Affinage

ACE2

Angiotensin-converting enzyme 2 · UniProt Q9BYF1

Round 2 corrected
Length
805 aa
Mass
92.5 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACE2 is a zinc-dependent type I transmembrane carboxypeptidase that counterbalances the renin–angiotensin system by cleaving angiotensin II to the vasodilatory peptide Ang-(1-7) with ~400-fold higher catalytic efficiency than its conversion of angiotensin I to Ang 1-9, and also processes apelin-13 and dynorphin A 1-13 (PMID:10924499, PMID:11815627). In vivo, ACE2 is essential for cardiac contractility, protection against acute lung injury, regulation of brown adipose thermogenesis via the Ang-(1-7)/Mas1/PKA/Akt axis, and maintenance of intestinal barrier integrity; its loss produces phenotypes rescued by concurrent ACE deletion, establishing it as the principal counter-regulatory arm of ACE (PMID:12075344, PMID:16001071, PMID:35014608, PMID:36448480). ACE2 also serves as the obligate entry receptor for SARS-CoV and SARS-CoV-2, binding the spike receptor-binding domain through its N-terminal peptidase domain while existing predominantly as a monomer on the plasma membrane, and its surface abundance is regulated transcriptionally by EZH2-mediated H3K27me3 and STAT3, and post-translationally by Nedd4-2-dependent ubiquitination and SARS-CoV-2-induced clathrin/AP2-dependent lysosomal degradation (PMID:14647384, PMID:32132184, PMID:36971081, PMID:32291076, PMID:35468992, PMID:37161607, PMID:36287912). Beyond the renin–angiotensin system, ACE2 chaperones the intestinal neutral amino acid transporter B0AT1 to the cell surface via its collectrin-like domain, functioning as a dimer of heterodimers (PMID:32132184, PMID:21814048).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Identification of ACE2 as a novel carboxypeptidase homologous to ACE resolved whether a second angiotensin-converting enzyme existed and established its distinct substrate specificity and insensitivity to classical ACE inhibitors.

    Evidence Recombinant expression in CHO cells with enzymatic assays, northern blotting, and immunohistochemistry across two independent discovery papers

    PMID:10924499 PMID:10969042

    Open questions at the time
    • Physiological role in vivo not yet determined
    • Full substrate repertoire unknown
    • Mechanism of ectodomain shedding uncharacterized
  2. 2002 High

    Comprehensive substrate profiling and kinetic analysis revealed that ACE2 preferentially degrades angiotensin II (400-fold over Ang I), along with apelin-13 and dynorphin A, establishing it as a dedicated angiotensin II inactivator rather than a general ACE-like enzyme.

    Evidence LC-MS screening of 126 peptides with purified ACE2 and kinetic constant determination

    PMID:11815627

    Open questions at the time
    • In vivo relevance of non-angiotensin substrates (apelin, dynorphin) not tested
    • Structural basis of substrate selectivity undetermined
  3. 2002 High

    Genetic ablation of ACE2 in mice demonstrated its essential role in cardiac function and placed it as the in vivo counter-regulatory enzyme to ACE, since the severe cardiac contractility defect of ACE2 knockouts was fully rescued by concurrent ACE deletion.

    Evidence ACE2 knockout mice with cardiac phenotyping, ACE/ACE2 double-knockout epistasis, QTL mapping in rat hypertension models

    PMID:12075344

    Open questions at the time
    • Downstream mediators of cardiac protection not fully delineated
    • Contribution of non-angiotensin substrates to cardiac phenotype unknown
  4. 2003 High

    The discovery that ACE2 serves as the functional receptor for SARS-CoV fundamentally expanded its biology beyond the renin–angiotensin system, showing that the viral spike S1 domain co-opts ACE2 for cell entry.

    Evidence Receptor identification from permissive cell lysates, syncytia formation, pseudovirus entry, antibody blockade, and viral replication in ACE2-transfected 293T cells

    PMID:14647384

    Open questions at the time
    • Structural details of spike–ACE2 interface unknown
    • Whether ACE2 enzymatic activity is altered by spike binding not addressed
  5. 2005 High

    Structural and functional studies established the atomic basis of SARS-CoV RBD–ACE2 recognition and demonstrated ACE2's protective role against acute lung injury through angiotensin II inactivation, unifying its enzymatic and receptor biology in lung pathology.

    Evidence Crystal structure of SARS-CoV RBD–ACE2 at 2.9 Å; ACE2-knockout mice with worsened ARDS rescued by recombinant ACE2 and by genetic ACE deletion

    PMID:16001071 PMID:16166518

    Open questions at the time
    • Therapeutic window for recombinant ACE2 in human ARDS not defined
    • Whether spike binding impairs ACE2 catalytic activity in vivo not resolved
  6. 2008 High

    Identification of the ERK1/2 MAP kinase pathway as the mechanism by which angiotensin II downregulates ACE2—and Ang-(1-7) opposes this via MAP kinase phosphatase activation—revealed a feedback loop governing ACE2 expression.

    Evidence Pharmacological dissection (ERK inhibitors, phosphatase inhibitors) in rat aortic VSMCs with ACE2 mRNA and activity readouts

    PMID:18768926

    Open questions at the time
    • Identity of the specific MAP kinase phosphatase not determined
    • Relevance in human cells not confirmed
  7. 2011 Medium

    Recognition that ACE2's collectrin-like domain chaperones the neutral amino acid transporter B0AT1 to the intestinal surface linked ACE2 to amino acid absorption and Hartnup disorder, revealing a non-catalytic structural function.

    Evidence Review synthesizing functional and genetic data on ACE2/collectrin/B0AT1 transport complexes

    PMID:21814048

    Open questions at the time
    • Direct structural visualization of the ACE2–B0AT1 complex not yet obtained
    • Whether ACE2 enzymatic activity and transporter chaperoning are coupled is unknown
  8. 2020 High

    Confirmation that SARS-CoV-2 uses ACE2 as its entry receptor (with TMPRSS2-mediated priming), combined with cryo-EM structures of full-length ACE2–B0AT1 and ACE2–spike complexes, provided the molecular framework for understanding pandemic coronavirus cell entry and showed ACE2 dimerizes via its collectrin-like domain.

    Evidence Virus isolation and neutralization; pseudovirus and authentic virus entry assays with TMPRSS2 inhibitor; cryo-EM of ACE2–B0AT1 ± SARS-CoV-2 RBD at 2.9 Å; X-ray crystallography of RBD–ACE2; single-cell RNA-seq across species

    PMID:32015507 PMID:32075877 PMID:32132184 PMID:32142651 PMID:32155444 PMID:32225176 PMID:32376634 PMID:32413319

    Open questions at the time
    • Mechanism by which spike binding triggers ACE2 internalization not fully resolved
    • Whether ACE2 enzymatic function is directly impaired during SARS-CoV-2 infection in vivo remains unclear
  9. 2020 High

    Transcriptional regulation of ACE2 was placed under epigenetic and cytokine-driven control: EZH2-mediated H3K27me3 silences ACE2, interferon signaling induces it as an ISG, and ACE2 localizes to motile cilia of upper airway epithelial cells as the initial site of viral contact.

    Evidence EZH2 knockout in hESCs with ChIP-seq; interferon stimulation with scRNA-seq; multiplexed immunofluorescence on human airway tissue

    PMID:32291076 PMID:32413319 PMID:33116139

    Open questions at the time
    • Whether interferon-driven ACE2 upregulation is protective or detrimental during infection not resolved
    • Relative contributions of epigenetic vs. cytokine regulation in different tissues unknown
  10. 2021 High

    The PDZ scaffold NHERF1 was identified as a direct interactor that tethers ACE2 at the plasma membrane and facilitates SARS-CoV-2 internalization, establishing a host scaffolding mechanism for receptor-mediated viral entry.

    Evidence Proximity ligation assay in human lung/intestine cells, mutagenesis of PDZ motifs, pseudotyped virus entry assays

    PMID:34189428

    Open questions at the time
    • Whether NHERF1 modulates ACE2 enzymatic activity is untested
    • Role of other PDZ-domain proteins in ACE2 membrane stabilization unknown
  11. 2022 High

    Post-translational regulation of ACE2 was mechanistically dissected: SARS-CoV-2 triggers clathrin/AP2-dependent endocytosis and lysosomal degradation of ACE2, while Nedd4-2-mediated ubiquitination at C-terminal lysines promotes proteasomal degradation relevant to neurogenic hypertension; ACE2 exists as monomers on the cell surface at low density.

    Evidence Clathrin/AP2 knockdown and lysosomal inhibitors; Nedd4-2 identification by proteomics with ACE2-5R mutagenesis and in vivo blood pressure telemetry; dSTORM super-resolution imaging of endogenous ACE2

    PMID:36287912 PMID:36971081 PMID:37161607

    Open questions at the time
    • Whether other E3 ligases also target ACE2 is unexplored
    • How monomeric ACE2 density affects viral entry efficiency across tissues is unquantified
  12. 2022 High

    ACE2's metabolic role was expanded beyond the cardiovascular system: the ACE2/Ang-(1-7)/Mas1 axis activates PKA/Akt signaling to drive UCP1 expression and thermogenesis in brown adipose tissue, and intestinal ACE2 maintains gut barrier integrity to prevent diabetic complications including retinopathy.

    Evidence ACE2 and Mas1 knockout mice with thermogenesis phenotyping, BAT transplantation, Ang-(1-7) infusion; transgenic intestinal ACE2 overexpression in diabetic mice with ocular endpoint measurements

    PMID:35014608 PMID:36448480

    Open questions at the time
    • Whether ACE2's non-angiotensin substrates contribute to metabolic phenotypes untested
    • Relative importance of local vs. circulating Ang-(1-7) in BAT thermogenesis unknown
  13. 2022 High

    CRISPR screens and STAT3 ChIP identified cell-type-specific transcriptional regulators of ACE2 surface abundance (including SMAD4, EP300, KDM6A, and STAT3), revealing that ACE2 expression is governed by distinct regulatory networks in different tissues.

    Evidence Genome-scale CRISPR screens in HuH7 and Calu-3 cells; ChIP and luciferase reporter assays for STAT3 at the ACE2 promoter

    PMID:35231079 PMID:35468992

    Open questions at the time
    • How these regulators interact with the EZH2 epigenetic axis is uncharacterized
    • In vivo validation of CRISPR screen hits in primary tissues is lacking
  14. 2025 High

    Cryo-EM capture of an ACE2-induced early fusion intermediate conformation (E-FIC) of the SARS-CoV-2 spike revealed the structural mechanism by which ACE2 binding triggers the conformational cascade leading to membrane fusion, and enabled design of a dual-function antiviral targeting this intermediate.

    Evidence Cryo-EM structure of E-FIC; recombinant antiviral protein AL5E with in vitro and in vivo efficacy against ACE2-using coronaviruses

    PMID:39889696

    Open questions at the time
    • Whether E-FIC is a universal intermediate across all ACE2-using coronaviruses is unconfirmed
    • Kinetics of E-FIC to late fusion transition on live cells not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether SARS-CoV-2 spike binding directly impairs ACE2 catalytic activity in vivo, the physiological relevance of ACE2's non-angiotensin substrates (apelin, dynorphin) in organ-specific contexts, and how distinct transcriptional and post-translational regulatory inputs are integrated across tissues to set ACE2 surface levels.
  • No in vivo measurement of ACE2 catalytic activity during active SARS-CoV-2 infection
  • Apelin and dynorphin substrate cleavage not studied in knockout models
  • No integrated model of ACE2 transcriptional/epigenetic/post-translational regulation across cell types

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 2 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-382551 Transport of small molecules 2
Partners
EP300EZH2NEDD4LNHERF1SLC6A19SMAD4STAT3TMPRSS2
Complex memberships
ACE2-B0AT1 dimer of heterodimers

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ACE2 was identified as the first human homologue of ACE; it is a zinc metalloprotease with a single HEXXH active site that functions exclusively as a carboxypeptidase, cleaving the C-terminal leucine from angiotensin I to generate angiotensin 1-9, and is not inhibited by classical ACE inhibitors (captopril, lisinopril). The gene maps to chromosome Xp22 and encodes an 805-amino-acid type I transmembrane glycoprotein secreted as a soluble form by cleavage N-terminal to the transmembrane domain. Recombinant protein expression in CHO cells, in vitro enzymatic assay, substrate cleavage characterization, northern blotting, immunohistochemistry The Journal of biological chemistry High 10924499
2000 ACE2 converts angiotensin I to angiotensin 1-9 and also cleaves angiotensin II; recombinant ACE2 is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. ACE2 transcripts were detected specifically in heart, kidney, and testis, and immunohistochemistry localized ACE2 protein predominantly to coronary/intrarenal vascular endothelium and renal tubular epithelium. cDNA library cloning, recombinant expression, in vitro enzymatic assay, northern blot, immunohistochemistry Circulation research High 10969042
2002 Comprehensive substrate profiling of purified ACE2 against 126 biological peptides revealed that ACE2 hydrolyzes angiotensin II (kcat/Km = 1.9×10⁶ M⁻¹s⁻¹), apelin-13 (kcat/Km = 2.1×10⁶ M⁻¹s⁻¹), and dynorphin A 1-13 (kcat/Km = 3.1×10⁶ M⁻¹s⁻¹) with highest efficiency; in each case only the C-terminal residue is removed. Catalytic efficiency for angiotensin II is 400-fold higher than for angiotensin I. ACE2 does not hydrolyze bradykinin. Protein purification, LC-MS substrate screening panel (126 peptides), kinetic assays The Journal of biological chemistry High 11815627
2002 Targeted disruption of ACE2 in mice causes severe cardiac contractility defect with increased angiotensin II levels and upregulation of hypoxia-induced genes in the heart; genetic ablation of ACE on the ACE2-null background completely rescues the cardiac phenotype, placing ACE2 functionally downstream/counter-regulatory to ACE in the renin-angiotensin system in vivo. ACE2 mRNA and protein are markedly reduced in three different rat hypertension models, and the ace2 locus maps to a hypertension QTL on the X chromosome. Knockout mouse generation, cardiac function measurements, genetic epistasis (ACE/ACE2 double knockout), QTL mapping, mRNA/protein expression in rat models Nature High 12075344
2003 ACE2 was identified as the functional receptor for SARS-CoV: the S1 domain of the SARS-CoV spike protein binds ACE2 efficiently; soluble ACE2 (but not soluble ACE1) blocks S1-domain association with Vero E6 cells; 293T cells transfected with ACE2 form syncytia with S-protein-expressing cells and support SARS-CoV replication; anti-ACE2 antibody (but not anti-ACE1) blocks viral replication. Receptor identification from permissive cell lysates, transfection assay, pseudovirus/syncytia assay, antibody blockade, viral replication assay Nature High 14647384
2004 ACE2 protein is expressed on the surface of lung alveolar epithelial cells and enterocytes of the small intestine, and in arterial/venous endothelial cells and smooth muscle cells of all organs examined, establishing tissue tropism relevant to SARS-CoV pathogenesis. Immunohistochemistry on multiple human organ samples The Journal of pathology High 15141377
2005 ACE2 protects mice from severe acute lung injury: ACE2-deficient mice show dramatically worsened ARDS (induced by acid aspiration or sepsis), while recombinant ACE2 administration rescues lung function. The pathway involves ACE2 inactivating angiotensin II; angiotensin II acting via AT1a receptor promotes lung edema and injury, while ACE2 and AT2 receptor are protective. ACE-knockout mice show markedly improved lung injury. ACE2 knockout and recombinant ACE2 rescue in mouse ARDS models (acid aspiration, sepsis), lung function measurements, genetic epistasis with ACE KO and receptor KOs Nature High 16001071
2005 ACE2 activity and mRNA increase in the border/infarct zone after myocardial infarction in rats (day 3 and day 28) and in viable myocardium by day 28; ACE2 protein localizes to macrophages, vascular endothelium, smooth muscle, and cardiomyocytes post-MI. Ramipril (ACE inhibitor) attenuates cardiac hypertrophy and inhibits ACE but does not suppress elevated ACE2 mRNA post-MI. ACE2 immunoreactivity also increases in failing human hearts. Rat MI model, quantitative RT-PCR, immunohistochemistry, in vitro autoradiography, enzymatic activity assays European heart journal High 15671045
2005 Crystal structure (2.9 Å) of the SARS-CoV RBD bound to the peptidase domain of human ACE2 revealed that the RBD presents a gently concave surface cradling the N-terminal lobe of the ACE2 peptidase domain; atomic details clarify residues enabling cross-species infection and human-to-human transmission. X-ray crystallography at 2.9 Å resolution Science (New York, N.Y.) High 16166518
2008 Angiotensin II downregulates ACE2 mRNA and activity in rat vascular smooth muscle cells via the MAP kinase (ERK1/2) pathway; angiotensin-(1-7) prevents this downregulation by activating a MAP kinase phosphatase (effect blocked by tyrosine and serine-threonine phosphatase inhibitors). ANG II treatment increases ERK1/2 activity, which is reduced by ANG-(1-7) pretreatment. This MAP kinase/phosphatase axis is the primary molecular mechanism for ACE2 regulation. Cell-based assays in rat aortic VSMCs, ACE2 activity and mRNA measurement, ERK1/2 kinase assay, pharmacological inhibitors (PD98059, sodium vanadate, okadaic acid), receptor antagonist blockade American journal of physiology. Cell physiology High 18768926
2011 ACE2 acts as an amino acid transporter chaperone: its collectrin-like domain (transmembrane domain) is required for surface expression of neutral amino acid transporter B0AT1 in the intestine, linking ACE2 to amino acid absorption and the pathogenesis of Hartnup disorder. Review synthesizing functional and genetic studies on ACE2/collectrin/B0AT1 transporter complexes in kidney and intestine Channels (Austin, Tex.) Medium 21814048
2020 Cryo-EM structures of full-length human ACE2 in complex with the neutral amino acid transporter B0AT1 (with and without SARS-CoV-2 RBD) at 2.9 Å resolution revealed: (1) ACE2-B0AT1 assembles as a dimer of heterodimers, with ACE2's collectrin-like domain mediating homodimerization; (2) the SARS-CoV-2 RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. Cryo-electron microscopy at 2.9 Å overall resolution (3.5 Å at ACE2-RBD interface) Science (New York, N.Y.) High 32132184
2020 SARS-CoV-2 uses ACE2 as its entry receptor and requires TMPRSS2 for spike protein priming; a clinically approved TMPRSS2 inhibitor (camostat mesylate) blocks SARS-CoV-2 entry. Convalescent SARS-CoV-1 sera cross-neutralize SARS-CoV-2 spike-driven entry. Pseudovirus entry assay, authentic virus infection, TMPRSS2 inhibitor treatment, antibody neutralization Cell High 32142651
2020 2019-nCoV (SARS-CoV-2) uses the same cell entry receptor ACE2 as SARS-CoV, confirmed by demonstrating that the isolated virus can be neutralized by sera from SARS patients and that the new virus shares 79.6% sequence identity with SARS-CoV. Virus isolation, whole-genome sequencing, neutralization assay with convalescent sera Nature High 32015507
2020 Crystal structure of SARS-CoV-2 RBD bound to human ACE2 peptidase domain at atomic resolution showed the overall binding mode is nearly identical to SARS-CoV RBD-ACE2, but key substitutions in SARS-CoV-2 RBD strengthen the interaction and increase ACE2-binding affinity compared to SARS-CoV. X-ray crystallography, surface plasmon resonance binding affinity measurements Nature High 32225176
2020 Cryo-EM structure of SARS-CoV-2 spike trimer demonstrated that the receptor-binding domain (RBD) binds ACE2 with higher affinity than SARS-CoV spike; in the predominant prefusion state, one of three RBDs is rotated 'up' in a receptor-accessible conformation. Cryo-EM at 3.5 Å, biolayer interferometry binding assay Science (New York, N.Y.) High 32075877
2020 SARS-CoV-2 spike protein harbors a furin cleavage site at the S1/S2 boundary (absent in SARS-CoV) that is processed during biogenesis; SARS-CoV-2 S and SARS-CoV S RBDs bind human ACE2 with similar affinities. SARS-CoV polyclonal antibodies potently inhibit SARS-CoV-2 spike-mediated cell entry. Cryo-EM structure determination, cell-cell fusion assay, pseudovirus entry assay, flow cytometry binding, antibody neutralization Cell High 32155444
2020 SARS-CoV-2 RBD has higher ACE2-binding affinity than SARS-CoV RBD, but the intact SARS-CoV-2 spike has comparable or lower ACE2 affinity than SARS-CoV spike (due to less-exposed RBD). SARS-CoV-2 cell entry is pre-activated by proprotein convertase furin, reducing its dependence on target cell proteases. SARS-CoV-2 enters cells primarily through endocytosis and requires PIKfyve, TPC2, and cathepsin L. Biochemical binding assays, pseudovirus entry assays, furin inhibitor treatment, endocytosis pathway inhibitors Proceedings of the National Academy of Sciences of the United States of America High 32376634
2020 ACE2 is an interferon-stimulated gene (ISG) in human airway epithelial cells: type I and type III interferon treatment induces ACE2 expression in vitro, and ACE2 is upregulated in vivo during viral infections. ACE2 and TMPRSS2 are co-expressed in lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Single-cell RNA sequencing (human, NHP, mouse), in vitro interferon stimulation assays, in vivo viral infection transcriptomics Cell High 32413319
2020 ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells of the upper respiratory tract, representing the likely initial subcellular site of SARS-CoV-2 entry. ACE inhibitor or ARB use does not increase ciliary ACE2 expression. Multiplexed immunofluorescence (CODEX) on banked human nasal and pulmonary tissue, immunohistochemistry Nature communications High 33116139
2020 EZH2-mediated H3K27me3 at the ACE2 promoter region inhibits ACE2 expression: EZH2 knockout in human embryonic stem cells significantly increased ACE2 expression, ChIP-seq confirmed decreased H3K27me3 and increased H3K27ac at the ACE2 promoter upon EZH2 knockout, and reduction of H3K27me3 (but not H3K4/9/36me3) upregulated Ace2 in a mouse germ cell line. EZH2 knockout in hESCs, RNA-seq, ChIP-seq, qPCR in mouse GC-2 cells with histone methylation manipulation Biochemical and biophysical research communications High 32291076
2021 ACE2 interacts directly with the PDZ scaffold protein NHERF1 through its C-terminal PDZ-recognition motif; both NHERF1 PDZ domains bind ACE2. Disruption of NHERF1 PDZ motifs or ACE2 PDZ recognition sequence eliminates interaction. NHERF1 tethers ACE2 at the cell membrane and facilitates SARS-CoV-2 internalization: elimination of the ACE2 C-terminal PDZ-binding motif decreased ACE2 membrane residence and reduced pseudotyped virus entry. Proximity ligation assay (PLA) in human lung/intestine cells, mutagenesis of PDZ motifs, pseudotyped virus entry assay, ACE2 membrane localization quantification iScience High 34189428
2022 SARS-CoV-2 infection down-regulates ACE2 in vivo (animal model) and in cultured cells by inducing clathrin- and AP2-dependent endocytosis leading to lysosomal degradation. ACE2 knockdown cells exhibit similar transcriptional changes to SARS-CoV-2-S-treated cells (activated cytokine signaling). A soluble ACE2 fragment with stronger SARS-CoV-2 S-binding efficiently blocks ACE2 downregulation and viral infection. In vivo infection model, cell-based endocytosis assays with clathrin/AP2 knockdown, lysosomal degradation inhibitors, ACE2 knockdown transcriptomics, pseudovirus neutralization with soluble ACE2 fragment Molecular biology of the cell High 36287912
2022 ACE2 pathway (ACE2 cleaving Ang II to generate Ang-(1-7) acting via Mas1 receptor) is a critical regulator of thermogenesis and energy expenditure: Ace2 and Mas1 knockout mice display impaired thermogenesis; cold stimulation increases ACE2 and Ang-(1-7) in brown adipose tissue (BAT); ACE2 overexpression or Ang-(1-7) infusion ameliorates impaired thermogenesis in obese mice; mechanistically, the ACE2/Ang-(1-7)/Mas1 axis activates Akt/FoxO1 and PKA signaling, inducing UCP1 and activating mitochondrial function and white adipose browning. ACE2 and Mas1 knockout mice, BAT transplantation, ACE2 overexpression, Ang-(1-7) infusion, high-fat diet and Lepr-mutant obese models, UCP1/PKA/Akt pathway analysis eLife High 35014608
2022 ACE2 endogenous receptors are present as monomers in the plasma membrane at densities of 1–2 receptors/μm², and binding of trimeric SARS-CoV-2 spike proteins does not induce ACE2 oligomerization; a single spike protein interaction with a monomeric ACE2 is sufficient for viral infection. Direct stochastic optical reconstruction microscopy (dSTORM), single-molecule localization, VSV pseudotyped virus infection assays Angewandte Chemie (International ed. in English) High 36971081
2022 STAT3 binds the ACE2 promoter and controls ACE2 expression in bronchial epithelial cells stimulated with IL-6; inhibition of STAT3-ACE2 promoter interaction by the compound 6-OAP suppresses ACE2 transcription and blocks SARS-CoV-2 pseudovirus entry into lung epithelial cells. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, qPCR, western blot, SARS-CoV-2 pseudovirus entry assay, in vivo mouse lung ACE2 measurement Acta pharmacologica Sinica High 35468992
2023 Nedd4-2 is the first E3 ubiquitin ligase identified to promote ACE2 ubiquitination, leading to ACE2 downregulation in neurogenic hypertension. Mutation of lysine residues in the ACE2 C-terminal domain generates a ubiquitination-resistant ACE2 (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 paraventricular nucleus and reduced hypertension, establishing ACE2's role on GABAergic neurons in sympathetic regulation. Bioinformatics + proteomics identification of E3 ligase, in vitro gain/loss-of-function, ACE2 mutagenesis (ACE2-5R), optogenetics, blood pressure telemetry, AAV-mediated brain expression, capillary western analysis Cardiovascular research High 37161607
2013 A live bat SL-CoV (WIV1) closely related to SARS-CoV was isolated from bat fecal samples and demonstrated to use ACE2 from humans, civets, and Chinese horseshoe bats for cell entry, confirming ACE2 as the functional receptor for bat progenitor viruses of SARS-CoV. Virus isolation in Vero E6 cells, whole-genome sequencing, pseudovirus entry assay with ACE2 orthologs Nature High 24172901
2021 ACE2 inhibits breast cancer angiogenesis by suppressing the VEGFa/VEGFR2/ERK pathway: ACE2 expression in breast cancer cells downregulates VEGFa and inactivates phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in endothelial cells, inhibiting tube formation, migration, and neo-angiogenesis in a zebrafish model. Transwell migration assay, tube formation assay, wound healing assay, western blot (phospho-VEGFR2/MEK/ERK), qPCR, zebrafish xenograft model Journal of experimental & clinical cancer research : CR Medium 31023337
2022 ACE2 maintains intestinal barrier integrity and prevents diabetic retinopathy through intestinal MasR activation: genetic overexpression of intestinal ACE2 in Akita (T1D) mice preserved gut barrier integrity, reduced systemic inflammation, improved hyperglycemia via GSK-3β/c-Myc-mediated decrease in intestinal glucose transporter expression, and delayed/reversed diabetic retinopathy. Transgenic intestinal ACE2 overexpression (Vil-Cre.hAce2KI-Akita mice), Lactobacillus-expressed ACE2 probiotic, intestinal permeability assays, ocular endpoint measurements, western blot pathway analysis Circulation research High 36448480
2021 Auto-antibodies against ACE2 develop in the majority (81–93%) of patients after SARS-CoV-2 infection; plasma from these patients inhibits exogenous ACE2 enzymatic activity and is associated with lower soluble ACE2 activity in plasma, consistent with autoantibody-mediated ACE2 inhibition contributing to post-acute sequelae. ELISA for ACE2 antibodies, fluorometric ACE2 enzymatic activity assay with patient plasma, soluble ACE2 protein measurement PloS one Medium 34478478
2021 Deep mutational scanning of all possible single amino-acid substitutions in the SARS-CoV-2 RBD identified mutations that enhance or reduce ACE2 binding affinity; most mutations are deleterious, but a subset (including at ACE2 interface residues conserved across sarbecoviruses) enhance ACE2 affinity. Constrained surface regions were identified as potential vaccine/therapeutic targets. Deep mutational scanning (yeast display), high-throughput ACE2 binding measurements across all single-amino-acid RBD variants Cell High 32841599
2022 CRISPR loss-of-function screens identified cell-type-specific regulators of ACE2 surface abundance: in HuH7 cells, SMAD4, EP300, PIAS1, and BAMBI regulate ACE2 at the mRNA level and influence SARS-CoV-2 susceptibility; in Calu-3 lung cells, KDM6A, MOGS, GPAA1, and UGP2 are distinct ACE2 modifiers, demonstrating cell-type specificity of ACE2 regulatory networks. High-throughput CRISPR screens for ACE2 surface abundance, individual KO validation, SARS-CoV-2 infection susceptibility assays PLoS pathogens High 35231079
2021 LiGaMD simulations captured spontaneous binding/unbinding of the ACE2 inhibitor MLN-4760 and showed that unliganded ACE2 samples distinct Open, Partially Open, Closed, and Fully Closed conformations; upon ligand binding, the conformational ensemble shifts toward the Closed state (as seen in the X-ray structure), suggesting a conformational selection mechanism for ligand recognition by ACE2. All-atom ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations, microsecond timescale, validated against X-ray experimental structure The journal of physical chemistry letters Low 33999630
2025 Cryo-EM structure captured an ACE2-induced early fusion intermediate conformation (E-FIC) of SARS-CoV-2 spike in which HR1 in S2 has ejected while S1 remains attached; this E-FIC transitions to the late fusion intermediate after S2' cleavage. An E-FIC-targeted dual-functional antiviral protein (AL5E) was designed that inactivated ACE2-using coronaviruses and protected animals. Cryo-EM structure determination of ACE2-induced spike E-FIC, recombinant antiviral protein design (AL5E), in vitro and in vivo antiviral efficacy assays Cell High 39889696

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 14323 32142651
2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 13891 32015507
2020 Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, N.Y.) 6485 32075877
2020 Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 6362 32155444
2020 Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 4546 32225176
2003 Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 4385 14647384
2004 Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. The Journal of pathology 4025 15141377
2020 Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science (New York, N.Y.) 3685 32132184
2020 Structural basis of receptor recognition by SARS-CoV-2. Nature 2752 32225175
2020 Cell entry mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences of the United States of America 2420 32376634
2000 A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation research 2338 10969042
2020 Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature communications 2296 32221306
2020 Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature microbiology 2243 32094589
2020 Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 2225 32275855
2005 Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 1915 16001071
2020 SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell 1843 32413319
2020 High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International journal of oral science 1662 32094336
2000 A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. The Journal of biological chemistry 1641 10924499
2020 Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. Cell 1576 32841599
2020 Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 1559 32422645
2013 Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 1527 23486063
2020 Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Frontiers of medicine 1522 32170560
2005 Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science (New York, N.Y.) 1486 16166518
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 1377 32454513
2002 Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 1367 12075344
2013 Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 1188 24172901
2020 Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cellular & molecular immunology 1164 32203189
2002 Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. The Journal of biological chemistry 1146 11815627
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2020 Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Critical care (London, England) 751 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 556 33389262
2020 COVID-19, ACE2, and the cardiovascular consequences. American journal of physiology. Heart and circulatory physiology 518 32228252
2005 Myocardial infarction increases ACE2 expression in rat and humans. European heart journal 345 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 267 32582574
2016 Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease. Shock (Augusta, Ga.) 229 27082314
2019 ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. Journal of experimental & clinical cancer research : CR 219 31023337
2017 Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse. International journal of molecular sciences 208 28273875
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 176 34782609
2022 ACE2 binding is an ancestral and evolvable trait of sarbecoviruses. Nature 172 35114688
2020 Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene 157 32882331
2010 Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circulation journal : official journal of the Japanese Circulation Society 150 20134095
2021 Development of ACE2 autoantibodies after SARS-CoV-2 infection. PloS one 148 34478478
2015 ACE and ACE2 in kidney disease. World journal of nephrology 143 25664248
2022 Close relatives of MERS-CoV in bats use ACE2 as their functional receptors. Nature 136 36477529
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 129 33110195
2020 Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter? Respiratory medicine 127 32364961
2022 Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science (New York, N.Y.) 126 34990214
2014 ACE and ACE2 in inflammation: a tale of two enzymes. Inflammation & allergy drug targets 122 25019157
2020 Expression of the COVID-19 receptor ACE2 in the human conjunctiva. Journal of medical virology 100 32374427
2020 ACE2 and COVID-19 and the resulting ARDS. Postgraduate medical journal 93 32522846
2008 MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. American journal of physiology. Cell physiology 87 18768926
2020 Advances in research on ACE2 as a receptor for 2019-nCoV. Cellular and molecular life sciences : CMLS 84 32780149
2020 The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clinical and experimental pharmacology & physiology 81 31901211
2017 Circulating ACE2 in Cardiovascular and Kidney Diseases. Current medicinal chemistry 80 28413960
2021 SARS-CoV-2 Entry: At the Crossroads of CD147 and ACE2. Cells 79 34201214
2021 Targeting ACE2 for COVID-19 Therapy: Opportunities and Challenges. American journal of respiratory cell and molecular biology 78 33296619
2014 Angiotensin-converting enzyme 2 (ACE2) activator diminazene aceturate ameliorates endotoxin-induced uveitis in mice. Investigative ophthalmology & visual science 76 24854854
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 75 33607284
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 SARS-CoV-2 interacts with platelets and megakaryocytes via ACE2-independent mechanism. Journal of hematology & oncology 71 33926500
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
2021 Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2. PLoS pathogens 58 33836016
2012 Role of ACE2 in diastolic and systolic heart failure. Heart failure reviews 58 21638102
2008 Pharmacologic modulation of ACE2 expression. Current hypertension reports 58 18775121
2022 SARS-CoV-2 down-regulates ACE2 through lysosomal degradation. Molecular biology of the cell 54 36287912
2020 Manipulation of ACE2 expression in COVID-19. Open heart 54 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 50 35003058
2022 SARS-CoV-2 cell entry beyond the ACE2 receptor. Molecular biology reports 49 35754059
2020 ACE2, Metformin, and COVID-19. iScience 48 32818905
2020 ACE2 mouse models: a toolbox for cardiovascular and pulmonary research. Nature communications 48 33057007
2023 Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis. Nature communications 46 36759512
2020 ACE2 in the renin-angiotensin system. Clinical science (London, England : 1979) 46 33264412
2022 Scanning the RBD-ACE2 molecular interactions in Omicron variant. Biochemical and biophysical research communications 44 35007846
2021 Downregulation of Membrane-bound Angiotensin Converting Enzyme 2 (ACE2) Receptor has a Pivotal Role in COVID-19 Immunopathology. Current drug targets 41 33081670
2025 Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses. Cell 40 39922192
2025 Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses. Cell 38 39922191
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 34 35151768
2022 Genetic Landscape of the ACE2 Coronavirus Receptor. Circulation 34 35387486
2021 Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome. PloS one 34 33725024
2022 Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes. Circulation research 33 36448480
2020 An update on ACE2 amplification and its therapeutic potential. Acta physiologica (Oxford, England) 33 32469114
2020 Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer's disease brain. bioRxiv : the preprint server for biology 33 33052346
2021 Resveratrol supplementation reduces ACE2 expression in human adipose tissue. Adipocyte 32 34402717
2022 ACE2 and COVID-19 Susceptibility and Severity. Aging and disease 31 35371596
2020 Kidney ACE2 expression: Implications for chronic kidney disease. PloS one 31 33125431
2020 Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications. Clinical science (London, England : 1979) 30 32901821
2020 A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacology & therapeutics 30 33275999
2023 Nedd4-2 up-regulation is associated with ACE2 ubiquitination in hypertension. Cardiovascular research 28 37161607
2022 ACE2 pathway regulates thermogenesis and energy metabolism. eLife 28 35014608
2020 COVID-19 susceptibility: potential of ACE2 polymorphisms. The Egyptian journal of medical human genetics 28 38624559
2011 Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis. Kidney & blood pressure research 28 21346373
2021 RAAS, ACE2 and COVID-19; a mechanistic review. Saudi journal of biological sciences 27 34305426
2021 Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection. Journal of virology 27 34668773
2020 Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2). Journal of clinical pathology 26 32759311
2020 Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2. bioRxiv : the preprint server for biology 26 33083800
2008 Renal ACE and ACE2 expression in early diabetic rats. Nephron. Experimental nephrology 25 18679036
2025 Early fusion intermediate of ACE2-using coronavirus spike acting as an antiviral target. Cell 24 39889696
2022 Effect of age on human ACE2 and ACE2-expressing alveolar type II cells levels. Pediatric research 24 35739259
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
2021 Identifying Primate ACE2 Variants That Confer Resistance to SARS-CoV-2. Molecular biology and evolution 22 33674876
2023 Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. Acta neuropathologica communications 21 37784209
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 Natural Products Modulating Angiotensin Converting Enzyme 2 (ACE2) as Potential COVID-19 Therapies. Frontiers in pharmacology 20 34012391
2021 Expression of ACE2 in the Intact and Acutely Injured Kidney. Kidney360 20 35368365
2007 Collectrin, a homologue of ACE2, its transcriptional control and functional perspectives. Biochemical and biophysical research communications 20 17825789
2025 ACE2 from Pipistrellus abramus bats is a receptor for HKU5 coronaviruses. Nature communications 19 40436893
2022 ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19. Oral diseases 19 35000261
2022 Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells. Acta pharmacologica Sinica 19 35468992
2021 Mechanism of Ligand Recognition by Human ACE2 Receptor. The journal of physical chemistry letters 19 33999630
2021 ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. iScience 19 34189428
2014 Role of collectrin, an ACE2 homologue, in blood pressure homeostasis. Current hypertension reports 18 25182162
2023 Coronaviruses Use ACE2 Monomers as Entry-Receptors. Angewandte Chemie (International ed. in English) 16 36971081
2022 Identification of cell type specific ACE2 modifiers by CRISPR screening. PLoS pathogens 16 35231079
2022 GSTO1, GSTO2 and ACE2 Polymorphisms Modify Susceptibility to Developing COVID-19. Journal of personalized medicine 16 35330457
2020 ACE2, the kidney and the emergence of COVID-19 two decades after ACE2 discovery. Clinical science (London, England : 1979) 16 33135725
2025 A MERS-CoV-like mink coronavirus uses ACE2 as an entry receptor. Nature 15 40306315
2023 Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies. Nature microbiology 15 37188812