarkers of inflammation, hemostasis, and endothelial function. Further studies should confirm the possible effect of ACE inhibitors on the fibrinolysis pathway.
| S-EPMC4384444 | 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.
| S-EPMC7129862 | biostudies-literature
Project description:Experimental and clinical evidence supports an active role of the renin–angiotensin system (RAS) in the pathogenesis and progression of lung diseases. Angiotensin II (Ang II), a key vasoactive peptide of the RAS, has been implicated in pulmonary disorders such as pulmonary arterial hypertension, lung fibrosis, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Over the past few years, the classical concept of the RAS has undergone substantial changes to include several new active components. Among them, the identification of angiotensin-converting enzyme 2 (ACE2), its metabolic product angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor has been of biological significance since these components form a counterregulatory axis (ACE2/Ang-(1-7)/Mas) that opposes the detrimental actions of Ang II. In this chapter, we will discuss the role of the ACE2/Ang-(1-7)/Mas axis in lung diseases and describe novel therapeutic approaches to activate this axis for the treatment of pulmonary disorders.
| S-EPMC7149638 | biostudies-literature
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