Affinage

ACE

Angiotensin-converting enzyme · UniProt P12821

Round 2 corrected
Length
1306 aa
Mass
149.7 kDa
Annotated
2026-04-28
130 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACE is a membrane-bound zinc dipeptidyl carboxypeptidase that converts angiotensin I to angiotensin II and inactivates bradykinin, thereby serving as a central regulator of the renin–angiotensin and kallikrein–kinin systems (PMID:4322742, PMID:15283675). The somatic enzyme contains two homologous catalytic domains (N and C), each bearing a zinc-coordinating HEXXH motif and requiring chloride for activation; the C-domain preferentially hydrolyzes angiotensin I, whereas the N-domain exhibits high selectivity for the hemoregulatory peptide AcSDKP, and both domains cooperate in degrading amyloid-β peptides (PMID:1851160, PMID:7876104, PMID:16154999). A testis-specific isoform corresponding to the C-domain alone is transcribed from an alternative promoter in spermatids (PMID:2554286). Beyond its classical vascular role, myeloid ACE expression defines an antimicrobial macrophage subset that restricts intracellular Salmonella and attenuates atherosclerosis, linking ACE to innate immune function (PMID:31615657, PMID:36608122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1970 High

    Establishing ACE's core enzymatic identity as a dipeptidyl carboxypeptidase resolved how angiotensin I is activated and bradykinin inactivated in a single catalytic step.

    Evidence In vitro enzymatic assay with purified enzyme measuring C-terminal dipeptide release

    PMID:4322742

    Open questions at the time
    • Structural basis of substrate recognition unknown
    • Number and independence of catalytic sites not yet established
  2. 1984 High

    Demonstration that ACE also cleaves neuropeptides (substance P, neurotensin) in a chloride-dependent manner broadened its substrate repertoire beyond the renin–angiotensin system and identified an essential active-site arginine residue.

    Evidence In vitro enzymatic assay with purified human ACE; HPLC product analysis; chemical modification of arginine

    PMID:6208535

    Open questions at the time
    • No three-dimensional structure to explain chloride activation mechanism
    • Physiological significance of neuropeptide cleavage not demonstrated in vivo
  3. 1988 High

    Cloning of full-length somatic ACE cDNA revealed the two-domain architecture arising from gene duplication, each carrying an HEXXH zinc-binding motif, fundamentally reframing ACE as a tandem metallopeptidase.

    Evidence cDNA cloning and sequencing from human vascular endothelial cells

    PMID:2849100

    Open questions at the time
    • Catalytic independence of the two domains not yet proven
    • Whether the testis-specific transcript encodes a single-domain enzyme unclear
  4. 1989 High

    Cloning of testicular ACE showed it corresponds to the C-domain alone, transcribed from an alternative promoter, proving the C-domain is independently catalytically sufficient.

    Evidence cDNA cloning and sequencing of human testicular ACE; sequence comparison with somatic isoform

    PMID:2554286

    Open questions at the time
    • Functional role of tACE in fertilization not established
    • Substrate preferences of isolated C-domain vs. full-length enzyme unknown
  5. 1991 High

    Site-directed mutagenesis demonstrated that both N- and C-domains are independently active, each requiring its own zinc-binding histidines and catalytic glutamate, and that the two domains differ in chloride sensitivity and kinetic parameters.

    Evidence Site-directed mutagenesis of active-site residues in each domain; expression in CHO cells; enzymatic assay

    PMID:1851160

    Open questions at the time
    • Structural basis for differential chloride activation not resolved
    • Whether negative cooperativity between domains occurs with physiological substrates unknown
  6. 1995 High

    Identifying AcSDKP as a highly N-domain-selective substrate established the first clear functional distinction between the two active sites, linking the N-domain specifically to hematopoietic stem cell regulation.

    Evidence In vitro kinetic assay using wild-type and single-active-site mutant ACE; domain-specific antibody inhibition

    PMID:7876104

    Open questions at the time
    • In vivo significance of N-domain AcSDKP hydrolysis not directly tested
    • Whether other N-domain-selective substrates exist is unknown
  7. 2001 High

    Showing that ACE degrades amyloid-β peptide at a defined cleavage site and inhibits Aβ aggregation expanded ACE's roles to neurodegeneration-relevant biology.

    Evidence In vitro cleavage with purified ACE; HPLC, MALDI-TOF/MS product identification; EM fibril assay; cytotoxicity assay

    PMID:11604391

    Open questions at the time
    • In vivo relevance in brain parenchyma not established
    • Relative contribution of N- vs. C-domain to Aβ degradation unknown at this point
  8. 2003 High

    The 2.0 Å crystal structure of tACE–lisinopril complex revealed an unexpected fold related to neurolysin rather than carboxypeptidase A, providing the structural basis for inhibitor binding and rational domain-selective inhibitor design.

    Evidence X-ray crystallography at 2.0 Å resolution of human tACE in complex with lisinopril

    PMID:12540854

    Open questions at the time
    • N-domain crystal structure not yet determined
    • Structural explanation for negative cooperativity between domains still missing
  9. 2004 High

    Comprehensive kinetic profiling of both ACE domains, ACE2, and neprilysin with angiotensin peptides established quantitative substrate preferences and demonstrated negative cooperativity between the two ACE active sites, clarifying the enzyme's role in the angiotensin cascade relative to ACE2.

    Evidence In vitro kinetics with active-site-titrated purified enzymes; fluorogenic substrate assays

    PMID:15283675

    Open questions at the time
    • Molecular mechanism of negative cooperativity not structurally defined
    • In vivo contributions of each domain to angiotensin processing not separated
  10. 2005 High

    Demonstrating that both ACE domains contribute to Aβ degradation in living cells, and that pharmacological ACE inhibition causes Aβ accumulation, established a cell-biological context for ACE's amyloidolytic activity.

    Evidence Active-site mutagenesis; Aβ accumulation assay in neuroblastoma cells expressing APP; captopril treatment

    PMID:16154999

    Open questions at the time
    • No in vivo brain model confirming ACE-dependent Aβ clearance
    • Relative importance of ACE vs. other Aβ-degrading enzymes not quantified
  11. 2008 Medium

    Discovery that the bradykinin B2 receptor physically interacts with ACE and enhances its catalytic activity introduced receptor-mediated allosteric regulation of ACE, validated by B2 receptor knockout endothelial cells.

    Evidence Co-expression in CHO cells; fluorescent ACE activity assay; B2 receptor antagonist; B2 receptor KO mouse endothelial cells

    PMID:18212275

    Open questions at the time
    • No direct structural evidence of ACE–B2 receptor complex
    • Stoichiometry and binding interface unknown
    • Not independently replicated
  12. 2014 Medium

    Covalent homocysteinylation of ACE by homocysteine metabolites was shown to enhance ACE activity and promote angiotensin II–NADPH oxidase–superoxide-mediated endothelial dysfunction, providing a molecular link between hyperhomocysteinemia and vascular disease.

    Evidence In vitro modification of purified ACE with Hcy metabolites; isolated artery vascular function studies with pharmacological inhibitors

    PMID:25416191

    Open questions at the time
    • Specific modified residues not identified
    • In vivo demonstration of homocysteinylated ACE in hyperhomocysteinemia not provided
    • Single study without independent replication
  13. 2016 Medium

    Genetic epistasis in C. elegans placed the ACE ortholog acn-1 in a daf-16/FOXO-dependent longevity pathway distinct from caloric restriction and mitochondrial insufficiency, extending ACE biology to aging regulation.

    Evidence C. elegans RNAi; captopril treatment; lifespan assay; double mutant epistasis analysis

    PMID:26918946

    Open questions at the time
    • Whether mammalian ACE similarly regulates lifespan is untested
    • Substrate(s) of acn-1 mediating longevity are unidentified
    • Catalytic vs. non-catalytic roles of acn-1 not distinguished
  14. 2019 Medium

    Myeloid-specific ACE overexpression was shown to be atheroprotective in ApoE-deficient mice through bone marrow transplantation, establishing a cell-autonomous role for macrophage ACE in limiting atherosclerosis.

    Evidence ACE10 transgenic mice crossed with ApoE−/−; bone marrow transplantation; atherogenic diet; plaque quantification

    PMID:31615657

    Open questions at the time
    • Downstream effector peptides or substrates in macrophages not identified
    • Whether N-domain, C-domain, or both mediate the atheroprotective effect is unknown
    • Single study without independent replication
  15. 2023 Medium

    Single-cell transcriptomics identified ACE as a marker of a distinct antimicrobial macrophage subset in granulomas that restricts intracellular Salmonella, with TNF signaling maintaining this population, linking ACE to innate immune defense.

    Evidence scRNA-seq; flow cytometry; S. Typhimurium mouse infection model; TNF neutralization

    PMID:36608122

    Open questions at the time
    • Whether ACE enzymatic activity is required for the antimicrobial phenotype is untested
    • Mechanism by which ACE+ macrophages restrict bacteria is unknown
    • Not replicated in human infection settings

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of inter-domain negative cooperativity in full-length somatic ACE, the identity of ACE substrates mediating macrophage antimicrobial and atheroprotective functions, and whether ACE regulates mammalian lifespan through a FOXO-dependent pathway as suggested by the C. elegans ortholog.
  • Full-length somatic ACE crystal structure with both domains resolved is lacking
  • Macrophage-specific ACE substrates not identified
  • Mammalian aging phenotype of ACE modulation not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 6
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 2
Partners
AGTBDKRB2

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1970 ACE (angiotensin-converting enzyme) functions as a dipeptidyl carboxypeptidase that converts angiotensin I to angiotensin II and inactivates bradykinin by cleaving C-terminal dipeptides. In vitro enzymatic assay with purified enzyme Biochimica et biophysica acta High 4322742
1984 Purified human ACE cleaves substance P at Phe8-Gly9 and Gly9-Leu10 (releasing C-terminal tri- and dipeptides in ~4:1 ratio) and cleaves neurotensin at Tyr11-Ile12; hydrolysis is Cl⁻-dependent, inhibited by captopril, and requires an active-site arginine residue (modification of Arg abolishes hydrolysis of substance P, bradykinin, and Bz-Gly-Phe-Arg by 80–93%). In vitro enzymatic assay with purified ACE; HPLC analysis; chemical modification of active-site arginine Peptides High 6208535
1988 Molecular cloning of human ACE cDNA revealed the enzyme contains 1306 residues with a signal peptide, a C-terminal membrane anchor, and two large homologous domains arising from gene duplication, each bearing a putative zinc metallopeptidase active site (HEXXH motif). A shorter testis-specific 3.0 kb transcript was also detected. Molecular cloning and cDNA sequencing of human vascular endothelial cell ACE mRNA Proceedings of the National Academy of Sciences of the United States of America High 2849100
1989 Human testicular ACE (tACE) is identical to the C-terminal half (second domain) of somatic endothelial ACE, containing only the second putative metal-binding site (His-Glu-Met-Gly-His), and is encoded by a distinct shorter mRNA with a unique 5' region generated by an alternative promoter. This established that the C-terminal domain of somatic ACE contains a functionally active catalytic site. cDNA cloning and sequencing of human testicular ACE; comparison with somatic ACE sequence Proceedings of the National Academy of Sciences of the United States of America High 2554286
1991 Both the N-terminal and C-terminal domains of somatic ACE are independently catalytically active and each requires zinc; both are activated by chloride and are inhibited by competitive ACE inhibitors. The two domains display different catalytic constants and different patterns of chloride activation, with the C domain hydrolyzing substrates faster than the N domain at high chloride. His-361/365 (N domain) and His-959/963 (C domain) are essential for activity (zinc binding), and Glu-362 (N domain) and Glu-960 (C domain) are essential catalytic residues. Site-directed mutagenesis of each domain's active site residues; expression in CHO cells; enzymatic assay with Hip-His-Leu and angiotensin I as substrates The Journal of biological chemistry High 1851160
1995 The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), a negative regulator of hematopoietic stem cell proliferation, is a highly specific natural substrate of the N-terminal active site of ACE. The N-active site hydrolyzes AcSDKP ~50-fold faster than the C-active site (kcat/Km: 0.5 vs 0.01 µM⁻¹·s⁻¹). This was confirmed using mutant ACE proteins with a single functional domain and a domain-specific monoclonal antibody. In vitro enzymatic assay using wild-type and single-active-site mutant recombinant ACE; inhibition with domain-specific monoclonal antibody The Journal of biological chemistry High 7876104
1999 ACE isoform expression in the testis is developmentally regulated: the testicular isoform (tACE) is expressed in spermatids and spermatozoa but not in normal spermatogonia or spermatocytes, whereas in neoplastic germ cells (intratubular germ cell neoplasm, seminomas) and fetal germ cells, the somatic ACE isoform (sACE) is expressed instead, suggesting that neoplastic germ cells recapitulate a fetal pattern of ACE expression. RT-PCR on laser-captured individual cell populations; immunohistochemistry with isoform-specific antibodies on human testicular tissues Laboratory investigation; a journal of technical methods and pathology Medium 10576213
2000 ACE2, the first human homologue of ACE, was identified from a heart failure ventricle cDNA library. ACE2 contains a single metalloprotease active site and functions as a carboxypeptidase that cleaves the C-terminal leucine from angiotensin I to generate angiotensin 1-9, and also cleaves des-Arg bradykinin and neurotensin, but not bradykinin itself. ACE2 is not inhibited by lisinopril or captopril, distinguishing it enzymatically from ACE. ACE generates angiotensin II from angiotensin 1-9 in vitro and in cardiomyocyte culture. ACE2 protein is predominantly found in coronary and intrarenal vascular endothelium and renal tubular epithelium. cDNA cloning; recombinant protein expression; enzymatic assay with angiotensin peptides; immunohistochemistry Circulation research High 10969042
2000 A human ACE homolog (ACEH/ACE2) with 40% identity and 61% similarity to human ACE was identified. It contains a single HEXXH zinc-binding domain and functions exclusively as a carboxypeptidase, cleaving single residues from angiotensin I and angiotensin II but not bradykinin or Hip-His-Leu. ACEH activity is inhibited by EDTA but not by captopril, lisinopril, or enalaprilat. Active ACEH is secreted from cells by cleavage N-terminal to the transmembrane domain. cDNA cloning; heterologous expression in CHO cells; enzymatic assay with multiple substrates; inhibitor testing The Journal of biological chemistry High 10924499
2001 Purified ACE degrades amyloid beta-peptide Aβ(1-40) by cleaving at the Asp7-Ser8 bond, generating Aβ(1-7) and Aβ(8-40), fragments with reduced aggregation and cytotoxicity. ACE also inhibits Aβ aggregation and fibril formation in a dose-dependent, lisinopril-inhibitable manner, and reduces Aβ deposition and Aβ-induced PC12 cytotoxicity in vitro. In vitro enzymatic assay; reverse-phase HPLC; amino acid sequencing; MALDI-TOF/MS; electron microscopy; cytotoxicity assay The Journal of biological chemistry High 11604391
2002 ACE inhibitors at nanomolar concentrations directly activate the bradykinin B1 receptor independently of ACE and in the absence of peptide ligands. This activation is mediated by the HEXXH zinc-binding motif (residues 195–199) in the B1 receptor's extracellular domain; site-directed mutagenesis of H195 to alanine abolished activation by ACE inhibitors but not by the peptide ligand. ACE inhibitor-induced B1 activation elevates intracellular calcium and releases NO from cultured cells. Cell-based calcium signaling assay; NO measurement; site-directed mutagenesis of B1 receptor H195; peptide competition experiments International immunopharmacology Medium 12489793
2003 Crystal structure of human testicular ACE (tACE) in complex with lisinopril at 2.0 Å resolution revealed that ACE bears little structural similarity to carboxypeptidase A despite prior mechanistic assumptions, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase. The structure shows lisinopril coordinating the active-site zinc and forming hydrogen bonds with key residues, explaining high-affinity inhibition and providing a template for domain-selective inhibitor design. X-ray crystallography at 2.0 Å resolution of human tACE-lisinopril complex Nature High 12540854
2004 Kinetic characterization of full-length human ACE, its separate N- and C-domains, ACE2, and neprilysin (NEP) showed: (1) Angiotensin I is effectively cleaved by NEP (kcat/Km 6.2×10⁵ M⁻¹s⁻¹) but is a poor substrate for ACE2 (kcat/Km 3.3×10⁴ M⁻¹s⁻¹); (2) Angiotensin II is cleaved efficiently by ACE2 to Ang(1-7) (kcat/Km 2.2×10⁶ M⁻¹s⁻¹); (3) Angiotensin(1-7) is cleaved with similar efficiency by both N- and C-domains of ACE; (4) The two active sites of ACE exhibit negative cooperativity when Ang I or Ang(1-7) is substrate; (5) ACE inhibitors do not inhibit ACE2. In vitro enzymatic kinetics using active-site-titrated enzyme preparations and fluorogenic substrates; inhibitor testing The Biochemical journal High 15283675
2004 In mice with 1, 2, or 3 genomic copies of the ACE gene, higher ACE gene dosage (3-copy mice) conferred resistance to high-fat diet-induced weight gain and increased peri-epididymal adipose tissue independently of angiotensin II AT1 receptor signaling. Mass spectrometry identified ACE substrates in adipose tissue including peptides (LVVYPWTQRY, VVYPWTQRY) that inhibited protein kinase C phosphorylation in vitro, suggesting ACE influences body weight via generation of oligopeptides that modulate adipose tissue enzymes. ACE gene copy number mouse model; high-fat diet metabolic phenotyping; AT1 blocker treatment; affinity-based substrate isolation with catalytically inactive EP24.15; LC-ESI-MS/MS peptide identification; in vitro PKC assay Physiological genomics Medium 15522949
2005 Cellular ACE expressed in human neuroblastoma cells promotes degradation of naturally secreted Aβ40 and Aβ42. Both N- and C-terminal active sites contribute to Aβ clearance, as an ACE construct bearing inactivating mutations in each catalytic domain had no effect on Aβ levels. Pharmacological inhibition of ACE with captopril promoted accumulation of cell-derived Aβ in media, demonstrating that ACE activity is required for Aβ degradation in living cells. Cloning of ACE from human neuroblastoma cells; site-directed mutagenesis of both active sites; Aβ accumulation assay in Aβ precursor protein-expressing cells; captopril treatment The Journal of biological chemistry High 16154999
2008 ACE enzymatic activity is modulated by its physical interaction with the kinin B2 receptor. Co-expression of somatic ACE with the kinin B2 receptor in CHO cells increased ACE catalytic activity, and this effect was blocked by the B2 receptor antagonist icatibant. Endothelial cells from B2 receptor knockout mice showed decreased ACE activity compared to wild-type cells, confirming the interaction in a physiological context. Co-expression in CHO cells; fluorescent substrate-based ACE activity assay; B2 receptor antagonist pharmacology; endothelial cells from B2 receptor KO mice Hypertension (Dallas, Tex. : 1979) Medium 18212275
2009 ACE activities (both ACE1 and ACE2) are present in porcine ocular tissues including vitreous body, retina, and ciliary body. ACE1 activity was markedly higher in ciliary body than retina, while ACE2 activities were comparable across tissues. ACE-inhibitory tripeptides (Ile-Pro-Pro, Val-Pro-Pro, Leu-Pro-Pro) inhibited ACE1 at ~1/1000th the concentration required to inhibit ACE2, demonstrating distinct pharmacological profiles for the two enzymes in ocular tissue. Fluorometric enzymatic activity assays on porcine ocular tissue fractions; inhibitor concentration-response studies Journal of ocular pharmacology and therapeutics Medium 19232015
2014 Homocysteine (Hcy) metabolites (Hcy-S-S-Hcy and Hcy thiolactone) directly homocysteinylate ACE protein via covalent modification of amino and/or sulfhydryl moieties, resulting in enhanced ACE enzymatic activity. In vitro exposure of purified ACE to these metabolites produced homocysteinylated ACE and increased ACE activity. In isolated coronary and mesenteric arteries exposed to Hcy metabolites or incubated with methionine, ACE activity was similarly enhanced, promoting angiotensin II–NADPH oxidase–superoxide-mediated endothelial dysfunction. In vitro incubation of purified ACE with Hcy metabolites; activity assay; isolated artery vascular function studies; NADPH oxidase inhibitor and AT1 receptor blocker pharmacology American journal of physiology. Heart and circulatory physiology Medium 25416191
2016 In C. elegans, reducing activity of acn-1 (the C. elegans ACE homolog) extended mean lifespan, delayed age-related degeneration, and increased stress resistance. The lifespan extension by captopril (an ACE inhibitor) required acn-1 and could not further extend lifespan of acn-1-reduced animals, placing captopril and acn-1 in the same pathway. The ACE/acn-1 longevity pathway is additive with caloric restriction and mitochondrial insufficiency, does not require sir-2.1, hsf-1, or rict-1, but requires daf-16 (FOXO transcription factor). C. elegans genetic epistasis analysis; RNAi knockdown; pharmacological treatment with captopril; lifespan assay; stress resistance assay; double mutant analysis PLoS genetics Medium 26918946
2019 Myeloid-specific overexpression of ACE (in ACE10 mice) paradoxically reduced atherosclerotic plaque formation in ApoE-deficient mice fed an atherogenic diet, demonstrating that enhanced macrophage ACE expression is protective against atherosclerosis. Bone marrow transplantation experiments confirmed the effect was hematopoietic cell-autonomous: recipients of ACE10 bone marrow had significantly reduced lesion areas, while ACE-deficient bone marrow had no impact. Transgenic mouse model (ACE10 myeloid ACE overexpression) crossed with ApoE-/- mice; bone marrow transplantation; atherogenic diet; plaque area quantification Biochemical and biophysical research communications Medium 31615657
2022 Radiation exposure increased ACE activity specifically in lung immune cells (myeloid cells) and promoted generation of reactive oxygen species (ROS) via NADPH oxidase 2 in human monocytes. ACE inhibition with lisinopril blocked radiation-induced ACE activity increases, ROS generation, and reduced ACE-expressing CD11b+ myeloid cell frequency in the lung. In vitro, radiation-induced ROS was blocked by inhibition of either NADPH oxidase 2 or the AT1 receptor, placing ACE upstream of the AT1/NADPH oxidase 2/ROS axis. Rat partial body irradiation and fractionated radiotherapy models; flow cytometry; in vitro human monocyte radiation experiments; NADPH oxidase inhibitor; AT1 receptor blocker; lisinopril treatment; BAL fluid cytokine analysis International journal of radiation oncology, biology, physics Medium 35093482
2023 ACE (angiotensin-converting enzyme) defines a subset of granuloma macrophages that are nonpermissive for intracellular Salmonella Typhimurium. ACE+ macrophages in infected mouse spleens are functionally distinct from ACE- macrophage populations; their abundance anticorrelates with tissue bacterial burden. TNF neutralization preferentially depleted ACE+ macrophages, linking TNF signaling to maintenance of this antimicrobial macrophage population. Single-cell RNA sequencing; flow cytometry sorting; S. Typhimurium infection mouse model; TNF neutralization experiment; spatial localization analysis Science advances Medium 36608122

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation research 2338 10969042
2012 A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of cell biology 1850 22412018
1992 Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1796 1328889
2004 Identification and proteomic profiling of exosomes in human urine. Proceedings of the National Academy of Sciences of the United States of America 1724 15326289
2000 A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. The Journal of biological chemistry 1641 10924499
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
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2011 Human metabolic individuality in biomedical and pharmaceutical research. Nature 801 21886157
1999 Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nature genetics 769 10391210
2006 mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes & development 735 16815998
1988 Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proceedings of the National Academy of Sciences of the United States of America 716 2849100
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS letters 609 12459472
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2003 Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 582 12540854
1970 A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochimica et biophysica acta 539 4322742
2004 Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. The Biochemical journal 483 15283675
1984 Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides 459 6208535
1992 Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. Nature genetics 384 1338766
2005 A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA (New York, N.Y.) 367 16177138
1999 Sequence variation in the human angiotensin converting enzyme. Nature genetics 357 10319862
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2005 Myocardial infarction increases ACE2 expression in rat and humans. European heart journal 346 15671045
1991 The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. The Journal of biological chemistry 338 1851160
2006 ACE polymorphisms. Circulation research 317 16690893
2004 Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Archives of neurology 313 15534175
2002 Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. American journal of respiratory and critical care medicine 307 12204859
2002 The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci. RNA (New York, N.Y.) 303 12515382
2001 Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. The Journal of biological chemistry 300 11604391
2004 Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 281 15023884
1995 The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensin-converting enzyme. The Journal of biological chemistry 275 7876104
1989 Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proceedings of the National Academy of Sciences of the United States of America 273 2554286
2005 Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. The Journal of biological chemistry 270 16154999
1988 ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene. Molecular and cellular biology 238 3043194
2014 CYP6 P450 enzymes and ACE-1 duplication produce extreme and multiple insecticide resistance in the malaria mosquito Anopheles gambiae. PLoS genetics 235 24651294
2005 The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules. Journal of cell science 233 15731006
2006 Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development. The Plant cell 220 17158604
2014 Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. The Cochrane database of systematic reviews 167 25148386
2003 The angiotensin converting enzyme (ACE). The international journal of biochemistry & cell biology 149 12676162
2002 The DEAD box protein Dhh1 stimulates the decapping enzyme Dcp1. The EMBO journal 147 12032091
2012 A direct interaction between DCP1 and XRN1 couples mRNA decapping to 5' exonucleolytic degradation. Nature structural & molecular biology 139 23142987
2020 A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance. British journal of pharmacology 126 32333398
1997 Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema. The British journal of dermatology 125 9068723
2008 Structural basis of dcp2 recognition and activation by dcp1. Molecular cell 115 18280239
1982 Angiotensin converting enzyme (ACE) inhibitors. Annual review of pharmacology and toxicology 114 6282189
2007 Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues. Blood 100 17993616
1991 A copper-thiolate polynuclear cluster in the ACE1 transcription factor. Proceedings of the National Academy of Sciences of the United States of America 98 2068093
2003 Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. Journal of cellular physiology 95 12767053
2009 Reinventing the ACE inhibitors: some old and new implications of ACE inhibition. Hypertension research : official journal of the Japanese Society of Hypertension 92 19911001
2012 Dehydration stress activates Arabidopsis MPK6 to signal DCP1 phosphorylation. The EMBO journal 86 22407295
1992 Cough and ACE inhibitors. Archives of internal medicine 76 1497404
2021 Angiotensin converting enzyme (ACE). Clinica chimica acta; international journal of clinical chemistry 75 34728179
2003 Angiotensin-converting enzyme (CD143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Experimental hematology 75 14662338
1989 Cooperative activation of a eukaryotic transcription factor: interaction between Cu(I) and yeast ACE1 protein. Proceedings of the National Academy of Sciences of the United States of America 75 2664778
1986 Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. Medical toxicology 75 3023783
2021 Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 73 33676010
2009 Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. Clinical and experimental pharmacology & physiology 72 19793108
1999 Screening of Zulu medicinal plants for angiotensin converting enzyme (ACE) inhibitors. Journal of ethnopharmacology 72 10624863
1992 Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update. Drug safety 72 1536695
2000 ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1. Kidney international 71 10620209
2000 The eukaryotic mRNA decapping protein Dcp1 interacts physically and functionally with the eIF4F translation initiation complex. The EMBO journal 70 10944120
2015 Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae. Chemical science 67 29142718
1990 Inhibition of angiotensin-converting enzyme (ACE) in plasma and tissue. Journal of cardiovascular pharmacology 67 1691409
2007 A divergent Sm fold in EDC3 proteins mediates DCP1 binding and P-body targeting. Molecular and cellular biology 65 17923697
2019 ACE inhibitor-mediated angioedema. International immunopharmacology 63 31835086
2005 Independent metalloregulation of Ace1 and Mac1 in Saccharomyces cerevisiae. Eukaryotic cell 62 16278453
2006 Expression of Magnaporthe grisea avirulence gene ACE1 is connected to the initiation of appressorium-mediated penetration. Eukaryotic cell 57 17142568
2005 Caenorhabditis elegans decapping proteins: localization and functional analysis of Dcp1, Dcp2, and DcpS during embryogenesis. Molecular biology of the cell 57 16207815
2009 Activities of angiotensin-converting enzymes ACE1 and ACE2 and inhibition by bioactive peptides in porcine ocular tissues. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 55 19232015
1993 Clinical pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors in renal failure. Clinical pharmacokinetics 55 8462229
2012 Angiotensin-converting enzyme (CD143) specifies emerging lympho-hematopoietic progenitors in the human embryo. Blood 54 22282502
2004 The ectopeptidases CD10, CD13, CD26, and CD143 are upregulated in gastric cancer. International journal of oncology 53 15492809
2009 RNAi of ace1 and ace2 in Blattella germanica reveals their differential contribution to acetylcholinesterase activity and sensitivity to insecticides. Insect biochemistry and molecular biology 50 19900550
2007 Demystifying the ACE polymorphism: from genetics to biology. Current pharmaceutical design 50 17504229
1990 The DNA and Cu binding functions of ACE1 are interdigitated within a single domain. The New biologist 50 2088504
2023 Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1. Cancer communications (London, England) 49 37533188
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