Angiotensin-converting enzyme 2
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Location (UCSC) | Chr X: 15.56 – 15.6 Mb | Chr X: 162.92 – 162.97 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Angiotensin-converting enzyme 2 (ACE2)
mACE2 also serves as the entry point into cells for some
Structure
Angiotensin-converting enzyme 2 | |||||||||
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ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Membrane bound angiotensin-converting enzyme 2 (mACE2) is a zinc-containing
mACE2 is a single-pass
Location within the human body
mACE2 is attached to the cell membrane of mainly
Function
As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to the
sACE2, as part of RAAS's protective phase, cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator angiotensin (1-7) (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure.[24][17] sACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[17]
mACE2 also regulates the membrane trafficking of the neutral amino acid transporter
Research in mice has shown that ACE2 (whether it is the membrane bound version or soluble is inconclusive) is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed.[28][29]
As a transmembrane protein, mACE2 serves as the main entry point into cells for some
The binding of the SARS-CoV-2 virus through mACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In a study done during the SARS outbreak, SARS virus RNA was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS.[41] It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals.[42] This entry process also requires priming of the S protein by the host serine protease TMPRSS2, the inhibition of which is under current investigation as a potential therapeutic.[43][21] It has also been shown that disruption of S-protein glycosylation significantly impairs viral entry, indicating the importance of glycan-protein interactions in the process.[44]
This has led some to hypothesize that decreasing the levels of mACE2, in cells, might help in fighting the infection. Furthermore, according to studies conducted on
On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the
Both ACE inhibitors and angiotensin II receptor blockers (ARBs) that are used to treat high blood pressure have been shown in rodent studies to upregulate mACE2 expression, possibly affecting the severity of coronavirus infections.[48][49]
However, a systematic review and meta-analysis published on July 11, 2012, found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." Moreover, "the risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."[50] An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for patients with hypertension who were taking ACE inhibitors or ARBs. The death rate was compared with 9.8% of hospitalized patients with hypertension not taking such drugs, suggesting that ACE inhibitors and ARBs are not harmful and may help against the coronavirus.[51]
Despite lack of conclusive evidence, some have advocated for or against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.[52] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[53][54][55]
Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients, with higher plasma levels being correlated with worse disease outcomes. Patients with high blood pressure or heart disease show elevated ACE2 plasma levels.[56]
Given its role as the SARS-CoV-2 entry receptor, it has been repeatedly hypothesised that population variation in ACE2 may contribute to an individual's
Recombinant human ACE2
Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for
An in vitro study focused on the early stages of infection found that clinical-grade human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 recovery from vero cells by a factor of 1,000–5,000. The equivalent mouse rsACE2 did not have such an effect. This study suggests that rhsACE2 not only restores the renin-angiotensin system to balance as in the earlier ARDS studies, but also directly slows down infection by this virus – possibly as a decoy.[66] ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise the virus in vitro.[67] An ACE2 triple mutant that displayed nanomolar binding to Spike (sACE2.v2.4),[67] was later shown to block pseudovirus cell entry in human lung cell lines and prevent SARS-CoV-2 induced ARDS in an ACE2 humanized mouse model.[68]
Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome (ARDS).[69] rhACE2 is in phase II trial for severe COVID-19.[70]
See also
- Renin–angiotensin system
- SARS-CoV-2 § Structural biology
- LRRC15
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000130234 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015405 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c "Gene: ACE2, angiotensin I converting enzyme 2". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. 2020-02-28.
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The discovery of ACE2 and its role in counteracting the effect of Ang-II through Ang(1-7) formation ... An imbalance in ACE2/Ang-(1–7) and ACE/Ang-II axes is critical in the development of cardiovascular diseases. The central role of ACE2, therefore, appears to counter ACE activity by reducing Ang-II bioavailability and increasing Ang(1-7) formation ... The use of RAS-modulating agents and molecules as novel therapeutic agents in hypertension and cardiovascular therapeutic research.
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Studies with recombinant human ACE2 (rhACE2) have shown beneficial cardiac effects [18, 36]. rhACE2 has anti-fibrotic properties and can attenuate effect on systolic and diastolic dysfunction, presumably via Ang-II inhibition.
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the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.
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Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors).
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Once SARS-CoV binds to its receptor, the abundance on the cell surface, mRNA expression and the enzymatic activity of ACE2 are significantly reduced. ... These effects are, in part, due to enhanced shedding/internalizing processes. ... The spike protein binds to ACE2 and subsequently down regulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia
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Our results suggest an important role of ACE inhibitors, but not ARBs, in reducing the risk of pneumonia. These data may discourage the withdrawal of ACE inhibitors in some patients with tolerable adverse events (namely, cough) who are at particularly high risk of pneumonia. ACE inhibitors also lowered the risk of pneumonia related mortality, mainly in patients with established disease, but the robustness of the evidence was weaker.
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- ^ "Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers". European Society of Cardiology (ESC). 13 March 2020.
- ^ "EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic". European Medicines Agency (EMA). 27 March 2020.
- ^ "HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19". American College of Cardiology (ACC). 27 March 2020.
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- ^ "Apeiron Biologics moves forward with APN01 for treatment of COVID-19". www.thepharmaletter.com. Retrieved 3 April 2020.
External links
- Human ACE2 genome location and ACE2 gene details page in the UCSC Genome Browser.
- Angiotensin-converting enzyme 2 in Membranome database
- 3D structure of OPM database
- Overview of all the structural information available in the PDB for UniProt: Q9BYF1 (Angiotensin-converting enzyme 2) at the PDBe-KB.