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Angiotensin-converting enzyme 2
Angiotensin-converting enzyme 2
Angiotensin-converting enzyme 2
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"ACE2" redirects here. For other uses, see Ace 2 (disambiguation).

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; OMA:ACE2 - orthologs
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: 162.92 – 162.97 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. mACE2 is cleaved by the enzyme ADAM17 in a process regulated by substrate 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 the hydrolysis of angiotensin II (a vasoconstrictor peptide which raises blood pressure) into angiotensin (1–7) (a vasodilator).[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 treating cardiovascular diseases.[13][14]

mACE2 also serves as the entry point into cells for some coronaviruses, including HCoV-NL63, SARS-CoV, and SARS-CoV-2.[5] While mACE2's function is not that of a biological receptor, because of its receptor-like interaction with viruses it is also referred to as the ACE2 receptor.[15] The human version of the enzyme can be referred to as hACE2.[16]

Tissue distribution

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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][17] In addition to the above-mentioned issues, mACE2 expression was 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.[18]

Structure

[edit]
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
Search
PMCarticles
PubMedarticles
NCBIproteins

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][19] mACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[19]

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–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]

Function

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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.[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 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][19] sACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[19]

mACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup'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]

Clinical significance

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Coronavirus entry point

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As a transmembrane protein, mACE2 is the main entry receptor for several coronaviruses, including HCoV-NL63,[5] SARS-CoV (the cause of SARS),[30][31][32] and SARS-CoV-2 (the cause of COVID-19).[33][34][35][36][37][38] The binding of the viral spike S1 protein to the enzymatic domain of mACE2 on host cells initiates endocytosis and translocation of both virus and enzyme into endosomes.[39][40] Blocking endocytosis in culture traps virus particles on the cell surface.[41] The spike protein itself can also damage the endothelium through downregulation 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 protease TMPRSS2, a potential therapeutic target,[45][18] and disruption of spike glycosylation 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 of angiotensin 1–7, a vasodilator, 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 that ACE inhibitors and angiotensin II receptor blockers (ARBs) upregulate mACE2, raising concern they might worsen infections.[50][51] However, a 2012 systematic review and meta-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 ACE2 missense 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 ACE2

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Recombinant human ACE2 (rhACE2) is being developed as an enzymatically active, soluble "decoy" that both binds the SARS-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 in viral 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 classic RAS inhibitors or in conditions with elevated circulating angiotensin II.[68]

Preclinical studies have demonstrated protective effects in lung injury. In a piglet model of lipopolysaccharide-induced acute respiratory distress syndrome (ARDS), rhACE2 improved pulmonary blood flow and oxygenation.[68] Clinical-grade human recombinant soluble ACE2 (hrsACE2) also reduced SARS-CoV-2 recovery from vero cells by 1,000–5,000-fold in 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-2 in 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 as Fc-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]

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Angiotensin-converting enzyme 2

View on Grokipedia
from Grokipedia
Angiotensin-converting 2 (ACE2) is a zinc-dependent carboxypeptidase that functions as a key regulator in the renin-angiotensin system (RAS), primarily by hydrolyzing angiotensin II (Ang II) to angiotensin-(1-7) (Ang-(1-7)), thereby counteracting the vasoconstrictive and pro-inflammatory effects of (ACE). Discovered in through screening of human expressed sequence tags and a cDNA library, ACE2 is a type I transmembrane consisting of an extracellular catalytic domain homologous to ACE, a transmembrane , and a short intracellular C-terminal tail fused to a collectrin-like domain that facilitates its localization to the plasma membrane. Beyond its role in the RAS, ACE2 also cleaves other peptides such as apelin-13, [des-Arg⁹]-bradykinin, and amyloid-β, contributing to cardioprotection, anti-fibrotic effects, and potential . ACE2 is widely expressed on the surface of endothelial and epithelial cells, with high levels in the lungs, , heart, kidneys, and vascular , where it promotes intestinal absorption via interaction with neutral transporters and helps maintain . Its expression and activity are tightly regulated at multiple levels, including transcriptional control by factors like hepatocyte nuclear factor 1α (HNF1α), posttranscriptional modulation by microRNAs such as miR-421, and posttranslational shedding by ADAM17 sheddase, which releases a soluble form (sACE2) into circulation. Dysregulation of ACE2 has been implicated in various pathologies; for instance, reduced ACE2 activity is associated with , , , and acute lung injury, while its upregulation may offer therapeutic benefits in these conditions. Notably, ACE2 serves as the functional receptor for severe acute respiratory syndrome coronaviruses, binding the of SARS-CoV and to facilitate viral entry into host cells, a discovery that has heightened its relevance in infectious research and development. This interaction underscores ACE2's dual role in both physiological protection against RAS overactivation and vulnerability to viral pathogens, influencing outcomes in where viral binding may downregulate membrane-bound ACE2, exacerbating and organ damage. Ongoing research explores ACE2 modulators as potential therapies for cardiovascular diseases and as strategies to mitigate viral entry without compromising its protective functions.

Molecular Structure and Genetics

Protein Structure

Angiotensin-converting enzyme 2 (ACE2) is a single-pass type I transmembrane comprising 805 in humans. The protein features an N-terminal (residues 1–18) that directs its translocation to the , followed by a large extracellular domain (residues 19–740), a single transmembrane (residues 741–761), and a short cytoplasmic tail (residues 762–805). The extracellular domain encompasses the functional core of ACE2, divided into a zinc metallopeptidase domain (residues 19–615) responsible for catalytic activity and a C-terminal collectrin-like domain (residues 616–740) that mediates homodimerization. Key structural elements include the zinc-binding motif (HEMGH) within the active site of the peptidase domain, which coordinates a catalytic zinc ion essential for peptidase function, and seven N-linked glycosylation sites (at Asn53, Asn90, Asn103, Asn322, Asn432, Asn546, and Asn690) that contribute to protein stability and trafficking. Crystal structures of the ACE2 ectodomain, such as the apo form (PDB ID: 1R42), reveal a clam-shell-like with two lobes forming a deep substrate-binding groove; the peptidase domain consists of a central eight-stranded β-sheet flanked by α-helices, including 20 helical segments overall. Additional structures, like the complex with SARS-CoV-2 receptor-binding domain and neutral amino acid transporter B(0)AT1 (PDB ID: 6M17), highlight dimerization interfaces and conformational flexibility in the collectrin-like domain. In comparison to angiotensin-converting enzyme 1 (ACE1), ACE2 possesses a single catalytic domain, whereas somatic ACE1 has two homologous domains (N- and C-terminal); the peptidase domains of ACE2 and ACE1 share approximately 42% sequence identity.

Gene and Expression Regulation

The ACE2 gene is located on the X chromosome at position Xp22.2 in humans, spanning approximately 89 kb of genomic DNA and consisting of 22 exons interrupted by 21 introns. This structure encodes the full-length ACE2 protein, a monocarboxypeptidase involved in the renin-angiotensin system. The gene's X-linked position contributes to its inheritance patterns and potential for sex-specific expression differences. ACE2 exhibits strong evolutionary conservation across mammalian at both the and protein sequence levels, reflecting its essential physiological roles in cardiovascular and renal . Key polymorphisms, such as rs2285666 located in intron 3, influence expression levels; the A can increase ACE2 mRNA expression by up to 50% through effects on or enhancer activity. Transcriptional regulation of ACE2 is mediated by promoters and enhancers responsive to various stimuli. upregulates ACE2 expression via (ESR1), promoting protective effects in tissues like the airway and myocardium. In contrast, cytokines such as interferon-gamma (IFN-γ) downregulate ACE2 in certain inflammatory contexts, potentially exacerbating viral susceptibility. Additionally, hypoxia-inducible factor 1-alpha (HIF-1α) modulates ACE2 during hypoxic conditions; while acute hypoxia may upregulate it, chronic exposure often leads to downregulation via HIF-1α binding to hypoxia-responsive elements. Post-transcriptional control further fine-tunes ACE2 levels. MicroRNAs, including miR-421, bind the 3'- of ACE2 mRNA to suppress its , reducing protein abundance in conditions like or . generates truncated variants, such as deltaACE2 (dACE2), which lacks the and is induced by interferons or viral infection, potentially altering receptor function without full enzymatic activity. Due to its X-linked location, ACE2 expression shows sex-based differences, with higher levels often observed in males across tissues like the lungs and heart, partly because the gene may escape X-inactivation in females. This dimorphism contributes to increased male susceptibility to diseases involving ACE2 dysregulation, such as severe COVID-19.

Tissue Distribution and Localization

Primary Locations in the Human Body

ACE2 exhibits high expression in several key organs and tissues in the human body, particularly those involved in cardiovascular and respiratory function. Notable sites include the lungs, where it is predominantly found in alveolar epithelial cells; the small intestine, with strong presence in enterocytes; the kidneys, specifically in proximal tubule cells; the heart, in cardiomyocytes and endothelial cells; and broadly across vascular endothelium. These patterns are supported by both RNA sequencing and proteomic analyses, highlighting ACE2's role in epithelial and endothelial barriers. Quantitative data from the GTEx database, derived from RNA-seq across multiple donors, further delineates these expression levels using median transcripts per million (TPM). The shows the highest median expression at approximately 55 TPM (varying by subregion: ~15 TPM, ~13 TPM), followed by the testis at 37 TPM, (primarily cortex) at 7 TPM, heart (atrial and ventricular) at around 7 TPM, and lungs at approximately 2 TPM, establishing a hierarchy where gastrointestinal and reproductive tissues lead, followed by renal and cardiac, with pulmonary expression low but present in specific cells. Moderate expression is observed in (~9 TPM), while liver, , and show low expression (<1 TPM). These distributions are corroborated by proteomic studies confirming protein-level consistency in enterocytes, renal tubules, cardiomyocytes, and endothelial cells. Developmentally, ACE2 expression is generally low in fetal tissues, with significant levels restricted primarily to the intestine and kidney, and minimal presence in the fetal lung or placenta. Postnatally, expression increases in response to physiological demands, such as maturation of the renin-angiotensin system, reaching adult levels in organs like the lung and heart. This ontogenetic shift underscores adaptive regulation tied to organ development. Species differences in ACE2 distribution are particularly evident in the lungs, where human expression is higher than in rodents, contributing to the limited utility of standard rodent models for studying respiratory pathologies involving ACE2. In mice, pulmonary ACE2 mRNA levels are notably lower (often <1 TPM), necessitating transgenic humanized models for accurate replication of human-like infection dynamics.

Cellular and Subcellular Localization

Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed as a membrane-bound glycoprotein anchored to the plasma membrane via a single transmembrane domain, with its extracellular ectodomain facing the extracellular space. In polarized epithelial cells, such as those in the lung alveoli and intestinal epithelium, ACE2 is primarily localized to the apical membrane, where it co-localizes with apical markers like glycoprotein gp135 and is associated with tight junction proteins, facilitating its positioning at the brush border. This apical distribution positions ACE2 optimally for interaction with luminal substrates and pathogens in these barrier tissues. A soluble form of ACE2 is generated through ectodomain shedding mediated by the disintegrin and metalloproteinase 17 (ADAM17) protease, which cleaves the protein near the transmembrane domain, releasing the catalytically active ectodomain into the extracellular space and circulation as circulating soluble ACE2. This shedding process is regulated and can be enhanced by inflammatory signals or ligand binding, contributing to variable levels of soluble ACE2 in plasma. Subcellularly, newly synthesized ACE2 undergoes post-translational modifications, including N-linked glycosylation in the endoplasmic reticulum and further processing in the Golgi apparatus, before being trafficked via vesicles to the plasma membrane. Once at the surface, ACE2 can undergo endocytic recycling, allowing it to be internalized and returned to the membrane, maintaining its surface expression. Immunohistochemical studies have confirmed ACE2's membrane localization in epithelial cells, showing strong apical staining and co-localization with tight junctions in respiratory and intestinal epithelia, while in neuronal cells, it exhibits a more intracellular, cytoplasmic distribution, often perinuclear. The localization of ACE2 is dynamic; upon binding to ligands such as the SARS-CoV-2 spike protein, it undergoes clathrin-mediated endocytosis, leading to internalization and potential lysosomal degradation or altered shedding rates, which can reduce surface levels. This trafficking regulation influences ACE2's availability for enzymatic function and receptor roles.

Biochemical Function

Enzymatic Activity and Mechanism

Angiotensin-converting enzyme 2 (ACE2) is classified as a zinc-dependent carboxypeptidase (EC 3.4.17.23) that catalyzes the hydrolysis of peptide bonds at the C-terminal end of substrates. This enzymatic activity is central to its role in processing bioactive peptides within the renin-angiotensin system. The active site of ACE2 contains a zinc ion (Zn²⁺) coordinated by the imidazole rings of histidine residues His383 and His387, as well as the carboxylate group of Glu402, forming a classic HEXXH zinc-binding motif typical of gluzincin metallopeptidases. In the catalytic mechanism, the coordinated Zn²⁺ polarizes the carbonyl group of the scissile peptide bond, facilitating nucleophilic attack by a water molecule; Glu402 acts as a proton shuttle, abstracting a proton from the water to generate the hydroxide nucleophile and later donating it to the departing amine group. This general acid-base catalysis ensures efficient C-terminal residue removal, with the process being strictly exopeptidase in nature. Kinetic parameters for ACE2 activity toward angiotensin II (Ang II) include a Michaelis constant (K_m) of approximately 2 μM and a turnover number (k_cat) of about 210 min⁻¹ (3.5 s⁻¹), yielding a catalytic efficiency (k_cat/K_m) of 1.8 × 10⁶ M⁻¹ s⁻¹. The enzyme exhibits an optimal pH range of 6.5–7.5, with activity enhanced by monovalent anions such as chloride and sharply declining outside this range. ACE2 is inhibited by metal chelators like EDTA, which sequesters the essential Zn²⁺ cofactor, confirming its metalloprotease nature. ACE2 forms homodimers through its C-terminal collectrin-like domain, which promotes proper orientation of the peptidase domains and increases substrate affinity compared to the monomeric form. Beyond its catalytic function, ACE2 plays a non-enzymatic structural role in facilitating neutral amino acid transport; its collectrin-like domain interacts with the transporter B⁰AT1 (SLC6A19) at the apical membrane of intestinal epithelial cells, stabilizing surface expression and enhancing transport efficiency independently of peptidase activity, as demonstrated by catalytically inactive mutants. This interaction mirrors the function of collectrin (TMEM27) in the kidney but is tissue-specific to the gut for ACE2.

Substrates, Products, and Interactions

Angiotensin-converting enzyme 2 (ACE2) primarily catalyzes the hydrolysis of angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)] by removing the C-terminal phenylalanine residue, thereby counterbalancing the effects of the classical renin-angiotensin system pathway. This conversion is a key biochemical transformation mediated by ACE2's carboxypeptidase activity. In addition to Ang II, ACE2 processes angiotensin I (Ang I) into Ang-(1-9) through the removal of a single C-terminal leucine residue, although with lower catalytic efficiency compared to the Ang II reaction. Other notable substrates include apelin-13, which is cleaved to apelin-12; kinetensin; des-Arg⁹-bradykinin; and amyloid-β peptides, all of which undergo C-terminal hydrolysis. ACE2 demonstrates a substrate preference for peptides featuring hydrophobic residues, such as proline, leucine, or phenylalanine, at the penultimate C-terminal position, facilitating selective cleavage. The products of ACE2-mediated hydrolysis play significant roles in physiological signaling. Ang-(1-7), the principal product from Ang II, functions as an endogenous ligand for the Mas receptor (MasR), activating downstream pathways that promote vasodilation, anti-inflammatory responses, and cardioprotection. In contrast, Ang-(1-9) acts primarily as an intermediate peptide, which can be further degraded by neutral endopeptidase or ACE to yield Ang-(1-7), thereby contributing indirectly to MasR activation. These transformations highlight ACE2's role in generating bioactive heptapeptides that oppose angiotensin II-mediated effects. Beyond enzymatic substrates, ACE2 engages in key protein-protein interactions that influence its localization and function. Allosteric modulation of ACE2 activity occurs through binding of small molecules, such as the selective inhibitor MLN-4760, which targets a site distinct from the catalytic zinc-binding domain to potently suppress enzymatic function.

Physiological Roles

Role in the Renin-Angiotensin-Aldosterone System

Angiotensin-converting enzyme 2 (ACE2) serves as a critical component of the renin-angiotensin-aldosterone system (RAS), acting as a carboxypeptidase that hydrolyzes angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)], thereby counteracting the vasoconstrictive and pro-inflammatory effects of Ang II mediated through the angiotensin type 1 receptor (AT1R). This enzymatic activity positions ACE2 as a negative regulator of the classical RAS pathway, which involves angiotensinogen conversion to Ang I by renin, followed by ACE-mediated formation of Ang II. By degrading Ang II with approximately 400-fold higher catalytic efficiency than its action on Ang I to produce Ang-(1-9), ACE2 helps maintain RAS homeostasis, particularly in cardiovascular and renal tissues. In the broader RAS pathway, ACE2 integrates with the ACE/Ang II axis to prevent excessive Ang II accumulation; its deficiency results in elevated Ang II levels, leading to hypertension and cardiac hypertrophy, as demonstrated in ACE2 knockout mice that exhibit exacerbated pressure overload responses and impaired myocardial contractility. These models underscore ACE2's role in balancing the system, where loss of function amplifies the pathological effects of the classical pathway, such as increased blood pressure and ventricular remodeling. The ACE2/Ang-(1-7)/Mas receptor (MasR) axis forms a protective arm of the RAS, with Ang-(1-7) binding to MasR to promote vasodilation through nitric oxide release, while exerting anti-fibrotic and anti-inflammatory effects that oppose Ang II-induced tissue damage. This pathway mitigates fibrosis by inhibiting transforming growth factor-β signaling and reduces inflammation via suppression of pro-inflammatory cytokines, contributing to cardioprotection in models of heart failure. Feedback mechanisms further regulate ACE2 within the RAS; Ang II upregulates ACE2 expression in cardiac fibroblasts through AT1R and ERK-MAPK pathways, potentially serving as a compensatory response to elevated Ang II levels. Additionally, aldosterone influences ACE2 activity via mineralocorticoid receptors, where blockade of these receptors increases ACE2 expression and activity, suggesting aldosterone normally suppresses ACE2 to promote RAS imbalance.

Roles in Cardiovascular, Renal, and Other Systems

In the cardiovascular system, ACE2 contributes to endothelial protection by counteracting angiotensin II-mediated vasoconstriction and promoting vasodilation through the generation of angiotensin-(1-7), which enhances nitric oxide production in endothelial cells. This enzymatic activity also reduces oxidative stress by limiting reactive oxygen species formation in vascular tissues, thereby preventing endothelial dysfunction and supporting vascular integrity. Furthermore, ACE2 attenuates cardiac hypertrophy by mitigating angiotensin II-induced signaling pathways that promote cardiomyocyte growth, maintaining balanced cardiac remodeling under physiological conditions. In relation to atherosclerosis prevention, ACE2 overexpression has been shown to inhibit inflammatory responses in endothelial cells, reducing monocyte adhesion and early plaque formation while preserving arterial wall homeostasis. Within the renal system, ACE2 regulates glomerular filtration by modulating local angiotensin II levels in podocytes and tubular cells, ensuring appropriate sodium reabsorption and filtration barrier function. Its expression in podocytes specifically supports cellular integrity and reduces oxidative stress, which helps maintain the structural stability of the glomerular filtration barrier essential for efficient ultrafiltration. Through the ACE2/angiotensin-(1-7)/Mas receptor axis, ACE2 further promotes anti-inflammatory effects in renal tissues, counteracting potential disruptions to podocyte architecture and preserving overall renal hemodynamics. In the pulmonary system, ACE2 maintains alveolar fluid balance by facilitating electrolyte and liquid homeostasis in alveolar epithelial cells, preventing excessive fluid accumulation through balanced regulation of sodium transport and vascular permeability. It also exerts anti-inflammatory actions in the airways by degrading pro-inflammatory angiotensin II and producing anti-fibrotic angiotensin-(1-7), which supports epithelial cell survival and reduces cytokine-mediated inflammation in lung tissues. These functions collectively ensure proper alveolar gas exchange and airway patency under normal physiological states. Beyond these systems, ACE2 plays roles in other organs, including the gut, where it acts as a chaperone for the neutral amino acid transporter B⁰AT1, facilitating the absorption of dietary amino acids such as tryptophan and maintaining intestinal homeostasis. In the brain, ACE2 provides neuroprotection by activating the angiotensin-(1-7)/Mas axis, which inhibits neuronal apoptosis and oxidative damage, while its expression in cerebrovascular endothelial cells helps preserve blood-brain barrier integrity against permeability challenges. Recent insights from 2025 highlight ACE2's involvement in the pancreas, where low-level expression in β-cells enhances glucose-stimulated insulin secretion and supports overall glucose homeostasis by modulating local renin-angiotensin system balance. Circulating soluble ACE2, derived from ectodomain shedding, enables multi-organ interplay by systemically degrading angiotensin II and generating angiotensin-(1-7), thereby modulating inflammation across tissues and contributing to coordinated physiological responses. This soluble form briefly references its contribution to renin-angiotensin-aldosterone system balance without altering core pathway mechanics.

Pathological and Clinical Significance

Involvement in Viral Infections

Angiotensin-converting enzyme 2 (ACE2) serves as a critical receptor for the entry of several coronaviruses into host cells, primarily through binding of the viral spike protein's S1 subunit to the peptidase domain of ACE2. This interaction was first established for severe acute respiratory syndrome coronavirus (SARS-CoV), where the spike protein binds ACE2 with high affinity, facilitating viral attachment and subsequent membrane fusion. Key residues in ACE2, such as lysine 353 (K353) and tyrosine 385 (Y385), form essential contacts within the receptor-binding motif of the SARS-CoV spike, enabling species-specific tropism and efficient entry into human airway epithelial cells. Similarly, , the causative agent of , exploits the same receptor, with its receptor-binding domain (RBD) engaging ACE2 via conserved interfaces involving K353, which forms a salt bridge with glutamic acid 484 in the viral spike, underscoring the structural conservation that allows cross-reactivity between these betacoronaviruses. The entry mechanism of SARS-CoV-2 into cells involves ACE2-mediated attachment followed by proteolytic priming of the spike protein, which can occur via two primary pathways. At the plasma membrane, transmembrane serine protease 2 (TMPRSS2) cleaves the spike at the S1/S2 boundary, promoting direct fusion; alternatively, if TMPRSS2 activity is low, the virus undergoes clathrin-mediated endocytosis, where endosomal acidification activates cathepsin L to perform the cleavage, releasing the S2 subunit for membrane fusion. This dual-route dependency enhances SARS-CoV-2's infectivity across diverse cell types expressing ACE2, such as alveolar epithelial cells and endothelial cells. Beyond SARS coronaviruses, human coronavirus NL63 (HCoV-NL63), an alphacoronavirus causing mild respiratory illness, also utilizes ACE2 as its receptor, with its spike binding a distinct but overlapping region of the peptidase domain, highlighting ACE2's broader role in coronavirus pathogenesis. Viral engagement of ACE2 triggers downstream dysregulation, notably the shedding of ACE2 from the cell surface via ADAM17-mediated cleavage, which generates soluble ACE2 (sACE2) but depletes membrane-bound ACE2. This "ACE2 shedding paradox" reduces production of the protective peptide angiotensin-(1-7) [Ang-(1-7)], tipping the renin-angiotensin system toward proinflammatory angiotensin II signaling and exacerbating lung injury and cytokine storm in severe cases. Post-2020 research on SARS-CoV-2 variants reveals altered ACE2 interactions; for instance, the Omicron subvariants (BA.1 and BA.2) exhibit higher binding affinity to ACE2 compared to the ancestral strain, driven by mutations like Q493R and N501Y that stabilize the RBD-ACE2 interface, contributing to enhanced transmissibility despite partial immune evasion. More recent variants, such as JN.1 as of 2025, continue to evolve with mutations maintaining or enhancing ACE2 binding, influencing ongoing COVID-19 dynamics and long-term sequelae. In long COVID, persistent ACE2 dysregulation, including sustained downregulation and vascular shedding, is linked to ongoing endothelial dysfunction and symptoms like fatigue and microvascular thrombosis, as evidenced by elevated circulating sACE2 levels in affected individuals months post-infection.

Implications in Cardiovascular, Metabolic, and Other Diseases

Angiotensin-converting enzyme 2 (ACE2) deficiency exacerbates cardiovascular pathologies by disrupting the balance of the renin-angiotensin system (RAS), leading to elevated angiotensin II (Ang II) levels that promote inflammation, fibrosis, and vascular contraction. In hypertension models, ACE2 knockout mice exhibit accelerated blood pressure elevation and increased cardiac hypertrophy, while ACE2 overexpression attenuates these effects by enhancing Ang-(1-7) production. Similarly, in heart failure, ACE2 loss in murine models results in systolic dysfunction, reduced ejection fraction, and worsened fibrosis, whereas recombinant human ACE2 (rhACE2) administration improves cardiac function by mitigating oxidative stress. Polymorphisms in the ACE2 gene, such as those in the promoter region, have been associated with increased risk of myocardial infarction in population studies, particularly in hypertensive individuals, highlighting genetic contributions to disease susceptibility. In metabolic disorders, reduced ACE2 expression in type 2 diabetes mellitus (T2DM) contributes to insulin resistance by impairing the ACE2/Ang-(1-7)/Mas axis, which normally enhances insulin signaling and glucose uptake in skeletal muscle and adipocytes. Studies in db/db mice demonstrate that ACE2 deficiency decreases β-cell mass and proliferation, leading to impaired glucose-stimulated insulin secretion and elevated fasting glucose, while Ang-(1-7) infusion restores β-cell function and improves glycemic control. Recent 2024-2025 reviews emphasize ACE2's role in glucose homeostasis, noting that activation of this axis reduces hepatic gluconeogenesis and promotes thermogenesis in brown adipose tissue via Akt/FOXO1 and PKA pathways in high-fat diet models. ACE2 dysregulation promotes renal injury, with loss accelerating acute kidney injury (AKI) in sepsis through unchecked Ang II-mediated vasoconstriction and inflammation. In ischemia-reperfusion AKI models, ACE2 knockout mice display exacerbated tubular damage, increased immune cell infiltration, and higher creatinine levels compared to wild-type controls, underscoring ACE2's protective role in maintaining glomerular filtration. For chronic kidney disease (CKD), diminished ACE2 expression drives progression via enhanced fibrosis, as evidenced by increased extracellular matrix deposition and TGF-β signaling in ACE2-deficient diabetic nephropathy models. The ACE2/Ang-(1-7)/Mas axis counteracts this by suppressing oxidative stress and epithelial-mesenchymal transition in proximal tubules. Beyond these systems, ACE2 influences other diseases through anti-inflammatory and anti-proliferative mechanisms. In Alzheimer's disease, reduced brain ACE2 levels correlate with neuroinflammation and cognitive decline, as ACE2 activation via small-molecule agonists like diminazene aceturate decreases amyloid-β accumulation and tau pathology in mouse models by modulating the RAS axis. In cancer, ACE2 exerts tumor-suppressive effects by inhibiting angiogenesis; for instance, ACE2 overexpression in renal cell carcinoma cells reduces vascular endothelial growth factor (VEGF) expression and tumor growth in xenografts, with higher ACE2 correlating to improved patient survival in multiple tumor types. Post-COVID-19 sequelae involve long-term endothelial dysfunction linked to ACE2 shedding and downregulation, leading to persistent vascular inflammation and increased cardiovascular risk, as observed in cohort studies showing elevated Ang II and reduced nitric oxide bioavailability up to two years post-infection. Plasma soluble ACE2 levels serve as an emerging biomarker for disease outcomes, with elevated concentrations predicting adverse events in heart failure patients, including hospitalization and mortality, independent of traditional markers like BNP. In CKD, higher soluble ACE2 correlates with faster eGFR decline and fibrosis progression in 2025 longitudinal data, reflecting ongoing RAS imbalance.

Therapeutic and Research Developments

Recombinant Human ACE2

Recombinant human ACE2 (rhACE2), also known as human recombinant soluble ACE2 (hrsACE2), was first developed in 2007 as a soluble ectodomain construct comprising residues 1-740 of the native protein to facilitate its secretion and enzymatic function outside the cell membrane. This form was produced by transient transfection of HEK293 cells using an expression construct that fused a signal peptide to the extracellular domain, allowing for purification from cell culture supernatant via affinity chromatography. The resulting protein mimics the catalytic domain of membrane-bound ACE2 while being amenable to systemic administration. The recombinant protein retains the core enzymatic activity of native ACE2, hydrolyzing angiotensin II (Ang II) to angiotensin-(1-7) with a Michaelis constant (Km) of approximately 5 μM, comparable to that reported for the endogenous enzyme. Its plasma half-life is about 10 hours following intravenous (IV) infusion, enabling transient elevation of ACE2 activity to modulate the renin-angiotensin system (RAS). Administered IV, rhACE2 has demonstrated good tolerability in preclinical models and early human studies, with rapid distribution to tissues expressing high ACE2 levels, such as the lungs and kidneys. Early clinical evaluation occurred in a phase I/II trial for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), initiated around 2012 and reporting results in 2017, where IV rhACE2 (GSK2586881) at doses up to 0.8 mg/kg was safe and well-tolerated over 3 days. The trial observed a dose-dependent reduction in circulating Ang II levels by up to 35% without significant adverse effects, supporting its potential to restore RAS balance in inflammatory lung conditions. No serious immunogenicity was noted in this short-term study. During the COVID-19 pandemic, hrsACE2 (APN01) advanced to phase II trials starting in 2020, including a randomized, placebo-controlled study in moderate-to-severe cases completed by late 2020 and an extension into 2022 evaluating nebulized delivery. These trials confirmed safety and tolerability at doses of 0.4 mg/kg IV twice daily for 7 days, with evidence of spike protein neutralization in vitro and ex vivo, reducing viral entry into cells by competing for receptor binding. Additionally, APN01 restored RAS equilibrium by lowering Ang II and increasing angiotensin-(1-7), correlating with improved oxygenation in some patients, though broader efficacy endpoints like mortality reduction were not conclusively met. Post-2022 analyses highlighted persistent challenges, including the protein's short half-life necessitating frequent dosing and potential immunogenicity from repeated administration, which could limit long-term use despite no acute antibody responses in initial cohorts.

Modulators, Inhibitors, and Emerging Therapies

Angiotensin-converting enzyme 2 (ACE2) inhibitors have been primarily developed for research purposes to modulate the renin-angiotensin system (RAS) and investigate ACE2's role in various pathologies. MLN-4760 is a highly selective small-molecule inhibitor that binds to the active site of ACE2 with high affinity (IC50 ≈ 0.44 nM), effectively blocking its enzymatic activity toward substrates like II. This compound has been widely used in preclinical studies to dissect ACE2-specific effects, such as in models of pulmonary injury where it attenuates lipopolysaccharide-induced by inhibiting ACE2-mediated conversion of II to angiotensin-(1-7). In contrast, , a classical , exhibits weak inhibitory activity against ACE2 (IC50 > 10 μM) and is not selective, but it has been employed in comparative studies to differentiate ACE from ACE2 contributions in glomerular injury and acute lung . These inhibitors highlight the potential for targeted RAS modulation, though clinical translation remains limited due to off-target effects and lack of disease-specific indications. Direct activators of ACE2 enzymatic activity are not currently available, but indirect modulation through upregulation of ACE2 expression has been achieved via (PPARγ) agonists. Pioglitazone, a thiazolidinedione-class drug, increases ACE2 protein levels in tissues such as liver, adipose, and , thereby enhancing the protective Ang-(1-7)/Mas receptor axis in models of non-alcoholic and . This upregulation occurs through PPARγ-mediated transcriptional activation, offering a strategy to counterbalance pathological RAS overactivation without directly altering enzymatic kinetics. Emerging therapies targeting ACE2 include approaches for overexpression in , where preclinical studies using (AAV)-mediated delivery of the ACE2 gene have demonstrated reduced cardiac , , and improved in rodent models of pressure overload-induced failure. Additionally, neutralizing monoclonal antibodies that disrupt the ACE2-spike protein interaction have been developed post-COVID-19, with broad-spectrum candidates like CV3-1 binding to conserved epitopes on the SARS-CoV-2 spike receptor-binding domain to prevent viral entry while preserving ACE2 function. These antibodies, elicited or refined from vaccine-induced responses, show promise against variants and other coronaviruses in preclinical assays. Recent preclinical studies as of 2024 have explored engineered variants of recombinant human ACE2 with enhanced stability and antiviral activity, demonstrating reduced infection in cellular and animal models. As of 2025, the clinical pipeline for ACE2-targeted interventions includes soluble ACE2 infusions for (ARDS), building on phase II trials of recombinant human ACE2 (e.g., APN01) that demonstrated safety and preliminary efficacy in reducing ventilator days and in COVID-19-associated ARDS patients. In preclinical models, diminazene aceturate serves as an ACE2 activator, lowering and mitigating vascular remodeling by enhancing Ang-(1-7) production, with ongoing studies exploring its translation to clinical use. Key challenges in ACE2 modulator development involve balancing cardioprotective benefits against the risk of facilitating viral entry, as enhanced ACE2 expression or activity could increase susceptibility to and related pathogens in at-risk populations. Furthermore, ACE2's X-linked genetic location necessitates consideration of sex-specific dosing, as females exhibit higher baseline expression due to incomplete X-chromosome inactivation, potentially requiring adjusted therapeutic levels to avoid over- or under-modulation in sex-biased contexts.

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