Affinage

ACE2

Angiotensin-converting enzyme 2 · UniProt Q9BYF1

Length
805 aa
Mass
92.5 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACE2 is a zinc-dependent monocarboxypeptidase ectoenzyme that anchors a protective arm of the renin-angiotensin system, counterbalancing the classical ACE/Ang II axis across cardiovascular, renal, intestinal, and metabolic tissues (PMID:12025971, PMID:35003058). Its single catalytic domain carries an HEMGH zinc-binding motif and cleaves angiotensin I to Ang 1-9 and angiotensin II to the vasodilatory angiotensin-(1-7), while remaining insensitive to classical ACE inhibitors; it additionally degrades apelin and B1-bradykinin (PMID:12025971, PMID:25815211, PMID:35003058). The ACE2/Ang-(1-7)/Mas1 axis drives downstream physiology in several settings: it activates Akt/FoxO1 and PKA signaling to induce UCP1 and brown-adipose thermogenesis (PMID:35014608), maintains intestinal barrier integrity and limits diabetic retinopathy through intestinal MasR/GSK-3β/c-Myc signaling (PMID:36448480), and in hypothalamic PVN GABAergic neurons supports inhibitory tone to presympathetic neurons, restraining blood pressure (PMID:31564162). As a type I transmembrane glycoprotein, ACE2 is a chimera of an ACE-like catalytic domain and a collectrin-like C-terminal domain, and it heterodimerizes with neutral amino acid transporters B0AT1/SLC6A19 (and SIT1/SLC6A20) to control their surface expression and neutral amino acid absorption (PMID:12025971, PMID:21814048, PMID:33140827). Its membrane abundance is set post-translationally: a C-terminal PDZ-recognition motif binds the scaffold NHERF1 to tether ACE2 at the surface (PMID:34189428), the E3 ligase Nedd4-2 ubiquitinates C-terminal lysines to drive angiotensin II-promoted degradation (PMID:37161607), and the gene is transcriptionally repressed by EZH2-mediated H3K27me3 at its promoter (PMID:32291076). ACE2 robustly localizes to airway motile cilia and serves as the obligate entry receptor for SARS-CoV, SARS-CoV-2, and NL63 coronaviruses; viral binding triggers clathrin/AP2-dependent endocytosis and lysosomal degradation of ACE2, and a soluble ACE2 fragment blocks both down-regulation and infection (PMID:17464936, PMID:33116139, PMID:36287912).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    Established ACE2 as a distinct zinc carboxypeptidase that processes angiotensin peptides but, unlike ACE, is insensitive to ACE inhibitors and does not cleave bradykinin, defining a separate enzymatic arm of the renin-angiotensin system.

    Evidence Cloning, functional expression, in vitro enzymatic assays, and domain analysis

    PMID:12025971

    Open questions at the time
    • Did not resolve the in vivo physiological consequence of Ang 1-7 generation
    • Substrate repertoire beyond angiotensin peptides not yet defined
  2. 2005 High

    Showed ACE2 is dynamically regulated and induced in injured myocardium independently of ACE, indicating a tissue-level cardiac protective response distinct from the classical pathway.

    Evidence RT-PCR, immunohistochemistry, activity assays in rat MI model and human failing hearts

    PMID:15671045

    Open questions at the time
    • Mechanism of transcriptional induction after injury not identified
    • Causal contribution of induced ACE2 to repair vs. fibrosis untested
  3. 2007 High

    Determined the ACE2 crystal structure and confirmed via genetic models its dual role as Ang II carboxypeptidase and coronavirus receptor, unifying enzymatic and viral-entry functions on one protein.

    Evidence Crystal structure determination plus knockout/knock-in mouse models and enzymatic assays

    PMID:17464936

    Open questions at the time
    • Structural basis of regulated surface trafficking not addressed
    • Did not connect receptor and enzymatic roles mechanistically
  4. 2008 Medium

    Demonstrated physiological up-regulation of ACE2 expression and activity in pregnancy, implicating it in uteroplacental hemodynamic adaptation.

    Evidence RT-PCR and enzymatic activity in normotensive and hypertensive rat pregnancy models

    PMID:18945956

    Open questions at the time
    • Signal driving pregnancy-associated induction unknown
    • Human placental relevance inferred from rat model
  5. 2011 Medium

    Defined a non-enzymatic chaperone function: ACE2 heterodimerizes with B0AT1 (and collectrin with B0AT3 in kidney) to enable transporter surface expression, linking ACE2 to neutral amino acid absorption and Hartnup-disorder pathology.

    Evidence Protein interaction and surface expression assays with tissue-specific analysis

    PMID:20134095 PMID:21814048

    Open questions at the time
    • Stoichiometry and structural basis of the heterodimer not resolved at this stage
    • Whether catalytic activity contributes to transport unclear
  6. 2019 High

    Placed ACE2 within central blood-pressure control, showing PVN GABAergic neuronal ACE2 sustains inhibitory tone to presympathetic neurons and restrains hypertension, with ADAM17 shedding opposing this.

    Evidence Conditional neuron-specific knockout mice, neuron cultures, photoactivation, BP telemetry, pharmacological blockade

    PMID:31564162

    Open questions at the time
    • Local peptide signaling (Ang-(1-7)/Mas) linking ACE2 to GABA tone not directly traced
    • Which downstream effectors set GABAergic strength unresolved
  7. 2019 Medium

    Revealed an anti-angiogenic, anti-metastatic role for ACE2 in breast cancer via suppression of VEGFa/VEGFR2-MEK-ERK signaling, extending ACE2 function beyond cardiovascular and viral contexts.

    Evidence Migration and tube-formation assays, pathway Western blotting, zebrafish xenograft

    PMID:31023337

    Open questions at the time
    • Whether the effect requires enzymatic activity or Ang-(1-7)/Mas signaling untested
    • Single zebrafish in vivo model
  8. 2020 High

    Localized ACE2 protein to airway motile cilia of upper and lower respiratory epithelium, identifying the initial subcellular site of SARS-CoV-2 entry and showing ACE inhibitors/ARBs do not raise ciliary ACE2.

    Evidence Immunofluorescence, multiplex imaging, and IHC across a diverse human tissue panel

    PMID:33116139

    Open questions at the time
    • Mechanism targeting ACE2 to the ciliary membrane not defined
    • Functional contribution of ciliary localization to enzymatic role unaddressed
  9. 2020 Medium

    Identified epigenetic repression of ACE2, with EZH2-mediated H3K27me3 silencing the promoter and EZH2 loss de-repressing ACE2, establishing a chromatin-level control of receptor/enzyme abundance.

    Evidence EZH2 knockout in hESCs with RNA-seq and ChIP-seq

    PMID:32291076

    Open questions at the time
    • Physiological signals modulating EZH2 occupancy at ACE2 unknown
    • Relevance in differentiated airway/intestinal cells not shown
  10. 2020 Medium

    Showed ACE2-B0AT1/SIT1 heterodimers assemble quaternary structures that present spike-binding surfaces, integrating the amino-acid-transport partnership with coronavirus recognition.

    Evidence Co-IP, structural studies, viral binding assays

    PMID:33140827

    Open questions at the time
    • Whether transporter association modulates infection in vivo untested
    • Single-lab structural interpretation
  11. 2021 High

    Defined post-translational control of ACE2 surface residence: direct binding of the ACE2 C-terminal PDZ motif to both NHERF1 PDZ domains tethers ACE2 at the membrane and tunes viral entry.

    Evidence Co-IP, proximity ligation in human lung/intestine cells, PDZ-motif mutagenesis, pseudovirus entry assays

    PMID:34189428

    Open questions at the time
    • How NHERF1 binding is dynamically regulated by physiological signals unknown
    • Interplay between NHERF1 tethering and Nedd4-2 degradation not jointly resolved
  12. 2021 Medium

    Showed post-infection ACE2 autoantibodies functionally inhibit ACE2 enzymatic activity, providing an acquired-immunity route to suppress the protective ACE2 axis.

    Evidence ELISA for ACE2 antibodies and in vitro plasma inhibition assays

    PMID:34478478

    Open questions at the time
    • Epitope and mechanism of catalytic inhibition undefined
    • In vivo physiological consequence not established
  13. 2022 High

    Connected ACE2 to whole-body energy balance, demonstrating the ACE2/Ang-(1-7)/Mas1 axis drives brown-fat thermogenesis through Akt/FoxO1 and PKA pathways inducing UCP1.

    Evidence Ace2 and Mas1 knockout mice, BAT transplantation, Ace2 overexpression, Ang-(1-7) infusion, pathway Western blotting

    PMID:35014608

    Open questions at the time
    • How cold stimulus induces ACE2 in BAT not mechanistically traced
    • Relative contribution of local vs. systemic Ang-(1-7) unresolved
  14. 2022 High

    Demonstrated an intestinal ACE2 gut-eye axis, where intestinal ACE2/MasR signaling via GSK-3β/c-Myc preserves barrier integrity and delays diabetic retinopathy.

    Evidence Intestinal ACE2 overexpression and ACE2-probiotic delivery in Akita mice, pathway analysis, permeability and retinal imaging

    PMID:36448480

    Open questions at the time
    • Mediators linking gut barrier to retinal protection not fully defined
    • Whether glucose-transporter downregulation is the sole effector unclear
  15. 2022 High

    Mechanistically dissected SARS-CoV-2-induced ACE2 down-regulation, showing clathrin/AP2-dependent endocytosis and lysosomal degradation drive loss of ACE2 and pathogenic cytokine signaling, blockable by soluble ACE2.

    Evidence In vivo infection model, cell culture, siRNA knockdown, gene-expression profiling, endocytosis inhibitor studies

    PMID:36287912

    Open questions at the time
    • Adaptor coupling spike binding to AP2 recruitment not pinpointed
    • Contribution of lost enzymatic vs. transporter function to disease not separated
  16. 2023 High

    Identified Nedd4-2 as the E3 ligase ubiquitinating ACE2 C-terminal lysines during Ang II hypertension; a ubiquitination-resistant ACE2-5R mutant resists degradation and lowers blood pressure when expressed in the BNST, defining a feedback loop coupling Ang II to ACE2 turnover.

    Evidence Proteomics, in vitro gain/loss-of-function, site-directed mutagenesis, optogenetics, BP telemetry

    PMID:37161607

    Open questions at the time
    • Signaling that activates Nedd4-2 toward ACE2 upon Ang II not fully traced
    • Interaction with NHERF1 tethering in setting turnover not co-analyzed
  17. 2023 Medium

    Revealed reciprocal ACE2-EGFR cross-talk in which ACE2 binds EGFR and spike-driven EGFR-MAPK activation regulates ACE2 abundance and supports infection, linking ACE2 to growth-factor signaling.

    Evidence Co-IP/proximity assays, EGFR inhibition, pseudotyped and authentic SARS-CoV-2 infection, Western blotting

    PMID:37402592

    Open questions at the time
    • Direct vs. indirect nature of the ACE2-EGFR interaction not fully resolved
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple layers controlling ACE2 abundance — NHERF1 tethering, Nedd4-2 ubiquitination, EZH2 repression, endocytic degradation, and EGFR cross-talk — are integrated to set tissue-specific ACE2 levels during physiology and infection remains unresolved.
  • No unified model coordinating transcriptional, trafficking, and degradative control
  • Quantitative contribution of each layer in different tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0001618 virus receptor activity 3 GO:0016787 hydrolase activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 1
Partners
EGFRNEDD4LNHERF1SLC6A19SLC6A20TMEM27
Complex memberships
ACE2-B0AT1 (SLC6A19) heterodimerACE2-SIT1 (SLC6A20) heterodimer

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ACE2 (ACEH) is a zinc metallocarboxypeptidase containing an N-terminal signal sequence, a single catalytic domain with zinc-binding motif (HEMGH), a transmembrane region, and a small C-terminal cytosolic domain. It functions as a carboxypeptidase on angiotensin I (cleaving to Ang 1-9) and angiotensin II (cleaving to Ang 1-7), does not hydrolyse bradykinin, and is insensitive to ACE inhibitors. The protein is proposed to have evolved as a chimera of a single ACE-like catalytic domain and a collectrin-like C-terminal domain. Cloning, functional expression, in vitro enzymatic assays, domain analysis Canadian journal of physiology and pharmacology High 12025971
2007 ACE2 3D crystal structure was determined, and the enzyme was shown to cleave angiotensin II to angiotensin-(1-7) and to serve as a receptor for SARS and NL63 coronaviruses. ACE2 protein structure and function were validated through knockout and knock-in mouse models. Crystal structure determination, knockout/knock-in mouse models, enzymatic activity assays The Journal of pathology High 17464936
2010 ACE2 functions as a key SARS-coronavirus receptor and plays a protective role in SARS pathogenesis. ACE2 also functions as an amino acid transporter (homologous to collectrin), explaining the pathogenic role of ACE2 mutations in Hartnup disorder. Genetic models (ACE2 knockout mice), collectrin homology analysis, amino acid transport assays Circulation journal : official journal of the Japanese Circulation Society Medium 20134095
2011 ACE2 heterodimerizes with the neutral amino acid transporter B0AT1 (SLC6A19) in the small intestine, and this association is required for surface expression of B0AT1. In the kidney, ACE2 associates with B0AT3 through its homolog collectrin (Tmem27) in a tissue-specific manner. Protein interaction studies, surface expression assays, tissue-specific expression analysis Channels (Austin, Tex.) Medium 21814048
2020 ACE2 protein robustly localizes within the motile cilia of airway epithelial cells in the upper (nasal) and lower (pulmonary) respiratory tract, representing the initial subcellular site of SARS-CoV-2 viral entry. ACE inhibitors or ARBs do not increase ciliary ACE2 expression. Immunofluorescence, multiplex imaging of banked human tissue, immunohistochemistry across diverse donor panel Nature communications High 33116139
2020 ACE2 protein heterodimerizes with B0AT1 (SLC6A19) or SIT1 (SLC6A20) in the small intestine, and these heterodimers can form quaternary structures that serve as binding sites for SARS-CoV-2 spike glycoproteins. ACE2-B0AT1 association is required for surface expression of the transporter and may favor substrate amino acid supply to B0AT1. Co-immunoprecipitation, structural studies, viral binding assays Clinical science (London, England : 1979) Medium 33140827
2019 ACE2 is expressed on GABAergic neurons in the hypothalamic paraventricular nucleus (PVN), where it supports inhibitory GABAergic tone to presympathetic neurons. ACE2 deletion from all neurons reduces inhibitory inputs to presympathetic neurons and increases blood pressure. ADAM17 co-localizes with AT1 receptors on Sim1 neurons and its knockdown prevents acute pressor response to centrally administered angiotensin-II and preserves ACE2 activity during salt-sensitive hypertension. Conditional neuron-specific knockout mice, primary neuron cultures, photoactivation, blood pressure telemetry, bicuculline pharmacological blockade Hypertension (Dallas, Tex. : 1979) High 31564162
2020 EZH2-mediated H3K27me3 at the ACE2 promoter region inhibits ACE2 expression. EZH2 knockout in human embryonic stem cells significantly increases ACE2 expression, confirmed by ChIP-seq showing decreased H3K27me3 and increased H3K27ac signals at the ACE2 promoter. EZH2 knockout in hESCs, RNA-seq, ChIP-seq, Western blotting Biochemical and biophysical research communications Medium 32291076
2022 SARS-CoV-2 infection down-regulates ACE2 by inducing clathrin- and AP2-dependent endocytosis, leading to lysosomal degradation of ACE2. ACE2 knockdown mimics the downstream gene expression pattern of SARS-CoV-2 S-treated cells (activated cytokine signaling associated with respiratory distress). A soluble ACE2 fragment can block this down-regulation and viral infection. In vivo animal infection model, in vitro cell culture, siRNA knockdown, gene expression profiling, inhibitor studies Molecular biology of the cell High 36287912
2021 ACE2 directly binds both PDZ domains of the scaffolding protein NHERF1 via its intracellular C-terminal PDZ-recognition motif. This interaction tethers ACE2 at the membrane, increasing ACE2 membrane residence; disruption of either NHERF1 PDZ core-binding motif or the ACE2 PDZ recognition sequence eliminates binding. Loss of this interaction decreases ACE2 membrane residence and reduces pseudotyped SARS-CoV-2 entry, while ablating NHERF1 interaction accelerated entry, revealing a regulatory role. Co-immunoprecipitation, proximity ligation assays in human lung and intestine cells, mutagenesis of PDZ motifs, pseudovirus entry assays iScience High 34189428
2023 Nedd4-2 is an E3 ubiquitin ligase that ubiquitinates ACE2, leading to its down-regulation during angiotensin II-mediated hypertension. Mutation of lysine residues in the C-terminal of ACE2 generates a ubiquitination-resistant mutant (ACE2-5R) with increased activity and resistance to Ang-II-mediated degradation. Expression of ACE2-5R in the bed nucleus of the stria terminalis enhanced GABAergic input to the PVN and reduced hypertension. Bioinformatics, proteomics, in vitro gain/loss-of-function experiments, site-directed mutagenesis, optogenetics, blood pressure telemetry, pharmacological blockade Cardiovascular research High 37161607
2022 ACE2 pathway (ACE2/Ang-(1-7)/Mas1 receptor axis) is a critical regulator of thermogenesis and energy expenditure. ACE2 is highly expressed in brown adipose tissue (BAT); cold stimulation increases ACE2 and Ang-(1-7) in BAT and serum. Ace2 knockout and Mas1 knockout mice display impaired thermogenesis. Ace2 pathway activates Akt/FoxO1 and PKA pathways, inducing UCP1 expression and mitochondrial activation. Overexpression of Ace2 or Ang-(1-7) infusion ameliorates impaired thermogenesis in obese mice. Ace2 and Mas1 knockout mice, BAT transplantation, Ace2 overexpression, Ang-(1-7) infusion, pathway analysis (western blotting for Akt/FoxO1, PKA, UCP1) eLife High 35014608
2021 ACE2 autoantibodies develop after SARS-CoV-2 infection and inhibit ACE2 enzymatic activity. Plasma from patients with ACE2 antibodies inhibits exogenous ACE2 activity in vitro, and these patients have lower soluble ACE2 activity in plasma despite similar ACE2 protein levels. ELISA for ACE2 antibodies, in vitro ACE2 activity inhibition assay using patient plasma PloS one Medium 34478478
2019 ACE2 in breast cancer cells inhibits angiogenesis by downregulating VEGFa expression and inactivating phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. ACE2 also inhibits breast cancer cell migration and metastasis in vivo (zebrafish model). Transwell migration assay, tube formation assay, Western blotting for pathway phosphorylation, zebrafish xenograft model Journal of experimental & clinical cancer research : CR Medium 31023337
2022 ACE2 maintains enteral intestinal barrier integrity and reduces diabetic retinopathy (DR) progression through intestinal MasR activation, leading to GSK-3β/c-Myc-mediated decrease in intestinal glucose transporter expression. Genetic overexpression of intestinal ACE2 or oral administration of ACE2-expressing probiotic preserved barrier integrity, reduced inflammation, improved hyperglycemia, and delayed/reversed DR in Akita mice. Genetic intestinal ACE2 overexpression (Vil-Cre.hAce2KI-Akita mice), probiotic oral delivery of ACE2, pathway analysis (MasR, GSK-3β, c-Myc), gut permeability assays, retinal imaging Circulation research High 36448480
2023 ACE2 interacts with EGFR; SARS-CoV-2 spike protein activates the EGFR-MAPK signaling axis. A cross-talk exists between ACE2 and EGFR that regulates ACE2 abundance and EGFR activation/subcellular localization. Inhibiting EGFR-MAPK activation reduces SARS-CoV-2 infection. Co-immunoprecipitation/proximity assays, EGFR inhibitor treatment, pseudotyped particle and authentic SARS-CoV-2 infection assays, Western blotting Life science alliance Medium 37402592
2005 ACE2 mRNA and protein expression increase in the border/infarct area after myocardial infarction (MI) in rats. ACE2 protein localizes to macrophages, vascular endothelium, smooth muscle, and myocytes post-MI. Ramipril (ACE inhibitor) had no effect on cardiac ACE2 mRNA, which remained elevated, suggesting independent regulation of ACE2 from ACE. Immunoreactivity of ACE2 was also increased in failing human hearts. Quantitative RT-PCR, immunohistochemistry, in vitro autoradiography, ACE2 activity assays, rat MI model, human failing heart specimens European heart journal High 15671045
2015 Apelin is a catalytic substrate for ACE2 in addition to angiotensin II. ACE2 cleaves and degrades apelin peptides, forming part of a negative feedback loop in the apelinergic system. Enzymatic substrate assays (in vitro cleavage), referenced in review International journal of hypertension Medium 25815211
2021 ACE2 is a carboxypeptidase that degrades angiotensin II, B1-bradykinin, and apelin, acting as a critical regulator of cardiovascular physiology. Both SARS-CoV-2 and SARS coronaviruses downregulate ACE2 expression upon infection, contributing to ARDS pathogenesis. Review of enzymatic substrate characterization studies, genetic animal models with ARDS phenotype readout Frontiers in immunology Medium 35003058
2008 ACE2 expression and activity are significantly enhanced during pregnancy, with placentas being the major contributors followed by kidney and uterus. Total ACE2 activity increases approximately twofold in pregnancy, consistent with a role in modulating systemic and local uteroplacental hemodynamics. Quantitative RT-PCR for mRNA, enzymatic activity assays, normotensive and hypertensive rat pregnancy model American journal of physiology. Regulatory, integrative and comparative physiology Medium 18945956

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Critical care (London, England) 757 32660650
2021 COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 564 33389262
2020 COVID-19, ACE2, and the cardiovascular consequences. American journal of physiology. Heart and circulatory physiology 525 32228252
2005 Myocardial infarction increases ACE2 expression in rat and humans. European heart journal 346 15671045
2007 The emerging role of ACE2 in physiology and disease. The Journal of pathology 339 17464936
2020 ACE2, Much More Than Just a Receptor for SARS-COV-2. Frontiers in cellular and infection microbiology 268 32582574
2016 Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease. Shock (Augusta, Ga.) 230 27082314
2019 ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. Journal of experimental & clinical cancer research : CR 224 31023337
2006 ACE2 of the heart: From angiotensin I to angiotensin (1-7). Cardiovascular research 196 17049503
2020 ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nature communications 194 33116139
2021 The glycosylation in SARS-CoV-2 and its receptor ACE2. Signal transduction and targeted therapy 179 34782609
2022 ACE2 binding is an ancestral and evolvable trait of sarbecoviruses. Nature 174 35114688
2020 Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene 157 32882331
2021 Development of ACE2 autoantibodies after SARS-CoV-2 infection. PloS one 153 34478478
2010 Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circulation journal : official journal of the Japanese Circulation Society 150 20134095
2015 ACE and ACE2 in kidney disease. World journal of nephrology 144 25664248
2022 Close relatives of MERS-CoV in bats use ACE2 as their functional receptors. Nature 139 36477529
2002 ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors. Canadian journal of physiology and pharmacology 132 12025971
2011 ACE2: more of Ang-(1-7) or less Ang II? Current opinion in nephrology and hypertension 131 21045683
2020 Comparative ACE2 variation and primate COVID-19 risk. Communications biology 130 33110195
2020 Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter? Respiratory medicine 127 32364961
2014 ACE and ACE2 in inflammation: a tale of two enzymes. Inflammation & allergy drug targets 122 25019157
2008 ACE2 expression and activity are enhanced during pregnancy. American journal of physiology. Regulatory, integrative and comparative physiology 116 18945956
2020 The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19. Molecular therapy. Methods & clinical development 107 32665962
2020 Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator. Acta pharmaceutica Sinica. B 102 33072500
2020 Expression of the COVID-19 receptor ACE2 in the human conjunctiva. Journal of medical virology 101 32374427
2020 ACE2 and COVID-19 and the resulting ARDS. Postgraduate medical journal 93 32522846
2021 Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients. Frontiers in immunology 88 34194422
2020 Advances in research on ACE2 as a receptor for 2019-nCoV. Cellular and molecular life sciences : CMLS 84 32780149
2020 ACE2 and gut amino acid transport. Clinical science (London, England : 1979) 81 33140827
2017 Circulating ACE2 in Cardiovascular and Kidney Diseases. Current medicinal chemistry 81 28413960
2015 ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy. Journal of cardiovascular pharmacology 79 26322922
2020 ACE2: the molecular doorway to SARS-CoV-2. Cell & bioscience 78 33380340
2021 Variants in ACE2; potential influences on virus infection and COVID-19 severity. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 77 33607284
2019 ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons. Hypertension (Dallas, Tex. : 1979) 76 31564162
2015 The ACE2/Apelin Signaling, MicroRNAs, and Hypertension. International journal of hypertension 75 25815211
2014 Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clinical science (London, England : 1979) 72 24329564
2021 Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. PloS one 70 33592054
2013 The ACE2 gene: its potential as a functional candidate for cardiovascular disease. Clinical science (London, England : 1979) 69 23013041
2020 Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes. Respiratory physiology & neurobiology 65 32956843
2005 ACE2, CBK1, and BUD4 in budding and cell separation. Eukaryotic cell 65 15947194
2022 ACE2 Shedding and the Role in COVID-19. Frontiers in cellular and infection microbiology 63 35096642
2020 Angiotensin-converting enzyme 2 (ACE2) receptor and SARS-CoV-2: Potential therapeutic targeting. European journal of pharmacology 63 32745604
2022 SARS-CoV-2 down-regulates ACE2 through lysosomal degradation. Molecular biology of the cell 59 36287912
2008 Pharmacologic modulation of ACE2 expression. Current hypertension reports 59 18775121
2020 Manipulation of ACE2 expression in COVID-19. Open heart 55 33443121
2020 EZH2-mediated H3K27me3 inhibits ACE2 expression. Biochemical and biophysical research communications 53 32291076
2020 Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age. Frontiers in physiology 52 33101066
2011 Collectrin and ACE2 in renal and intestinal amino acid transport. Channels (Austin, Tex.) 52 21814048
2021 Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19. Frontiers in immunology 51 35003058
2020 ACE2, Metformin, and COVID-19. iScience 49 32818905
2020 ACE2 mouse models: a toolbox for cardiovascular and pulmonary research. Nature communications 49 33057007
2020 ACE2 & TMPRSS2 Expressions in Head & Neck Tissues: A Systematic Review. Head and neck pathology 48 32816230
2011 Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma. Journal of the renin-angiotensin-aldosterone system : JRAAS 48 22048948
2023 Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis. Nature communications 47 36759512
2020 ACE2 in the renin-angiotensin system. Clinical science (London, England : 1979) 47 33264412
2020 ACE2: from protection of liver disease to propagation of COVID-19. Clinical science (London, England : 1979) 42 33284956
2025 Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses. Cell 41 39922192
2025 Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses. Cell 40 39922191
2021 COVID-19-A Theory of Autoimmunity Against ACE-2 Explained. Frontiers in immunology 38 33833750
2020 Lions, tigers and kittens too: ACE2 and susceptibility to COVID-19. Evolution, medicine, and public health 36 32974030
2022 Angiotensin-converting enzyme 2 (ACE2): Two decades of revelations and re-evaluation. Peptides 35 35151768
2022 Genetic Landscape of the ACE2 Coronavirus Receptor. Circulation 35 35387486
2022 Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes. Circulation research 35 36448480
2022 Engineering ACE2 decoy receptors to combat viral escapability. Trends in pharmacological sciences 34 35902282
2021 Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome. PloS one 34 33725024
2020 ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators. ChemMedChem 34 32663362
2025 Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target. Cell 33 39889696
2020 An update on ACE2 amplification and its therapeutic potential. Acta physiologica (Oxford, England) 33 32469114
2021 Resveratrol supplementation reduces ACE2 expression in human adipose tissue. Adipocyte 32 34402717
2020 Kidney ACE2 expression: Implications for chronic kidney disease. PloS one 32 33125431
2022 ACE2 and COVID-19 Susceptibility and Severity. Aging and disease 31 35371596
2021 ACE2 and TMPRSS2 in human saliva can adsorb to the oral mucosal epithelium. Journal of anatomy 31 34590312
2020 Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications. Clinical science (London, England : 1979) 31 32901821
2023 Nedd4-2 up-regulation is associated with ACE2 ubiquitination in hypertension. Cardiovascular research 29 37161607
2021 RAAS, ACE2 and COVID-19; a mechanistic review. Saudi journal of biological sciences 29 34305426
2020 COVID-19 susceptibility: potential of ACE2 polymorphisms. The Egyptian journal of medical human genetics 29 38624559
2011 Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis. Kidney & blood pressure research 29 21346373
2022 ACE2 pathway regulates thermogenesis and energy metabolism. eLife 28 35014608
2021 Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection. Journal of virology 27 34668773
2020 Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2. bioRxiv : the preprint server for biology 27 33083800
2020 Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2). Journal of clinical pathology 26 32759311
2022 Effect of age on human ACE2 and ACE2-expressing alveolar type II cells levels. Pediatric research 25 35739259
2021 ACE2-based decoy receptors for SARS coronavirus 2. Proteins 25 33973262
2008 Renal ACE and ACE2 expression in early diabetic rats. Nephron. Experimental nephrology 25 18679036
2023 S Protein, ACE2 and Host Cell Proteases in SARS-CoV-2 Cell Entry and Infectivity; Is Soluble ACE2 a Two Blade Sword? A Narrative Review. Vaccines 24 36851081
2023 ACE2-EGFR-MAPK signaling contributes to SARS-CoV-2 infection. Life science alliance 24 37402592
2021 ACE2: At the crossroad of COVID-19 and lung cancer. Gene reports 24 33723522
2017 The Angiotensin Converting Enzyme 2 (ACE2), Gut Microbiota, and Cardiovascular Health. Protein and peptide letters 23 28758592
2023 Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. Acta neuropathologica communications 22 37784209
2025 A MERS-CoV-like mink coronavirus uses ACE2 as an entry receptor. Nature 21 40306315
2025 ACE2 from Pipistrellus abramus bats is a receptor for HKU5 coronaviruses. Nature communications 21 40436893
2021 Natural Products Modulating Angiotensin Converting Enzyme 2 (ACE2) as Potential COVID-19 Therapies. Frontiers in pharmacology 21 34012391
2022 ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19. Neuromolecular medicine 20 35451691
2021 E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability. Environmental toxicology and pharmacology 20 33838329
2021 ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. iScience 20 34189428
2021 Expression of ACE2 in the Intact and Acutely Injured Kidney. Kidney360 20 35368365
2020 Angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor in gonadal and reproductive functions. Clinical science (London, England : 1979) 20 33196086
2022 ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19. Oral diseases 19 35000261
2020 Cell differentiation and aging accompanied by depletion of the ACE2 protein. Aging 19 33203793

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