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Kidney360 Dec 2022
Topics: Angiotensin-Converting Enzyme 2; Renin-Angiotensin System; Peptidyl-Dipeptidase A
PubMed: 36591363
DOI: 10.34067/KID.0005592022 -
The Lancet. Microbe May 2023Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune... (Review)
Review
Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune evasion capacity through key amino acid mutations, but can still bind human angiotensin-converting enzyme 2 (ACE2) through the spike protein and are, thus, sensitive to ACE2-mimicking decoys as inhibitors. In this Review, we examine advances in the development of ACE2 derivatives from the past 3 years, including the recombinant ACE2 proteins, ACE2-loaded extracellular vesicles, ACE2-mimicking antibodies, and peptide or mini-protein mimetics of ACE2. Several ACE2 derivatives are granted potent neutralisation efficacy against SARS-CoV-2 variants that rival or surpass endogenous antibodies by various auxiliary techniques such as chemical modification and practical recombinant design. The derivatives also represent enhanced production efficiency and improved bioavailability. In addition to these derivatives of ACE2, new effective therapeutics against SARS-CoV-2 variants are expected to be developed.
Topics: Humans; SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2; Pandemics; Peptidyl-Dipeptidase A; Antibodies, Viral; Recombinant Proteins
PubMed: 36934742
DOI: 10.1016/S2666-5247(23)00011-3 -
Frontiers in Cellular and Infection... 2021Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found... (Review)
Review
Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.
Topics: Angiotensin-Converting Enzyme 2; Cell Line; Humans; Peptidyl-Dipeptidase A; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35096642
DOI: 10.3389/fcimb.2021.789180 -
Best Practice & Research. Clinical... Jul 2023The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs,... (Review)
Review
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the virus has been detected in various amounts in all endocrine tissues in post-mortem samples from COVID-19 patients. The infection with SARS-CoV-2 may directly lead to organ damage or dysfunction, such as hyperglycaemia or in rare cases, new-onset diabetes. Furthermore, an infection with SARS-CoV-2 may have indirect effects affecting the endocrine system. The exact mechanisms are not yet completely understood and have to be further investigated. Conversely, endocrine diseases may affect the severity of COVID-19 and emphasis has to be laid on reducing the prevalence, or enhance the treatment, of these often non-communicable diseases in the future.
Topics: Humans; COVID-19; SARS-CoV-2; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme 2; Endocrine Glands
PubMed: 36907787
DOI: 10.1016/j.beem.2023.101761 -
Current Protocols in Protein Science Apr 2017Protein synthesis is initiated by methionine in eukaryotes and by formylmethionine in prokaryotes. N-terminal methionine can be co-translationally cleaved by the enzyme...
Protein synthesis is initiated by methionine in eukaryotes and by formylmethionine in prokaryotes. N-terminal methionine can be co-translationally cleaved by the enzyme methionine aminopeptidase (MAP). When recombinant proteins are expressed in bacterial and mammalian expression systems, there is a simple universal rule that predicts whether the initiating methionine will be processed by MAP based on the size of the residue adjacent (penultimate) to the N-methionine. In general, if the side chains of the penultimate residues have a radius of gyration of 1.29 Å or less, methionine is cleaved. © 2017 by John Wiley & Sons, Inc.
Topics: Amino Acid Sequence; Escherichia coli; Methionine; Methionyl Aminopeptidases; Protein Biosynthesis; Protein Modification, Translational; Recombinant Proteins; Substrate Specificity
PubMed: 28369664
DOI: 10.1002/cpps.29 -
Translational Neurodegeneration Sep 2022Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a life-threatening disease, especially in... (Review)
Review
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a life-threatening disease, especially in elderly individuals and those with comorbidities. The predominant clinical manifestation of COVID-19 is respiratory dysfunction, while neurological presentations are increasingly being recognized. SARS-CoV-2 invades host cells primarily via attachment of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor expressed on cell membranes. Patients with Alzheimer's disease (AD) are more susceptible to SARS-CoV-2 infection and prone to severe clinical outcomes. Recent studies have revealed some common risk factors for AD and COVID-19. An understanding of the association between COVID-19 and AD and the potential related mechanisms may lead to the development of novel approaches to treating both diseases. In the present review, we first summarize the mechanisms by which SARS-CoV-2 invades the central nervous system (CNS) and then discuss the associations and potential shared key factors between COVID-19 and AD, with a focus on the ACE2 receptor, apolipoprotein E (APOE) genotype, age, and neuroinflammation.
Topics: Aged; Alzheimer Disease; Angiotensin-Converting Enzyme 2; COVID-19; Humans; Pandemics; Peptidyl-Dipeptidase A; SARS-CoV-2
PubMed: 36089575
DOI: 10.1186/s40035-022-00316-y -
Molecular Biology of the Cell Dec 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry. ACE2 is a critical negative regulator of the renin-angiotensin system and plays a protective role in preventing tissue injury. Expression of ACE2 has been shown to decrease upon infection by SARS-CoV. However, whether SARS-CoV-2 down-regulates ACE2 and the underlying mechanism and biological impact of this down-regulation have not been well defined. Here we show that the SARS-CoV-2 infection down-regulates ACE2 in vivo in an animal model, and in cultured cells in vitro, by inducing clathrin- and AP2-dependent endocytosis, leading to its degradation in the lysosome. SARS-CoV-2 S-treated cells and ACE2 knockdown cells exhibit similar alterations in downstream gene expression, with a pattern indicative of activated cytokine signaling that is associated with respiratory distress and inflammatory diseases often observed in COVID-19 patients. Finally, we have identified a soluble ACE2 fragment with a stronger binding to SARS-CoV-2 S that can efficiently block ACE2 down-regulation and viral infection. Thus, our study suggests that ACE2 down-regulation represents an important mechanism underlying SARS-CoV-2-associated pathology, and blocking this process could be a promising therapeutic strategy.
Topics: Animals; Angiotensin-Converting Enzyme 2; SARS-CoV-2; COVID-19; Peptidyl-Dipeptidase A; Lysosomes; Protein Binding
PubMed: 36287912
DOI: 10.1091/mbc.E22-02-0045 -
Biochimie Nov 2019The huge exopeptidase, tripeptidyl-peptidase II (TPP II), appears to be involved in a large number of important biological processes. It is present in the cytosol of... (Review)
Review
The huge exopeptidase, tripeptidyl-peptidase II (TPP II), appears to be involved in a large number of important biological processes. It is present in the cytosol of most eukaryotic cells, where it removes tripeptides from free amino termini of longer peptides through a 'molecular ruler mechanism'. Its main role appears to be general protein degradation, together with the proteasome. The activity is increased by stress, such as during starvation and muscle wasting, and in tumour cells. Overexpression of TPP II leads to accelerated cell growth, genetic instability and resistance to apoptosis, whereas inhibition or down-regulation of TPP II renders cells sensitive to apoptosis. Although it seems that humans can survive without TPP II, it is not without consequences. Recently, patients with loss-of-function mutations in the TPP2 gene have been identified. They suffer from autoimmunity leading to leukopenia and other consequences. Furthermore, a missense mutation in the TPP2 gene is associated with a sterile brain inflammation condition mimicking multiple sclerosis. This review will summarise what is known today regarding the activity and structure of this very large enzyme complex, and its potential function in various cellular processes. It is clear that more research is needed to identify natural substrates and/or interaction partners of TPP II, which can explain the observed effects in different cellular contexts.
Topics: Aminopeptidases; Animals; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drosophila melanogaster; Humans; Mice; Mutation; Proteolysis; Rats; Serine Endopeptidases; Substrate Specificity
PubMed: 31108122
DOI: 10.1016/j.biochi.2019.05.012 -
Biotechnology Advances 2016Although substantial research has been focused on the 'hidden antigen' H11 of Haemonchus contortus as a vaccine against haemonchosis in small ruminants, little is know... (Review)
Review
Although substantial research has been focused on the 'hidden antigen' H11 of Haemonchus contortus as a vaccine against haemonchosis in small ruminants, little is know about this and related aminopeptidases. In the present article, we reviewed genomic and transcriptomic data sets to define, for the first time, the complement of aminopeptidases (designated Hc-AP-1 to Hc-AP-13) of the family M1 with homologues in Caenorhabditis elegans, characterised by zinc-binding (HEXXH) and exo-peptidase (GAMEN) motifs. The three previously published H11 isoforms (accession nos. X94187, FJ481146 and AJ249941) had most sequence similarity to Hc-AP-2 and Hc-AP-8, whereas unpublished isoforms (accession nos. AJ249942 and AJ311316) were both most similar to Hc-AP-3. The aminopeptidases characterised here had homologues in C. elegans. Hc-AP-1 to Hc-AP-8 were most similar in amino acid sequence (28-41%) to C. elegans T07F10.1; Hc-AP-9 and Hc-AP-10 to C. elegans PAM-1 (isoform b) (53-54% similar); Hc-AP-11 and Hc-AP-12 to C. elegans AC3.5 and Y67D8C.9 (26% and 50% similar, respectively); and Hc-AP-13 to C. elegans C42C1.11 and ZC416.6 (50-58% similar). Comparative analysis suggested that Hc-AP-1 to Hc-AP-8 play roles in digestion, metabolite excretion, neuropeptide processing and/or osmotic regulation, with Hc-AP-4 and Hc-AP-7 having male-specific functional roles. The analysis also indicated that Hc-AP-9 and Hc-AP-10 might be involved in the degradation of cyclin (B3) and required to complete meiosis. Hc-AP-11 represents a leucyl/cystinyl aminopeptidase, predicted to have metallopeptidase and zinc ion binding activity, whereas Hc-AP-12 likely encodes an aminopeptidase Q homologue also with these activities and a possible role in gonad function. Finally, Hc-AP-13 is predicted to encode an aminopeptidase AP-1 homologue of C. elegans with hydrolase activity, suggested to operate, possibly synergistically with a PEPT-1 ortholog, as an oligopeptide transporter in the gut for protein uptake and normal development and/or reproduction of the worm. An appraisal of structure-based amino acid sequence alignments revealed that all conceptually translated Hc-AP proteins, with the exception of Hc-AP-12, adopt a topology similar to those observed for the two subgroups of mammalian M1 aminopeptidases, which possess either three (I, II and IV) or four (I-IV) domains. In contrast, Hc-AP-12 lacks the N-terminal domain (I), but possesses a substantially expanded domain III. Although further work needs to be done to assess amino acid sequence conservation of the different aminopeptidases among individual worms within and among H. contortus populations, we hope that these insights will support future localisation, structural and functional studies of these molecules in H. contortus as well as facilitate future assessments of a recombinant subunit or cocktail vaccine against haemonchosis.
Topics: Animals; Biotechnology; CD13 Antigens; Caenorhabditis elegans; Haemonchus; Helminth Proteins; Membrane Proteins; Models, Molecular
PubMed: 26597954
DOI: 10.1016/j.biotechadv.2015.10.003 -
Current Opinion in Structural Biology Jun 2022The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and... (Review)
Review
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection. S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines. ACE2 is a peptidase that plays a physiologically important role in the renin-angiotensin system. Concurrently, it also forms dimer of heterodimer with the neutral amino acid transporter BAT1 to regulate intestinal amino acid metabolism. The symptoms of COVID-19 are closely correlated with the physiological functions of ACE2. In this review, we summarize the functional and structural studies on ACE2, BAT1, and their complex with S of SARS-CoV-2, providing insights into the various symptoms caused by viral infection and the development of therapeutic strategies.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Humans; Peptidyl-Dipeptidase A; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 35584583
DOI: 10.1016/j.sbi.2022.102388