Angiotensin-converting enzyme 2

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Protein ACE2 PDB 1r42.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesACE2, ACEH, angiotensin I converting enzyme 2, ACE 2
External IDsOMIM: 300335 MGI: 1917258 HomoloGene: 41448 GeneCards: ACE2
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr X: 15.56 – 15.6 MbChr X: 164.14 – 164.19 Mb
PubMed search[3][4]
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Angiotensin-converting enzyme 2 (ACE2)[5] is an enzyme attached to the membrane of cells in the intestines, kidney, testis, gallbladder, and heart.[6][7][8] ACE2 lowers blood pressure by catalyzing 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 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 epithelium via downregulation of ACE2.[14] The human version of the enzyme can be referred to as hACE2.[15]


Angiotensin-converting enzyme 2
EC no.
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum

Angiotensin-converting enzyme 2 is a zinc-containing metalloenzyme located on the surface of intestinal enterocytes, renal tubular cells and other cells.[6][16] ACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[16]

ACE2 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 ACE2 is cleaved from the transmembrane domain by another enzyme known as sheddase, and the resulting soluble protein is released into the bloodstream and ultimately excreted in the urine.[17][18]

Location within the human body[edit]

ACE2 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 ACE2 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] ACE2 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. Notably, very limited expression was seen within the respiratory system, both at protein and mRNA level, with absent or low expression within a subset of cells or individuals. The expression within the respiratory system was mainly restricted to ciliated cells of upper airway epithelia.


An important function of ACE2 is to act as a counterbalance to the 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).[16] ACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[16] ACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.[20][21][22] Research in mice has shown that ACE2 is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed.[23][24]

Coronavirus entry point[edit]

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),[25][26][27] and SARS-CoV-2[28] (the virus that causes COVID-19).[29][30][31] 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.[32][33] The binding of the SARS-CoV-2 virus through ACE2 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.[34] It was also observed that an already diseased heart has increased expression of ACE2 receptor contrasted to healthy individuals.[35] 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.[36] 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.[37]

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.[38] 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.[38][39]

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, possibly affecting the severity of coronavirus infections.[40][41] 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."[42] 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.[43]

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.[44] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[45][46][47]

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.[48]

Recombinant human ACE2[edit]

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.[49] 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.[49] 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.[49]

Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome (ARDS).[50]

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.[51] 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.[52]

See also[edit]


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