Angiotensin-converting enzyme 2

Angiotensin-converting enzyme 2 (ACE2)[5] is an enzyme attached to the cell membranes of cells in the lungs, arteries, heart, kidney, and intestines.[6][7] ACE2 lowers blood pressure by catalysing the hydrolysis of angiotensin II (a vasoconstrictor peptide) into angiotensin (1–7) (a vasodilator).[8][9][10] ACE2 counters the activity of the related angiotensin-converting enzyme (ACE) by reducing the amount of angiotensin-II and increasing Ang(1-7)[11] making it a promising drug target for treating cardiovascular diseases.[12][13]

ACE2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesACE2, ACEH, angiotensin I converting enzyme 2
External IDsOMIM: 300335 MGI: 1917258 HomoloGene: 41448 GeneCards: ACE2
Gene location (Human)
Chr.X chromosome (human)[1]
BandXp22.2Start15,561,033 bp[1]
End15,602,148 bp[1]
RNA expression pattern


More reference expression data
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

ACE2 also serves as the entry point into cells for some coronaviruses, including HCoV-NL63, SARS-CoV, and SARS-CoV-2.[5] The human version of the enzyme is often referred to as hACE2.[14]

Structure
Angiotensin-converting enzyme 2
Identifiers
EC number3.4.17.23
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

Angiotensin-converting enzyme 2 is a zinc containing metalloenzyme located on the surface of endothelial and other cells.[15] ACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[15]

ACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in lungs and other tissues.[6] The extracellular domain of ACE2 is cleaved from the transmembrane domain by another enzyme known as sheddase, and the resulting soluble protein is released into the blood stream and ultimately excreted into urine.[16][17]

Location within the body

ACE2 is present in most organs: ACE2 is attached to the cell membrane of mainly lung type II alveolar cells, enterocytes of the small intestine, arterial and venous endothelial cells and arterial smooth muscle cells in most organs. ACE2 mRNA expression is also found in the cerebral cortex, striatum, hypothalamus, and brainstem.[18] The expression of ACE2 in cortical neurons and glia make them susceptible to a SARS-CoV-2 attack, which was the possible basis of anosmia and incidences of neurological deficits seen in COVID-19.[19] As anosmia and dysgeusia are seen early in many COVID-19 patients, it was suggested to be considered to be a heralding clue in COVID-19,[20] which subsequently was declared as "significant symptoms" in COVID-19 by the American Academy of Otolaryngology–Head and Neck Surgery.[21]

Function

The primary function of ACE2 is to act as a counterbalance to Angiotensin-converting enzyme (ACE). ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin II. ACE2 in turn 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).[15] ACE2 can also cleave a number of other peptides including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[15] ACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.[22]

Coronavirus entry point

As a transmembrane protein, ACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63,[5] SARS-CoV (the virus that causes SARS),[23][24][25] and SARS-CoV-2[26] (the virus that causes COVID-19).[27][28][29] More specifically, the binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of ACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells.[30][31] 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.[32] It has also been shown that disruption of S-protein glycosylation significantly impairs viral entry, indicating an importance of glycan-protein interactions in the process.[33]

This has led some to hypothesize that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.[34] Furthermore, according to studies conducted on mice, the interaction of the spike protein of the coronavirus with ACE2 induces a drop in the levels of ACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[34][35]

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 ACE2 expression hence may affect the severity of coronavirus infections.[36][37] 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."[38] An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for hospitalized patients who had hypertension and were on ACE inhibitors or ARBs versus 9.8% for hospitalized patients with hypertension not on such drugs, suggesting that the drugs are not harmful and may help against the coronavirus.[39]

Despite lack of conclusive evidence, some have advocated for and others for the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.[40] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[41][42][43]

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.[44]

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.[45] 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.[45] 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.[45]

Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome.[46]

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See also

References
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  2. 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.
  5. "Gene: ACE2, angiotensin I converting enzyme 2". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. 2020-02-28.
  6. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H (June 2004). "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology. 203 (2): 631–7. doi:10.1002/path.1570. PMC 7167720. PMID 15141377.
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