Affinage

ECE2

Endothelin-converting enzyme 2 · UniProt P0DPD6

Length
811 aa
Mass
91.2 kDa
Annotated
2026-06-09
93 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ECE2 is an intracellular, acidic-pH-optimum (pH 5.5), phosphoramidon-sensitive zinc metalloprotease of the neprilysin-related family that processes endothelin precursors and a broad set of neuropeptides at non-classical cleavage sites within secretory and endolysosomal compartments (PMID:7797512, PMID:12560336, PMID:10222335). It converts big ET-1 to mature ET-1 by cleavage at Trp21-Val22 intracellularly rather than at the cell surface, and exists as multiple N-terminally distinct sub-isoforms with tissue-specific distributions that all localize to intracellular compartments (PMID:7797512, PMID:10222335, PMID:12054617). A neprilysin-based homology model and site-directed mutagenesis identify Tyr563 as a catalytic-site residue critical for activity and inhibitor binding (PMID:18507370). ECE2 resides in endosomal/lysosomal and autophagic vesicles, where it degrades intracellular pools of the amyloid-β peptide and α-synuclein; loss of ECE2 raises brain Aβ40 and Aβ42 and elevates α-synuclein, and ECE2 is dysregulated in Alzheimer's disease and dementia-with-Lewy-bodies brain tissue (PMID:12464614, PMID:23283972, PMID:28171705, PMID:19541930). In the nervous system ECE2 is enriched in somatostatin-expressing GABAergic interneurons and acts at synapses, shaping spinal-cord neuropeptide content and supporting learning and memory (PMID:21450041, PMID:21972895, PMID:27644077). Through post-endocytic hydrolysis of co-internalized peptide agonists, ECE2 regulates the recycling and resensitization of µ, δ, and κ opioid receptors in a substrate-specific manner, influencing opioid antinociception and morphine tolerance in vivo (PMID:24990314, PMID:24847082, PMID:21972895, PMID:41205376). ECE2 is also required for endothelin-ligand activation driving cardiac endocardial cushion/valve development, pigment-cell development, melanoma phenotype switching, and cortical neurogenesis and neuronal migration, the last linked to periventricular heterotopia caused by biallelic ECE2 variants (PMID:10811845, PMID:28181494, PMID:24857848, PMID:32207244). Rare peptidase-domain coding variants that impair Aβ-degrading activity, together with rescue of amyloid load and memory deficits by wild-type but not catalytically defective ECE2 in AD model mice, directly link ECE2 catalytic activity to Alzheimer's disease risk (PMID:32102983).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established ECE2 as a distinct endothelin-converting enzyme by showing it cleaves big ET-1 to ET-1 with an acidic pH optimum and acts intracellularly, distinguishing it from the neutral-pH, surface-acting ECE-1.

    Evidence In vitro enzymatic assay with inhibitor profiling and transfected CHO cell functional assay

    PMID:7797512

    Open questions at the time
    • Did not define the physiological compartment beyond trans-Golgi inference
    • Full substrate repertoire beyond big ET-1 unknown at this stage
  2. 1999 High

    Resolved where ECE2 acts by demonstrating it is intracellular rather than cell-surface, supporting a role in processing big ET-1 in transit through the secretory pathway.

    Evidence Sucrose-gradient subcellular fractionation, pH/inhibitor activity profiling, and confocal immunocytochemistry in HUVECs

    PMID:10222335

    Open questions at the time
    • Did not distinguish secretory vesicle from endosomal/lysosomal residence
    • Did not address non-endothelin substrates
  3. 2000 High

    Defined an in vivo developmental role by showing ECE2 contributes to cardiac endocardial cushion and valve formation, unmasked in the ECE-1 null background.

    Evidence Single and double knockout mice with genetic epistasis, in situ hybridization, and ET peptide immunoassay

    PMID:10811845

    Open questions at the time
    • ECE2 single knockouts are normal, leaving its independent requirement unclear
    • Molecular substrate driving the valve phenotype not pinpointed
  4. 2002 High

    Extended ECE2 function beyond endothelins by showing it physiologically limits brain Aβ accumulation and exists as tissue-specific sub-isoforms.

    Evidence Knockout mouse brain Aβ ELISA; RT-PCR and immunohistochemistry of isoforms in transfected cells

    PMID:12054617 PMID:12464614

    Open questions at the time
    • Direct enzymatic degradation of Aβ not yet shown
    • Functional consequence of isoform diversity unresolved
  5. 2003 High

    Characterized ECE2 as a non-classical neuropeptide-processing protease, cleaving at aliphatic/aromatic P1' residues across a 42-peptide panel including enkephalin-derived peptides and PEN-LEN.

    Evidence Purified recombinant enzyme with mass spectrometry-based substrate profiling

    PMID:12560336

    Open questions at the time
    • Which substrates are processed in vivo not established
    • Biological significance of altered peptide products not tested
  6. 2008 High

    Provided a structural and behavioral framework: an active-site model identified Tyr563 as catalytically important and selective inhibitors were derived, while knockout mice revealed learning and memory deficits; substrate boundaries were refined by showing somatostatin-14 is not a substrate.

    Evidence Neprilysin-based homology modeling with mutagenesis and virtual screening; behavioral testing of knockout mice; in vitro substrate assays with bafilomycin/SM-19712

    PMID:18276747 PMID:18507370 PMID:21450041

    Open questions at the time
    • No experimental crystal structure of ECE2
    • Molecular substrate linking ECE2 to memory not identified
    • SST-14 negative result limited to in vitro conditions
  7. 2010 High

    Built a selective toolkit by identifying an ECE2-specific fluorogenic substrate and a potent selective inhibitor, validated against knockout tissue.

    Evidence Fluorogenic substrate screening with kinetic characterization and ECE2 knockout tissue validation

    PMID:20807771

    Open questions at the time
    • Synthetic substrate does not identify endogenous physiological substrates
    • Inhibitor specificity in complex tissue not exhaustively profiled
  8. 2011 High

    Connected ECE2 to opioid pharmacology and in vivo neuropeptide homeostasis by showing knockouts have altered morphine responses and a shifted spinal-cord peptidome.

    Evidence Knockout mice with pain/tolerance/withdrawal assays and spinal-cord peptidomic mass spectrometry

    PMID:21972895

    Open questions at the time
    • Causal peptide substrates underlying morphine phenotypes not isolated
    • Did not separate direct opioid-peptide processing from broader peptidome changes
  9. 2013 High

    Refined ECE2's compartment to the endosomal-autophagic-lysosomal system, establishing it controls the intracellular Aβ pool distinct from ECE-1's broader action.

    Evidence Co-localization microscopy and pharmacological ECE inhibition in APP-overexpressing SH-SY5Y cells with Aβ ELISA

    PMID:23283972

    Open questions at the time
    • Pharmacological inhibition does not isolate ECE2 from ECE-1
    • Mechanism of Aβ entry into the degradative compartment not defined
  10. 2014 High

    Defined the mechanism of opioid receptor regulation as post-endocytic hydrolysis of co-internalized peptide agonists, controlling µ and δ receptor recycling and resensitization in a substrate-specific manner.

    Evidence Selective ECE2 inhibitors, receptor trafficking and cAMP assays, intracellular peptide degradation assays, primary neurons, and in vivo antinociception

    PMID:24847082 PMID:24990314

    Open questions at the time
    • Relied on pharmacological inhibition rather than genetic ablation in trafficking assays
    • Structural basis of ECE2-receptor proximity not resolved
  11. 2014 High

    Established that ECE2-mediated endothelin-ligand activation is required for pigment-cell development, identifying Edn3b as a processed ligand.

    Evidence Zebrafish forward genetics (kar mutant), morpholino knockdown, and genetic rescue

    PMID:24857848

    Open questions at the time
    • Direct biochemical cleavage of Edn3b by Ece2 not shown in this system
    • Relevance to mammalian pigment biology not addressed
  12. 2016 High

    Pinpointed the cellular source of ECE2 in the brain to somatostatin-expressing GABAergic interneurons and showed it is active at synapses, defining a cell-type context for Aβ degradation.

    Evidence In situ hybridization, cell-type-marker immunohistochemistry, and synaptosome enzymatic activity assays

    PMID:27644077

    Open questions at the time
    • Functional consequence of interneuron-specific Aβ degradation not tested
    • Did not establish synaptic substrate specificity
  13. 2017 High

    Broadened ECE2's degradative role to α-synuclein within the endolysosomal system and linked reduced ECE2 to Lewy body pathology; in cancer, ECE2-driven endothelin-3 production was shown to enable melanoma phenotype switching and metastasis.

    Evidence In vitro cleavage, siRNA knockdown, PLA co-localization, and postmortem ELISA for α-syn; CRISPR inactivation with live imaging in zebrafish melanoma

    PMID:28171705 PMID:28181494

    Open questions at the time
    • Whether ECE2 loss is cause or consequence of DLB pathology unresolved
    • Direct endothelin substrate in melanoma microenvironment not biochemically isolated
  14. 2020 High

    Causally tied ECE2 catalytic activity to Alzheimer's disease and identified a developmental neuronal-migration role, providing direct genetic links to human disease.

    Evidence Rare-variant identification with enzymatic assays and AAV wild-type vs. R186C rescue in APP-knockin mice; ECE2 manipulation in cerebral organoids and in utero electroporation with secretome proteomics, plus biallelic variants in periventricular heterotopia

    PMID:32102983 PMID:32207244

    Open questions at the time
    • Mechanism linking ECM/cytoskeleton effects to migration not fully dissected
    • Penetrance and full genetic spectrum of human variants not defined
  15. 2025 High

    Completed the opioid receptor regulatory model by showing ECE2 also controls κ opioid receptor trafficking through substrate-specific post-endocytic peptide processing.

    Evidence Proximity ligation assay, receptor internalization/recycling and cAMP assays with substrate-specificity controls in recombinant and endogenous cells

    PMID:41205376

    Open questions at the time
    • Single-lab pharmacological approach without genetic confirmation
    • In vivo consequences of KOR regulation not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ECE2's distinct functions — endothelin maturation, neuropeptide processing, Aβ/α-synuclein degradation, opioid receptor regulation, and cortical development — are partitioned across its sub-isoforms and subcellular compartments, and which substrates drive each in vivo phenotype, remains unresolved.
  • No experimental structure of ECE2
  • Isoform-specific functional assignments not established
  • Substrate-to-phenotype causality not mapped for most in vivo roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
OPRD1OPRK1OPRM1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ECE-2 is a membrane-bound, phosphoramidon-sensitive zinc metalloprotease that converts big ET-1 to mature ET-1 by cleavage at Trp21-Val22, with an acidic pH optimum of 5.5 (in contrast to ECE-1's neutral optimum). It is inhibited by phosphoramidon (250-fold more sensitive than ECE-1) and FR901533 but not by thiorphan or captopril. Transfection experiments in CHO cells showed it converts endogenously synthesized big ET-1 intracellularly but not exogenous big ET-1, indicating it acts as an intracellular enzyme in the trans-Golgi network. In vitro enzymatic assay, inhibitor profiling, transfected CHO cell functional assay The Journal of biological chemistry High 7797512
2000 ECE-2 knockout mice develop normally and are fertile, but when bred into an ECE-1 null background, cardiac outflow defects are more severe than in ECE-1 single knockouts, and ECE-1−/−;ECE-2−/− double-null embryos exhibit abnormal atrioventricular valve formation not seen in ECE-1 single knockouts. ECE-2 mRNA is expressed in endocardial cushion mesenchyme from E12.5. Together, this establishes ECE-2 has a role in murine cardiac development, particularly in endocardial cushion/valve formation. Homologous recombination knockout mice, genetic epistasis (double knockout), in situ hybridization, ET-1/ET-2 peptide measurement by immunoassay The Journal of clinical investigation High 10811845
2002 ECE-2 deficient mice show significant increases in both Aβ40 and Aβ42 levels in the brain compared to age-matched littermate controls, providing the first direct in vivo evidence that ECE-2 physiologically limits Aβ accumulation in the brain. ECE-2 knockout mouse model, brain Aβ measurement by ELISA/immunoassay The Journal of biological chemistry High 12464614
2003 Purified recombinant ECE-2 cleaves big ET-1 to ET-1 at Trp21-Val22 at acidic pH and processes a panel of 42 neuropeptides at non-classical (non-basic residue) sites, preferring aliphatic/aromatic residues in the P1' position. ECE-2 processes proenkephalin-derived peptides (bovine adrenal medulla peptides) and PEN-LEN (an endogenous inhibitor of prohormone convertase 1) into products with altered biological activity, indicating a role in non-classical neuropeptide processing. Purification of recombinant ECE-2, mass spectrometry-based substrate profiling with 42-peptide panel, in vitro enzymatic assay The Journal of biological chemistry High 12560336
1999 ECE-2 is localized intracellularly (not on the cell surface) in human umbilical vein endothelial cells. Using sucrose density gradient fractionation and pH/inhibitor profiling (sensitivity to 0.1 µM phosphoramidon at pH 5.4, IC50 1.5 nM; insensitive to ECE-1-selective inhibitor PD159790 at pH 5.4), ECE-2 activity was identified in intracellular fractions. Confocal microscopy showed punctate cytosolic staining consistent with secretory vesicles, suggesting a role in processing big ET-1 in transit via the constitutive secretory pathway. Subcellular fractionation (sucrose density gradient), pH-dependent enzymatic activity assay with selective inhibitors, confocal immunocytochemistry Circulation research High 10222335
2002 Four ECE-2 sub-isoforms (ECE-2a-1, ECE-2a-2, ECE-2b-1, ECE-2b-2) were identified that differ in their N-terminal cytoplasmic tails. RT-PCR showed strikingly different tissue distributions: ECE-2a-1 and ECE-2a-2 are expressed in liver, kidney, adrenal gland, testis, and endothelial cells, while ECE-2b-1 and ECE-2b-2 are enriched in brain and adrenal gland. Immunohistochemical analysis of CHO cells stably expressing ECE-2a-1 or ECE-2b-2 showed both isoforms localize to intracellular compartments, not the cell surface. RT-PCR, stable transfection of CHO cells, immunohistochemistry Biochemical and biophysical research communications Medium 12054617
2008 ECE-2 knockout mice show normal physical appearance and motor behavior but display significant deficits in learning and memory, including impaired performance in the Morris water maze, deficits in object recognition and location memory, and impaired social transmission of food preference. This establishes ECE-2 as required for normal learning and memory function in vivo. ECE-2 knockout mice, Morris water maze, novel object recognition, social transmission of food preference behavioral assays Genes, brain, and behavior High 21450041
2008 ECE-2 homology model based on neprilysin crystal structure was generated, and site-directed mutagenesis identified that Tyr563 in the catalytic site significantly affects catalytic activity and inhibitor binding, while Trp148 mutation had lesser effect. Virtual screening of 13,000 compounds using the model identified three compounds with high affinity and specificity for ECE-2 over neprilysin. Homology modeling using neprilysin crystal structure as template, site-directed mutagenesis, virtual screening, in vitro enzymatic inhibition assays Journal of medicinal chemistry High 18507370
2013 ECE-2 co-localizes with markers of the endosomal/lysosomal pathway (but not with a trans-Golgi network marker) and is detected in autophagic vesicles. Pharmacological inhibition of ECE activity in SH-SY5Y cells overexpressing APP leads to intracellular Aβ accumulation specifically in the endosomal-autophagic-lysosomal compartments. ECE-2 regulates mainly the intracellular pool of Aβ (produced and degraded within the endosomal-autophagic-lysosomal pathways), distinct from ECE-1 which regulates both intracellular and secreted Aβ pools. Co-localization immunofluorescence microscopy, pharmacological ECE inhibition in APP-overexpressing SH-SY5Y cells, Aβ measurement by ELISA The Journal of biological chemistry High 23283972
2014 ECE-2 inhibition with the selective inhibitor S136492 impairs µ opioid receptor recycling and resensitization specifically for ligands that are ECE2 substrates (endogenous opioid peptides), both in heterologous cells and cells endogenously co-expressing µ receptors with ECE2. In vivo, ECE2 inhibition attenuated antinociception mediated only by ECE2-substrate opioid peptides (intrathecal tail-flick assay). This establishes ECE2 as modulating µ opioid receptor function through post-endocytic processing of peptide agonists. Selective pharmacological ECE2 inhibition, µ opioid receptor trafficking assay (ELISA and microscopy), cAMP signaling assay, in vivo tail-flick antinociception assay British journal of pharmacology High 24990314
2014 ECE2 inhibition with selective inhibitors impairs δ opioid receptor recycling by protecting endocytosed peptide agonists from degradation, leading to decreased surface receptor signaling. ECE2 co-localizes intracellularly with δ opioid receptors following agonist treatment. In primary neurons, ECE2 inhibitor treatment increased intracellular co-localization of receptors with ECE2 and decreased recycling and surface receptor signaling. Selective ECE2 inhibitor treatment, δ opioid receptor trafficking assay (microscopy), intracellular peptide degradation assay (thin-layer chromatography), primary neuronal cultures The Journal of biological chemistry High 24847082
2010 An ECE-2-specific fluorogenic substrate (PL405; Ac-SKG-Pya-F-W-Nop-GGK-NH2) was identified; ECE-2 cleaves PL405 at the Pya-F amide bond with kcat/Km = 8.1 × 10³ M⁻¹ s⁻¹. The first potent and selective ECE-2 inhibitor was characterized (Ki = 7.7 nM). The assay was validated using wild-type and ECE-2 knockout tissues ex vivo, confirming it reflects ECE-2 expression patterns. Fluorogenic substrate screening (Fluofast library), in vitro enzymatic kinetics, ECE-2 knockout tissue validation The Journal of biological chemistry High 20807771
2011 ECE-2 knockout mice show decreased antinociceptive response to a single morphine injection and more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analysis of spinal cord revealed altered levels of multiple neuropeptides in ECE-2 KO mice compared to wild-type, consistent with ECE-2's role in non-classical in vivo spinal cord neuropeptide processing. ECE-2 knockout mice, hot-plate and tail-flick pain assays, naloxone-precipitated withdrawal, peptidomic mass spectrometry of spinal cord Journal of neurochemistry High 21972895
2016 ECE-2 is expressed predominantly in somatostatin-expressing GABAergic interneurons in hippocampus and neocortex (unlike ECE-1, which has broader distribution, and NEP, found in parvalbumin interneurons). ECE-2 was active in isolated synaptosomes, establishing that ECE-2 can degrade Aβ at inhibitory synapses relevant to Alzheimer's disease. In situ hybridization, immunohistochemistry with cell-type markers, synaptosome isolation and enzymatic activity assay Neurobiology of aging High 27644077
2017 ECE-1 and ECE-2 cleave and degrade α-synuclein in vitro. siRNA knockdown of ECE-1 or ECE-2 in SH-SY5Y cells significantly increased α-syn both intracellularly and extracellularly. ECE-2 co-localizes with α-syn within the endolysosomal system (confirmed by proximity ligation assay). ECE-2 levels are significantly reduced in postmortem cingulate cortex of dementia with Lewy bodies (DLB) patients and inversely correlate with severity of Lewy body pathology (α-syn phosphorylated at Ser129). In vitro enzymatic cleavage assay, siRNA knockdown, double immunofluorescence, proximity ligation assay, sandwich ELISA on postmortem tissue Journal of neurochemistry High 28171705
2017 CRISPR-mediated inactivation of ECE2 (the synthetic enzyme for EDN3) from the zebrafish microenvironment abrogates melanoma phenotype switching from invasive/MITF-low to proliferative/MITF-high state following extravasation, and increases animal survival. This establishes ECE2 as required for microenvironment-driven endothelin-3 production that promotes melanoma metastatic plasticity. CRISPR-mediated gene inactivation in zebrafish, live zebrafish imaging, melanoma phenotype switching assay Nature communications High 28181494
2014 Zebrafish karneol (kar) mutant, defective in ece2, displays reduced iridophore numbers and defects in adult pigment stripe patterning. Morpholino knockdown identified Endothelin 3b (Edn3b) as the ligand for endothelin receptor signaling in larval iridophores processed by Ece2, establishing that Ece2-mediated proteolytic activation of endothelin ligands is required for iridophore development and melanophore maintenance in zebrafish. Zebrafish forward genetics (kar mutant), morpholino-mediated knockdown, genetic rescue Biology open High 24857848
2020 ECE2 rare coding variants (R186C and F751S) located in the peptidase domain severely impair ECE2 enzymatic activity in Aβ degradation. Overexpression of wild-type ECE2 in the hippocampus of APP-knockin AD model mice reduced amyloid load, plaque formation, and improved learning and memory deficits, but the R186C mutant abolished these effects, directly linking ECE2 catalytic activity to Aβ clearance and AD-relevant phenotypes in vivo. Rare variant identification, in vitro enzymatic activity assay with Aβ substrate, stereotaxic AAV-mediated ECE2/R186C overexpression in APP-knockin mice, amyloid quantification, Morris water maze JCI insight High 32102983
2020 Manipulation of ECE2 levels in human cerebral organoids and in the developing mouse cortex leads to ectopic localization of neural progenitors and neurons. ECE2 is required for normal neurogenesis and neuronal migration during cortical development, and mechanistically is involved in the generation and secretion of extracellular matrix proteins as well as cytoskeleton and adhesion processes. Biallelic ECE2 variants were identified in patients with periventricular heterotopia. Human cerebral organoids (ECE2 manipulation), in utero electroporation in developing mouse cortex, proteomic/secretome analysis, immunostaining for ECE2 EMBO reports High 32207244
2025 ECE2 and κ opioid receptor (KOR) are in close proximity (demonstrated by proximity ligation assay) and co-internalize following activation by prodynorphin/proenkephalin-derived peptide substrates. ECE2 inhibition significantly attenuates KOR recycling and resensitization specifically for peptides that are ECE2 substrates but not for non-substrate peptides, establishing that ECE2 post-endocytically processes opioid peptides to regulate KOR trafficking and signaling. Proximity ligation assay, receptor internalization/recycling assay in recombinant and endogenously expressing cells, small molecule ECE2 inhibitor, cAMP signaling assay The Journal of pharmacology and experimental therapeutics High 41205376
2009 ECE-2 mRNA and protein are markedly elevated in postmortem temporal cortex in Alzheimer's disease (AD) but not in vascular dementia. Exposure of SH-SY5Y cells to monomeric or oligomeric Aβ(1-42) caused an initial decrease in ECE-2 mRNA at 4 hours followed by a marked increase by 24 hours, demonstrating that Aβ42 upregulates ECE-2 expression. Quantitative real-time PCR, sandwich ELISA on postmortem brain tissue, Aβ42 treatment of SH-SY5Y cells with ECE-2 mRNA measurement The American journal of pathology Medium 19541930
2008 ECE-1, but not ECE-2, cleaved somatostatin-14 (SST-14) in an acidic endosomal environment; ECE-2 did not hydrolyze SST-14 or octreotide. This negative result establishes substrate specificity boundaries: SST-14 is not an ECE-2 substrate. Pharmacological inhibition of ECE-1 with SM-19712, bafilomycin A1 to prevent endosomal acidification, radiolabeled substrate degradation assay Endocrinology Medium 18276747

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. The Journal of biological chemistry 391 7797512
2014 Mutational landscape of intrahepatic cholangiocarcinoma. Nature communications 353 25526346
1997 Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 344 9141502
2001 The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. BioEssays : news and reviews in molecular, cellular and developmental biology 334 11223883
2008 Abeta-degrading enzymes in Alzheimer's disease. Brain pathology (Zurich, Switzerland) 330 18363935
2002 Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. The Journal of biological chemistry 217 12464614
1996 Molecular pharmacology of endothelin converting enzymes. Biochemical pharmacology 200 8615890
1995 Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). The Journal of biological chemistry 186 8530372
2005 Abeta-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochemical Society transactions 180 16246055
2000 Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. The Journal of clinical investigation 149 10811845
2017 Microenvironment-derived factors driving metastatic plasticity in melanoma. Nature communications 120 28181494
2012 Endothelin-1 is elevated in Alzheimer's disease and upregulated by amyloid-β. Journal of Alzheimer's disease : JAD 107 22330820
2015 Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease. Brain pathology (Zurich, Switzerland) 100 26452729
2009 Endothelin-converting enzyme-2 is increased in Alzheimer's disease and up-regulated by Abeta. The American journal of pathology 96 19541930
2011 Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia 82 21826742
2013 The profibrotic role of endothelin-1: is the door still open for the treatment of fibrotic diseases? Life sciences 74 24378671
2006 Endothelin. Handbook of experimental pharmacology 74 16999223
2013 Endothelin-converting enzymes degrade intracellular β-amyloid produced within the endosomal/lysosomal pathway and autophagosomes. The Journal of biological chemistry 71 23283972
2003 Synthesis and degradation of endothelin-1. Canadian journal of physiology and pharmacology 68 12839262
2000 Molecular cloning and biochemical characterization of a new mouse testis soluble-zinc-metallopeptidase of the neprilysin family. The Biochemical journal 66 10749671
2017 Alizarin and Chrysazin Inhibit Biofilm and Hyphal Formation by Candida albicans. Frontiers in cellular and infection microbiology 62 29085811
1998 Purification of a novel endothelin-converting enzyme specific for big endothelin-3. FEBS letters 60 9654154
2013 Endothelin-converting enzyme-1 activity, endothelin-1 production, and free radical-dependent vasoconstriction in Alzheimer's disease. Journal of Alzheimer's disease : JAD 56 23629587
1996 The endothelins in the pulmonary system. Pulmonary pharmacology 53 8880948
2000 The neprilysin family in health and disease. Advances in experimental medicine and biology 52 10849750
2010 Endothelin receptor antagonists: potential in Alzheimer's disease. Pharmacological research 49 21193044
1997 Evidence of alternative promoters directing isoform-specific expression of human endothelin-converting enzyme-1 mRNA in cultured endothelial cells. Journal of molecular medicine (Berlin, Germany) 49 9253714
2020 ECE2 regulates neurogenesis and neuronal migration during human cortical development. EMBO reports 48 32207244
2017 Antibiofilm and Antihyphal Activities of Cedar Leaf Essential Oil, Camphor, and Fenchone Derivatives against Candida albicans. Frontiers in microbiology 48 28824600
2010 Transdifferentiation potentiality of human Wharton's jelly stem cells towards vascular endothelial cells. Journal of cellular physiology 47 20143331
2014 Endothelin signalling in iridophore development and stripe pattern formation of zebrafish. Biology open 45 24857848
2011 Expression pattern of endothelin system components and localization of smooth muscle cells in the human pre-ovulatory follicle. Human reproduction (Oxford, England) 45 21406445
2006 Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects. Hypertension (Dallas, Tex. : 1979) 45 16567585
2015 Inter- and intra-observer variability in the classification of extracapsular extension in p16 positive oropharyngeal squamous cell carcinoma nodal metastases. Oral oncology 44 26293844
1997 The endothelin system and endothelin-converting enzyme in the brain: molecular and cellular studies. Neurochemical research 44 9239759
2003 Characterization of endothelin-converting enzyme-2. Implication for a role in the nonclassical processing of regulatory peptides. The Journal of biological chemistry 43 12560336
2008 Animals lacking endothelin-converting enzyme-2 are deficient in learning and memory. Genes, brain, and behavior 39 21450041
2005 Endothelins in breast tumour cell invasion. Cancer letters 37 15863261
2007 Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension. Journal of human hypertension 36 17525706
1998 Soluble human endothelin-converting enzyme-1: expression, purification, and demonstration of pronounced pH sensitivity. Archives of biochemistry and biophysics 33 9808768
2010 Endothelin-converting enzyme-1 in Alzheimer's disease and vascular dementia. Neuropathology and applied neurobiology 32 20345647
2004 Endothelin axis expression is markedly different in the two main subtypes of renal cell carcinoma. Cancer 32 15139053
2010 Production and binding of endothelin-2 (EDN2) in the rat ovary: endothelin receptor subtype A (EDNRA)-mediated contraction. Reproduction, fertility, and development 31 20450830
2008 Endothelin-converting enzyme-1 degrades internalized somatostatin-14. Endocrinology 29 18276747
1999 Evidence for intracellular endothelin-converting enzyme-2 expression in cultured human vascular endothelial cells. Circulation research 29 10222335
1999 Cyclic expression of endothelin-converting enzyme-1 mediates the functional regulation of seminiferous tubule contraction. The Journal of cell biology 29 10352019
2016 Major amyloid-β-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex. Neurobiology of aging 28 27644077
1998 Physiologic shear stress suppresses endothelin-converting enzyme-1 expression in vascular endothelial cells. Journal of cardiovascular pharmacology 27 9595395
2000 Inhibitor potencies and substrate preference for endothelin-converting enzyme-1 are dramatically affected by pH. Journal of cardiovascular pharmacology 26 11078325
2000 Cellular expression of isoforms of endothelin-converting enzyme-1 (ECE-1c, ECE-1b and ECE-1a) and endothelin-converting enzyme-2. Journal of cardiovascular pharmacology 24 11078322
2020 Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene. JCI insight 22 32102983
2019 Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year. Epigenetics 22 31793401
2014 Endothelin-converting enzyme 2 differentially regulates opioid receptor activity. British journal of pharmacology 22 24990314
2002 Molecular isolation and characterization of novel four subisoforms of ECE-2. Biochemical and biophysical research communications 22 12054617
2005 Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells. Biochemical and biophysical research communications 21 16009335
2001 Human endothelin converting enzyme-2 (ECE2): characterization of mRNA species and chromosomal localization. Biochimica et biophysica acta 21 11718899
2014 Opioid receptor function is regulated by post-endocytic peptide processing. The Journal of biological chemistry 19 24847082
2016 Genome-Wide Mapping of Growth-Related Quantitative Trait Loci in Orange-Spotted Grouper (Epinephelus coioides) Using Double Digest Restriction-Site Associated DNA Sequencing (ddRADseq). International journal of molecular sciences 16 27058532
2009 Pathophysiology of the endothelin system - lessons from genetically manipulated animal models. European journal of medical research 16 19258203
1998 Endothelin peptide and converting enzymes in human endothelium. Journal of cardiovascular pharmacology 15 9595389
2008 Homology modeling and site-directed mutagenesis to identify selective inhibitors of endothelin-converting enzyme-2. Journal of medicinal chemistry 14 18507370
2016 GPER is required for the age-dependent upregulation of the myocardial endothelin system. Life sciences 13 26880534
2012 Genetic analysis of genes involved in amyloid-β degradation and clearance in Alzheimer's disease. Journal of Alzheimer's disease : JAD 12 22027013
2021 Identification of novel candidate genes for age at first calving in Nellore cows using a SNP chip specifically developed for Bos taurus indicus cattle. Theriogenology 11 34392169
2011 Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord. Journal of neurochemistry 11 21972895
2010 Transferase activity function and system development process are critical in cattle embryo development. Functional & integrative genomics 11 20844914
2017 A novel TCF7L2 type 2 diabetes SNP identified from fine mapping in African American women. PloS one 10 28253288
2005 Localization of endothelin-converting enzyme in bovine optic nerve and retina. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 10 16117692
2012 The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 9 22693153
2020 Ligand-specific recycling profiles determine distinct potential for chronic analgesic tolerance of delta-opioid receptor (DOPr) agonists. Journal of cellular and molecular medicine 8 32279433
2016 Endothelin as a local regulating factor in the bovine oviduct. Reproduction, fertility, and development 8 25370848
2014 Endothelin and vascular remodelling in colitis pathogenesis--appendicitis and appendectomy limit colitis by suppressing endothelin pathways. International journal of colorectal disease 8 25085204
2004 Endothelin converting enzyme-2: a processing enzyme involved in the generation of novel neuropeptides. Protein and peptide letters 8 15544567
2023 SNHG15 enhances cisplatin resistance in lung adenocarcinoma by affecting the DNA repair capacity of cancer cells. Diagnostic pathology 7 36864456
2011 The influence of tumour necrosis factor- α (TNF-α) on amyloid-β (Aβ)-degrading enzymes in vitro. International journal of molecular epidemiology and genetics 7 22200003
2006 Downregulation of renal endothelin-converting enzyme 2 expression in early autoimmune diabetes. Experimental biology and medicine (Maywood, N.J.) 7 16741043
2017 Endothelin-converting enzymes degrade α-synuclein and are reduced in dementia with Lewy bodies. Journal of neurochemistry 6 28171705
2010 Identification of an endothelin-converting enzyme-2-specific fluorigenic substrate and development of an in vitro and ex vivo enzymatic assay. The Journal of biological chemistry 6 20807771
2023 Anisomycin inhibits the activity of human ovarian cancer stem cells via regulating antisense RNA NCBP2-AS2/MEK/ERK/STAT3 signaling. The journal of gene medicine 4 37483091
2014 Transcriptional alterations of ET-1 axis and DNA damage in lung tissue of a rat obesity model. DNA and cell biology 4 25517973
2025 Novel Protective Role for Gut Microbiota-derived Metabolite PAGln in Doxorubicin-induced Cardiotoxicity. Cardiovascular drugs and therapy 3 39808382
2025 Mapping fatigue: discovering brain regions and genes linked to fatigue susceptibility. Journal of translational medicine 3 40055680
2017 Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1. Autoimmunity 3 28557628
2005 Characterization of endothelin-converting enzyme activities in ARPE-19 cells, a human retinal pigmented epithelial cell line. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 3 15969636
2025 Identification of ECE2 signaling in promoting non-small lung cancer progression through ET1/YAP1/MAGEA3 axis. Scientific reports 2 39955423
2023 Mutation analysis of the ECE1 gene in late-onset Alzheimer's disease. Neurobiology of aging 1 37271044
1990 Characterization of RD114-related endogenous cat retroviral elements ECE2. Archiv fur experimentelle Veterinarmedizin 1 2102652
2026 Lapatinib-Loaded Glucose-Functionalized Silver Nanoparticles Enhance Efficacy in HER2-Positive Breast Cancer Cells and Modulate Survival-Associated Genes. Pharmaceutical research 0 41741910
2025 Exploring the evolutionary conservation and functional implications of Endothelin Converting Enzyme 1 (ECE1) in lamprey (Lethenteron reissneri). Fish physiology and biochemistry 0 41099905
2025 Endothelin-converting enzyme 2 regulates κ opioid receptor trafficking and function. The Journal of pharmacology and experimental therapeutics 0 41205376
2024 Identification of potential differences in salivary proteomic profiles between estrus and diestrus stage of estrous cycle in dairy cows. Systems biology in reproductive medicine 0 39008339
2009 [Artificial endothelial cell. From stem cells to transdifferentiated endothelial cells]. Anales de la Real Academia Nacional de Medicina 0 20432672
2005 Histochemical distribution of endothelin-converting enzyme subtypes in Podarcis sicula (Squamata, Lacertidae) tissues. Journal of anatomy 0 16191167

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