Angiotensin-converting enzyme 2

ACE2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesACE2, ACEH, angiotensin I converting enzyme 2, ACE 2
External IDsOMIM: 300335 MGI: 1917258 HomoloGene: 41448 GeneCards: ACE2
Orthologs
SpeciesHumanMouse
Entrez

59272

70008

Ensembl

ENSG00000130234

ENSMUSG00000015405

UniProt

Q9BYF1

Q8R0I0

RefSeq (mRNA)

NM_021804
NM_001371415

NM_001130513
NM_027286

RefSeq (protein)

NP_068576
NP_001358344

NP_001123985
NP_081562

Location (UCSC)Chr X: 15.56 – 15.6 MbChr X: 164.14 – 164.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Angiotensin-converting enzyme 2 (ACE2)[5] is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2).[6][7][8] Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. While mACE2 does not appear to factor into the harmful phase of RAAS (the increase of blood pressure), its existence is vital in order for the enzyme ADAM17 to cleave its extracellular domain to create soluble ACE2 (sACE2). Soluble ACE2 lowers blood pressure by catalyzing the hydrolysis of angiotensin II (a vasoconstrictor peptide) into angiotensin (1–7) (a vasodilator)[8][9][10] which in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.[11] This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.[12][13]

mACE2 also serves as the entry point into cells for some coronaviruses, including HCoV-NL63, SARS-CoV, and SARS-CoV-2.[5] The SARS-CoV-2 spike protein itself is known to damage the endothelium via downregulation of ACE2.[14] The human version of the enzyme can be referred to as hACE2.[15]

Structure

Angiotensin-converting enzyme 2
Identifiers
EC no.3.4.17.23
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

Membrane bound Angiotensin-converting enzyme 2 (mACE2) is a zinc-containing metalloenzyme located on the surface of intestinal enterocytes, renal tubular cells and other cells.[6][16] mACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[16]

mACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in the intestines and other tissues.[6][7] The extracellular domain of mACE2 can be cleaved from the transmembrane domain by another enzyme known as ADAM17 a member of the sheddase enzyme family, during the protective phase of RAAS, the Renin Angiotension Aldosterone System which regulates our body's blood pressure. The resulting cleaved protein is known as soluble ACE2 or sACE2. It is released into the bloodstream where one of sACE2's functions is to turn excess angiotensin II into angiotensin 1-7 which binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. Excess sACE2 may ultimately be excreted in the urine.[17][18]

Location within the human body

mACE2 is attached to the cell membrane of mainly enterocytes of the small intestine and duodenum, proximal tubular cells of the kidneys, glandular cells of the gallbladder, as well as Sertoli cells and Leydig cells of the testis.[6] The expression profile of mACE2 in the human body was recently thoroughly evaluated by the Human Protein Atlas team using a large-scale multiomics approach combining several different methods for analysis of gene expression, including a stringent immunohistochemical analysis using two independent antibodies.[6][19] mACE2 expression was in addition to the above-mentioned tissues, also seen in endothelial cells and pericytes of blood vessels within certain tissues, cardiomyocytes in heart tissue, and a smaller subset of cells within the thyroid gland, epididymis, seminal vesicle, pancreas, liver and placenta. Despite the fact that the respiratory system is the primary route of SARS-CoV-2 infection, very limited expression is seen, both at protein and mRNA level. The expression within the respiratory system is mainly restricted to the upper bronchial and nasal epithelia, especially in the ciliated cells.[20]

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 angiotensin-converting enzyme (ACE). ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin II which causes a cascade of hormonal reactions which is part of the body's harmful phase of RAAS, which ultimately leads to an increase in the body's blood pressure. ACE2 has an opposing effect to ACE, degrading angiotensin II into angiotensin (1-7), thereby lowering blood pressure.[21][22]

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.[23][16] sACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[16]

mACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.[24][25][26]

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.[27][28]

Coronavirus entry point

As a transmembrane protein, mACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63,[5] SARS-CoV (the virus that causes SARS),[29][30][31] and SARS-CoV-2[32] (the virus that causes COVID-19).[33][34][35][36] More specifically, the binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of mACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells.[37][38] 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.[39] It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals.[40] 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.[41][20] 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.[42]

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 mice, the interaction of the spike protein of the coronavirus with mACE2 induces a drop in the levels of mACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[43][44]

On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.[43] Furthermore, some researchers have hypothesized that sACE2 (which is created during the Protective Phase of RAAS) is not only involved in binding to Angiotensin II to create Angiotensin I-7 which lowers blood pressure by vasodilation, but that free and soluble ACE2 may also be binding to coronavirus spike proteins, hence making those coronavirus spikes unavailable for binding to mACE-2 sites.[36] But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2 is present.[45]

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.[46][47]

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."[48] An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for patients suffering from 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.[49]

Despite lack of conclusive evidence, some have advocated for and against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.[50] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[51][52][53]

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.[54]

Recombinant human ACE2

Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for acute lung injury, and appeared to improve pulmonary blood flow and oxygen saturation in piglets with a lipopolysaccharide-induced acute respiratory distress syndrome.[55] The half-life of rhACE2 in human beings is about 10 hours, and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours.[55] Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic renin-angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.[55]

Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome (ARDS).[56]

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.[57] Virtual screening of the 1930 FDA-approved drugs followed by molecular dynamics analysis predicted ritonavir and naloxegol block the binding of the SARS-CoV-2 S protein to the human ACE2 receptor, much more effectively than those drugs undergoing clinical trials, including remdesivir, lopinavir, sofosbuvir, and daclatasvir.[58]

See also

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000015405 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  10. ↑ Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, et al. (August 2016). "Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System". Hypertension. 68 (2): 365–77. doi:10.1161/HYPERTENSIONAHA.115.06892. PMID 27217402. S2CID 829514.
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  47. ↑ Diaz JH (March 2020). "Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19". Journal of Travel Medicine. 27 (3). doi:10.1093/jtm/taaa041. PMC 7184445. PMID 32186711.
  48. ↑ Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J (July 2012). "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". BMJ. 345 (jul11 1): e4260. doi:10.1136/bmj.e4260. PMC 3394697. PMID 22786934. 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.
  49. ↑ Zhanf P, Zhu L, Cai J, et al. (April 2020). "Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19". Circ Res. 126 (12): 1671–1681. doi:10.1161/CIRCRESAHA.120.317134. PMC 7265882. PMID 32302265.
  50. ↑ Patel AB, Verma A (March 2020). "COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?". JAMA. 323 (18): 1769–1770. doi:10.1001/jama.2020.4812. PMID 32208485.
  51. ↑ "Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers". European Society of Cardiology (ESC). 13 March 2020. Lay summary – Medscape. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
  52. ↑ "EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic". European Medicines Agency (EMA). 27 March 2020. Lay summary – Medscape. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
  53. ↑ "HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19". American College of Cardiology (ACC). 27 March 2020. Lay summary – Medscape. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
  54. ↑ Kragstrup TW, Singh HS, Grundberg I, Nielsen AL, Rivellese F, Mehta A, et al. (2021). "Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients". PLOS ONE. 16 (6): e0252799. Bibcode:2021PLoSO..1652799K. doi:10.1371/journal.pone.0252799. PMC 8177449. PMID 34086837.
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  58. ↑ Bagheri M, Niavarani A (October 2020). "Molecular dynamics analysis predicts ritonavir and naloxegol strongly block the SARS-CoV-2 spike protein-hACE2 binding". Journal of Biomolecular Structure & Dynamics: 1–10. doi:10.1080/07391102.2020.1830854. PMID 33030105. S2CID 222217607.
  • Human ACE2 genome location and ACE2 gene details page in the UCSC Genome Browser.
  • Angiotensin-converting enzyme 2 in Membranome database
  • 3D structure of complex of a neurotransmitter sodium symporter B(0)AT1, ACE2, and SARS-CoV-2 receptor-binding domain in OPM database
  • Overview of all the structural information available in the PDB for UniProt: Q9BYF1 (Angiotensin-converting enzyme 2) at the PDBe-KB.
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