Angiotensin-converting enzyme 2 (ACE2)[5] is anenzyme that can be found either attached to themembrane of cells (mACE2) in theintestines,kidney,testis,gallbladder, andheart or in a soluble form (sACE2).[6][7][8] Both membrane bound and soluble ACE2 are integral parts of therenin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 in a process regulated bysubstrate presentation. ADAM17 cleavage releases the extracellular domain creating soluble ACE2 (sACE2).[9] ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing thehydrolysis ofangiotensin II (avasoconstrictorpeptide which raises blood pressure) intoangiotensin (1–7) (avasodilator).[8][10][11] Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.[12] This decrease in blood pressure makes the entire process a promising drug target for treatingcardiovascular diseases.[13][14]
mACE2 also serves as the entry point into cells for somecoronaviruses, includingHCoV-NL63,SARS-CoV, andSARS-CoV-2.[5] While mACE2's function is not that of abiological receptor, because of its receptor-like interaction with viruses it is also referred to as theACE2 receptor.[15] The human version of the enzyme can be referred to as hACE2.[16]
mACE2 is a single-passtype I membrane protein, with its enzymatically activedomain exposed on the surface of cells in the intestines and other tissues.[6][7] The extracellular domain of mACE2 can becleaved from thetransmembrane domain by another enzyme known asADAM17 a member of thesheddase enzyme family, during the protective phase ofRAAS, the Renin–Angiotensin–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.[20][21]
As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to theangiotensin-converting enzyme (ACE). ACE cleavesangiotensin I hormone into the vasoconstrictingangiotensin 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 intoangiotensin (1-7), thereby lowering blood pressure.[22][23]
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 vasodilatorangiotensin (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][19] sACE2 can also cleave numerous peptides, including[des-Arg9]-bradykinin,apelin,neurotensin,dynorphin A, andghrelin.[19]
mACE2 also regulates the membrane trafficking of the neutral amino acid transporterSLC6A19 and has been implicated inHartnup's disease.[25][26][27]
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 is the main entry receptor for severalcoronaviruses, includingHCoV-NL63,[5]SARS-CoV (the cause ofSARS),[30][31][32] andSARS-CoV-2 (the cause ofCOVID-19).[33][34][35][36][37][38] The binding of the viral spike S1 protein to the enzymatic domain of mACE2 on host cells initiatesendocytosis andtranslocation of both virus and enzyme intoendosomes.[39][40] Blocking endocytosis in culture traps virus particles on the cell surface.[41] The spike protein itself can also damage theendothelium throughdownregulation of ACE2.[42] The receptor-binding domain (RBD) of the spike protein specifically attaches to ACE2, enabling viral entry and replication,[38] while surfactant proteins SP-A and SP-D may reduce the strength of this interaction.[38]
Binding of SARS-CoV and SARS-CoV-2 through mACE2 in cardiac tissue has been linked to myocarditis. During the SARS outbreak, viral RNA was detected in heart specimens from 35% of fatal cases,[43] and diseased hearts express higher levels of mACE2 than healthy hearts.[44] Entry also requires priming of the spike protein by host serine proteaseTMPRSS2, a potential therapeutic target,[45][18] and disruption of spikeglycosylation strongly impairs viral entry.[46] In mice, spike binding reduces mACE2 through internalization and degradation, contributing to lung injury.[47][48] By contrast, sACE2 protects against lung injury by promoting formation ofangiotensin 1–7, avasodilator, and may also neutralize coronavirus spikes by binding them.[37] Even low mACE2 levels can allow entry if TMPRSS2 is present.[49]
Rodent studies have shown thatACE inhibitors andangiotensin II receptor blockers (ARBs) upregulate mACE2, raising concern they might worsen infections.[50][51] However, a 2012systematic review andmeta-analysis found ACE inhibitors reduced pneumonia risk by 34% and lowered pneumonia-related mortality.[52] A 2020 study in Hubei Province reported lower mortality in hypertensive COVID-19 patients taking ACE inhibitors or ARBs (3.7%) compared to those not taking them (9.8%).[53] Despite debate over discontinuation,[54] professional societies recommend continuing ACE inhibitors and ARBs in COVID-19 patients.[55][56][57] High plasma ACE2 levels predict worse COVID-19 outcomes, and are elevated in patients with hypertension and heart disease.[58]
Because ACE2 is the entry receptor for SARS-CoV-2, genetic variation may influence susceptibility to infection. Several studies report that ACE2missense variants alter spike-binding affinity[59][60][61] and susceptibility to pseudovirus entry.[62] Rare variants may even confer complete resistance.[61] Expression levels of ACE2 at the cell surface also influence susceptibility and tissue tropism,[62][63] since SARS-CoV-2 distribution depends on ACE2 expression across tissues.[64] A variant on the X chromosome (rs190509934:C) lowers ACE2 expression by 37% and has been associated with protection against severe COVID-19 outcomes.[65]
Recombinant human ACE2 (rhACE2) is being developed as an enzymatically active, soluble "decoy" that both binds theSARS-CoV-2 spike protein to block cell entry and converts angiotensin II to angiotensin-(1–7), thereby rebalancing the renin–angiotensin system. This dual mechanism underpins its proposed use inviral pneumonias and lung or vascular injury.[66][67] In humans, rhACE2 has a half-life of ~10 hours, an onset of action of about 30 minutes, and a duration of ~24 hours,[68] and may be useful for patients intolerant to classicRAS inhibitors or in conditions with elevated circulating angiotensin II.[68]
Preclinical studies have demonstrated protective effects in lung injury. In apiglet model oflipopolysaccharide-inducedacute respiratory distress syndrome (ARDS), rhACE2 improved pulmonaryblood flow andoxygenation.[68] Clinical-grade human recombinant soluble ACE2 (hrsACE2) also reduced SARS-CoV-2 recovery fromvero cells by 1,000–5,000-foldin vitro, whereas the mouse ortholog had no such effect, consistent with a decoy mechanism.[69] Engineered ACE2 mutants with enhanced affinity for the viral Spike protein neutralised SARS-CoV-2in vitro,[70] and a triple-mutant (sACE2.v2.4) with nanomolar Spike binding[70] blocked pseudovirus entry in lung cell lines and prevented SARS-CoV-2–induced ARDS in ACE2-humanized mice.[71] Novel formats such asFc-fusions,multimers, and affinity-enhanced constructs are being designed to prolong half-life and broaden neutralization against immune-evasive variants, positioning ACE2 decoys as a potentially variant-agnostic antiviral strategy.[67]
Clinically, intravenous rhACE2 (also termed APN01/GSK2586881) has been tested in ARDS,[72]pulmonary arterial hypertension (PAH), and severe COVID-19, including studies of nebulized or inhaled formulations for direct airway exposure.[67][73] Early trials showed acceptable safety and pharmacodynamic changes (decreased Ang II, increased Ang-(1–7)), and the agent progressed to phase II testing in COVID-19.[74] Nonetheless, reviews emphasize that clinical efficacy remains unproven, and further randomized studies are needed to clarify optimal dosing, delivery routes, and whether catalytic activity should be preserved versus "decoy-only" constructs.[67] Overall, rhACE2 and next-generation ACE2 decoys remain promising host-targeted therapeutics, particularly as monoclonal antibody antivirals lose potency against new SARS-CoV-2 variants.[66]
^Chamsi-Pasha MA, Shao Z, Tang WH (March 2014)."Angiotensin-converting enzyme 2 as a therapeutic target for heart failure".Current Heart Failure Reports.11 (1). Springer Science and Business Media LLC:58–63.doi:10.1007/s11897-013-0178-0.PMC3944399.PMID24293035.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.
^abcdTurner AJ (2015). "Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions". In Unger T, Ulrike M, Steckelings UM, dos Santos RA (eds.).The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications. Academic Press. pp. 185–189.doi:10.1016/B978-0-12-801364-9.00025-0.ISBN978-0-12-801364-9.PMC7149539.S2CID88645177.{{cite book}}:|journal= ignored (help)
^Niu MJ, Yang JK, Lin SS, Ji XJ, Guo LM (2008). "Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice".Endocrine.34 (1–3):56–61.doi:10.1007/s12020-008-9110-x.PMID18956256.S2CID46331895.
^Fehr AR, Perlman S (2015). "Coronaviruses: an overview of their replication and pathogenesis".Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer New York. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2437-0.PMC4369385.PMID25720466.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).
^abcYousefbeigi S, Marsusi F (February 2025). "Structural insights into ACE2 interactions and immune activation of SARS-CoV-2 and its variants: anin-silico study".Journal of Biomolecular Structure & Dynamics.43 (2):665–678.doi:10.1080/07391102.2023.2283158.PMID37982275.
^Jia H (September 2016). "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease".Shock.46 (3):239–248.doi:10.1097/SHK.0000000000000633.PMID27082314.S2CID3639219.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
^Santos TM, Lisboa AB, Rodrigues W, Gomes H, Abrahão J, Del-Bem LE (February 2022). "Human variation in the protein receptor ACE2 affects its binding affinity to SARS-CoV-2 in a variant-dependent manner".Journal of Biomolecular Structure & Dynamics.41 (7):2947–2955.doi:10.1080/07391102.2022.2042387.PMID35196964.S2CID247083671.
