ECE1

Summary

ECE1 (endothelin converting enzyme 1, HGNC:3146) is a protein-coding gene on chromosome 1p36.12, encoding Endothelin-converting enzyme 1 (P42892). Converts big endothelin-1 to endothelin-1.

The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 1889 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hirschsprung disease, cardiac defects, and autonomic dysfunction (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 179 total — 1 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3146
Approved symbol	ECE1
Name	endothelin converting enzyme 1
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000117298
Ensembl biotype	protein_coding
OMIM	600423
Entrez	1889

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000264205, ENST00000357071, ENST00000374893, ENST00000415912, ENST00000436918, ENST00000463334, ENST00000470394, ENST00000473505, ENST00000481130, ENST00000526194, ENST00000527991, ENST00000528294, ENST00000531334, ENST00000649812

RefSeq mRNA: 4 — MANE Select: NM_001397 NM_001113347, NM_001113348, NM_001113349, NM_001397

CCDS: CCDS215, CCDS44081, CCDS44082, CCDS44083

Canonical transcript exons

ENST00000374893 — 19 exons

Exon	Start	End
ENSE00000874517	21227931	21228041
ENSE00000874518	21227159	21227226
ENSE00000874519	21225250	21225440
ENSE00000874520	21221747	21221842
ENSE00001694132	21233558	21233661
ENSE00001878452	21217250	21220131
ENSE00002301044	21290364	21290463
ENSE00003487916	21236746	21236844
ENSE00003489510	21247221	21247363
ENSE00003506015	21260271	21260392
ENSE00003511904	21257525	21257590
ENSE00003541965	21238134	21238244
ENSE00003544184	21255947	21256138
ENSE00003560100	21244989	21245103
ENSE00003662858	21235850	21235927
ENSE00003669083	21272699	21272911
ENSE00003681056	21279191	21279332
ENSE00003688268	21258693	21258839
ENSE00003759046	21290070	21290156

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.8186 / max 2316.9694, expressed in 1802 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10844	38.4321	1735
10828	13.7985	1548
10827	4.0942	1009
10820	2.3809	392
10830	1.9630	184
10821	1.0698	261
10847	0.9426	602
10822	0.4128	148
10825	0.2601	111
10831	0.2180	59

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.32	gold quality
adrenal tissue	UBERON:0018303	97.64	gold quality
left adrenal gland cortex	UBERON:0035825	97.50	gold quality
left adrenal gland	UBERON:0001234	97.49	gold quality
right adrenal gland	UBERON:0001233	97.31	gold quality
popliteal artery	UBERON:0002250	97.30	gold quality
adrenal gland	UBERON:0002369	97.30	gold quality
tibial artery	UBERON:0007610	97.30	gold quality
adrenal cortex	UBERON:0001235	97.21	gold quality
right adrenal gland cortex	UBERON:0035827	97.16	gold quality
right lung	UBERON:0002167	97.07	gold quality
right coronary artery	UBERON:0001625	96.89	gold quality
mucosa of stomach	UBERON:0001199	96.76	gold quality
endocervix	UBERON:0000458	96.66	gold quality
left ovary	UBERON:0002119	96.63	gold quality
islet of Langerhans	UBERON:0000006	96.34	gold quality
body of pancreas	UBERON:0001150	96.18	gold quality
left coronary artery	UBERON:0001626	96.17	gold quality
aorta	UBERON:0000947	96.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.12	gold quality
coronary artery	UBERON:0001621	95.93	gold quality
right atrium auricular region	UBERON:0006631	95.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.92	gold quality
right ovary	UBERON:0002118	95.89	gold quality
upper lobe of left lung	UBERON:0008952	95.82	gold quality
sural nerve	UBERON:0015488	95.82	gold quality
omental fat pad	UBERON:0010414	95.76	gold quality
peritoneum	UBERON:0002358	95.71	gold quality
tibial nerve	UBERON:0001323	95.64	gold quality
nerve	UBERON:0001021	95.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F2, ETS1, KDM5D, STAT3

miRNA regulators (miRDB)

80 targeting ECE1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4319	99.76	69.83	2586

Literature-anchored findings (GeneRIF, showing 40)

• ECE-1alpha is expressed at significant levels in various types of human skin cells (including keratinocytes) and that it plays a constitutive role in the processing and UVB-inducible secretion of ET-1 by human keratinocytes (PMID:11723113)
• Toward an optimal joint recognition of the S1’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). (PMID:11906289)
• identification of potential residues involved in phosphorylation (PMID:12244060)
• Data demonstrate that the targeting signals specific for endothelin-converting enzyme 1b constitute a regulatory domain that could modulate the localization and the activity of other isoforms. (PMID:12393864)
• ECE1 has a role in limiting Abeta accumulation in the mouse brain (PMID:12464614)
• It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE. (PMID:12609744)
• Cis-acting elements bind CAAT-box binding protein NF-YB, GATA-2, E2F-2, and a GC-box binding factor associated with transcriptional start sites of ECE-1c. Three polymorphic dinucleotide repeats. Methylation suppressed ECE-1c promoter in endothelium. (PMID:14597855)
• The main isoform to increase in response to high glucose was ECE-1c and it may be one of the factors contributing to the elevated ET-1 peptide levels observed in diabetes. (PMID:15010576)
• This EVA-based study suggests that ECE1 interacts with ET1 to influence blood pressure in women. (PMID:15126915)
• Neuronal ECE-1 expression was observed in various cortical regions of nondemented subjects. In a case-control study involving patients with late-onset AD, homozygous carriers of the A allele of ECE1 gene had a reduced risk of AD. (PMID:15340356)
• locally synthesized AII could be one of the mediators involved in the down-regulation of ECE-1 (PMID:15665524)
• ECE-1 protein expression, prepro-endothelin-1 mRNA, and endothelin-1 peptide release were increased in response to native LDL or oxidized LDL. (PMID:16023075)
• Observations strongly suggest that the expression of ECE is enhanced in neointimal smooth muscle cells at early stages after percutaneous coronary intervention injury in human coronary arteries. (PMID:16531800)
• increased neuronal PKCepsilon activity can promote Abeta clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity (PMID:16698938)
• These findings suggest that endothelin-converting enzyme (ECE) is upregulated in the neointima at early stages after percutaneous coronary intervension (PCI) injury. ECE may be one of the mediators in the repair processes after PCI in humans. (PMID:16986361)
• Homozygous carriers of the ECE-1 -839G variant allele exhibited a decreased risk of coronary artery disease (PMID:17264805)
• Data show that CD133 and ECE expressions are associated with lymphoid metastasis and prognosis of NSCLC, and their overexpression often suggests unfavorable prognosis of NSCLC. (PMID:17545092)
• Endosomal peptidase ECE-1 degrades neuropeptides in endosomes to disrupt the peptide-receptor-beta-arrestin complex, thereby controlling postendocytic trafficking and signaling of receptors. (PMID:17592116)
• ECE-1b-338C to A variant might be associated with increased risk of CAD in Chinese population. (PMID:17618613)
• genotyped 5 single nucleotide polymorphisms in the ECE1 gene in 1,873 individuals from a general Japanese population and identified one associated with hypertension in women (PMID:17664854)
• Endothelin-1 and endothelin-converting enzyme-1 have roles in human granulomatous pathology of eyelid (PMID:17701914)
• Spacio-temporal expression of two endopeptidases, ECE-1 and NEP, involved in the synthesis and degradation of ET-1, might regulate ET-1 action in human endometrium. (PMID:17712175)
• Results show catalytically active ECE-1 was detected in the media of human umbilical vein endothelial cells, and was confirmed by mass spectrometry based assays. (PMID:17761169)
• A mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/beta-arrestin complex, freeing internalized receptors from beta-arrestins and promoting recycling and resensitization, is proposed. (PMID:18039931)
• A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years (PMID:18334739)
• Transient ECE-1c overexpression increased PC-3 invasiveness through matrigel, whereas transient ECE-1a expression suppressed invasion (PMID:18781169)
• Enhanced ECE-1 expression induced by hyperglycemia is partly due to activation of the PKC-delta isoform. Thus, inhibition of this PKC isoform may prevent diabetes-related increase in ET-1. (PMID:18974277)
• The crystal structure of the extracellular domain (residues 90-770) of human ECE-1 (C428S) with the generic metalloprotease inhibitor phosphoramidon determined at 2.38 A resolution. (PMID:18992253)
• By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK(1) receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. (PMID:19222484)
• C-338 polymorphism of the ECE1 gene might be associated with increased risk of carotid atherosclerosis in the Chinese population. (PMID:19289136)
• Endosomal endothelin-converting enzyme-1 is a regulator of beta-arrestin-dependent ERK signaling (PMID:19531493)
• study argues that the ECE1 338A allele is protective against late-onset Alzheimer disease in a Chinese population (PMID:20037208)
• any disease-specific contribution of ECE-1 to the accumulation of Abeta or reduction in local microvascular blood flow in Alzheimer disease or Vascular dementia is probably small. (PMID:20345647)
• These data indicate for the first time that PKC activation induces the trafficking and shedding of ECE to and from the cell surface, respectively. (PMID:20558134)
• ECE-1 is not correlated with amyloig beta or clinical diagnosis Alzheimer disease (PMID:20663017)
• ECE-1 influences prostate cancer cell invasion via both ET-1-mediated FAK phosphorylation and ET-1 independent mechanisms. (PMID:20725143)
• 4,4’-dihydroxy-trans-stilbene strongly inhibits ECE-1 activity, whereas resveratrol is inactive. (PMID:21554123)
• Our results point to a regulatory function of ET-1, its type B receptor (ET(B)) and endothelin-converting enzyme-1 proteins in transendothelial passage of monocytes (PMID:21777246)
• Results of this study suggest lack of direct correlation of Lys198Asn ET-1 and Thr341lle ECE-1 gene polymorphisms with risk of gestational hypertension and preeclampsia in the studied population of Polish women (PMID:21851036)
• Te results of this study suggested taht genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort. (PMID:22027013)

Cross-species orthologs

25 orthologs

Organism	Symbol	Gene ID
danio_rerio	ece1	ENSDARG00000061737
mus_musculus	Ece1	ENSMUSG00000057530
rattus_norvegicus	Ece1	ENSRNOG00000014241
drosophila_melanogaster	Nepl21	FBGN0027578
drosophila_melanogaster	Nep3	FBGN0031081
drosophila_melanogaster	Nepl3	FBGN0031678
drosophila_melanogaster	Nepl12	FBGN0037727
drosophila_melanogaster	Nep4	FBGN0038818
drosophila_melanogaster	Nepl15	FBGN0039024
drosophila_melanogaster	Nep7	FBGN0039564
drosophila_melanogaster	Nepl18	FBGN0039611
drosophila_melanogaster	Nepl19	FBGN0039612
drosophila_melanogaster	Nepl20	FBGN0039613
caenorhabditis_elegans		WBGENE00013785
caenorhabditis_elegans		WBGENE00013786
caenorhabditis_elegans		WBGENE00013926
caenorhabditis_elegans		WBGENE00016778
caenorhabditis_elegans		WBGENE00016896
caenorhabditis_elegans		WBGENE00017550
caenorhabditis_elegans		WBGENE00017553
caenorhabditis_elegans		WBGENE00017554
caenorhabditis_elegans		WBGENE00017555
caenorhabditis_elegans		WBGENE00018196
caenorhabditis_elegans		WBGENE00018227
caenorhabditis_elegans		WBGENE00020293

Paralogs (6): PHEX (ENSG00000102174), MMEL1 (ENSG00000142606), ECE2 (ENSG00000145194), ECEL1 (ENSG00000171551), MME (ENSG00000196549), KEL (ENSG00000197993)

Protein

Protein identifiers

Endothelin-converting enzyme 1 — P42892 (reviewed: P42892)

All UniProt accessions (6): A0A3B3ISF9, B4DKB2, E9PHZ1, E9PJG1, E9PN99, P42892

UniProt curated annotations — full annotation on UniProt →

Function. Converts big endothelin-1 to endothelin-1.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with PPP1R16B. Interacts with TSPAN8; this interaction recruits the endothelin converting enzyme ECE1 to tetraspanin-enriched microdomains and positively modulates its enzymatic activity.

Subcellular location. Cell membrane.

Tissue specificity. All isoforms are expressed in umbilical vein endothelial cells, polynuclear neutrophils, fibroblasts, atrium cardiomyocytes and ventricles. Isoforms A, B and C are also expressed in placenta, lung, heart, adrenal gland and phaeochromocytoma; isoforms A and C in liver, testis and small intestine; isoform B, C and D in endothelial cells and umbilical vein smooth muscle cells; isoforms C and D in saphenous vein cells, and isoform C in kidney.

Disease relevance. Hirschsprung disease, cardiac defects, and autonomic dysfunction (HCAD) [MIM:613870] A disorder characterized by skip-lesions Hirschsprung disease, craniofacial abnormalities and other dysmorphic features, cardiac defects including ductus arteriosus, small subaortic ventricular septal defect, small atrial septal defect, and autonomic dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by phosphoramidon. Activated by K49-P1-20, a twenty-residue synthetic peptide shortened from the snake B.asper myotoxin II.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M13 family.

Isoforms (4)

UniProt ID	Names	Canonical?
P42892-1	B	yes
P42892-2	A
P42892-3	C
P42892-4	D

RefSeq proteins (4): NP_001106818, NP_001106819, NP_001106820, NP_001388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000718	Peptidase_M13	Family
IPR008753	Peptidase_M13_N	Domain
IPR018497	Peptidase_M13_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR042089	Peptidase_M13_dom_2	Homologous_superfamily

Pfam: PF01431, PF05649

Enzyme classification (BRENDA):

• EC 3.4.24.71 — endothelin-converting enzyme 1 (BRENDA: 7 organisms, 68 substrates, 197 inhibitors, 13 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BIG ENDOTHELIN-1	0.0002–0.0483	7
AMYLOID BETA 40	0.0164–0.0239	2
BIG ENDOTHELIN-3	0.0001–0.0003	2
(7-METHOXYCOUMARIN-4-YL)ACETYL-ARG-PRO-PRO-GLY-P	0.0046	1
BIG ENDOTHELIN-2	0.0005	1

UniProt features (84 total): helix 34, strand 12, glycosylation site 10, turn 6, disulfide bond 5, splice variant 3, binding site 3, topological domain 2, sequence variant 2, active site 2, chain 1, modified residue 1, transmembrane region 1, mutagenesis site 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3DWB	X-RAY DIFFRACTION	2.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42892-F1	91.16	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 608; 671 (proton donor)

Ligand- & substrate-binding residues (3): 607; 611; 667

Post-translational modifications (1): 25

Disulfide bonds (5): 99–104, 122–755, 130–715, 185–435, 644–767

Glycosylation sites (10): 166, 187, 210, 270, 316, 362, 383, 539, 632, 651

Mutagenesis-validated functional residues (1):

Position	Phenotype
428	abolishes dimerization.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors

MSigDB gene sets: 431 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOCC_VACUOLAR_MEMBRANE, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, XU_HGF_SIGNALING_NOT_VIA_AKT1_48HR_UP

GO Biological Process (25): positive regulation of receptor recycling (GO:0001921), regulation of systemic arterial blood pressure by endothelin (GO:0003100), G protein-coupled receptor signaling pathway (GO:0007186), heart development (GO:0007507), substance P catabolic process (GO:0010814), bradykinin catabolic process (GO:0010815), calcitonin catabolic process (GO:0010816), protein processing (GO:0016485), peptide hormone processing (GO:0016486), regulation of vasoconstriction (GO:0019229), endothelin maturation (GO:0034959), embryonic heart tube development (GO:0035050), hormone catabolic process (GO:0042447), embryonic digit morphogenesis (GO:0042733), ear development (GO:0043583), pharyngeal system development (GO:0060037), axonogenesis involved in innervation (GO:0060385), sympathetic neuron axon guidance (GO:0097492), semaphorin-plexin signaling pathway involved in axon guidance (GO:1902287), proteolysis (GO:0006508), signal transduction (GO:0007165), axon guidance (GO:0007411), anatomical structure morphogenesis (GO:0009653), gene expression (GO:0010467), neuron projection development (GO:0031175)

GO Molecular Function (10): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), peptide hormone binding (GO:0017046), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): lysosomal membrane (GO:0005765), endosome (GO:0005768), early endosome (GO:0005769), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), endosome membrane (GO:0010008), membrane (GO:0016020), vesicle (GO:0031982), Weibel-Palade body (GO:0033093), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catabolic process	2
hormone metabolic process	2
axon guidance	2
peptidase activity	2
endosome	2
cellular anatomical structure	2
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
regulation of systemic arterial blood pressure by hormone	1
G protein-coupled receptor activity	1
signal transduction	1
animal organ development	1
circulatory system development	1
neuropeptide catabolic process	1
hormone catabolic process	1
proteolysis	1
protein maturation	1
signaling receptor ligand precursor processing	1
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
regulation of systemic arterial blood pressure by endothelin	1
peptide hormone processing	1
heart development	1
tube development	1
embryonic organ development	1
epithelium development	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
sensory organ development	1
chordate embryonic development	1
system development	1
axonogenesis	1
innervation	1
semaphorin-plexin signaling pathway	1
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1

Protein interactions and networks

STRING

1046 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ECE1	EDN1	P05305	939
ECE1	EDN3	P14138	936
ECE1	EDNRA	P25101	917
ECE1	EDNRB	P24530	906
ECE1	EDN2	P20800	847
ECE1	IDE	P14735	823
ECE1	APP	P05067	692
ECE1	ACE	P12821	672
ECE1	REN	P00797	579
ECE1	GNRH1	P01148	567
ECE1	PTGIS	Q16647	562
ECE1	PIP	P12273	548
ECE1	GFRA1	P56159	536
ECE1	PRKCE	Q02156	532
ECE1	AGT	P01019	517

IntAct

112 interactions, top by confidence:

A	B	Type	Score
CLK2	ECE1	psi-mi:“MI:0915”(physical association)	0.720
ECE1	CLK2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
LRRC32	SMPD2	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
	ECE1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	ECE1	psi-mi:“MI:0915”(physical association)	0.560
ECE1		psi-mi:“MI:0915”(physical association)	0.560
ECE1	KRTAP10-5	psi-mi:“MI:0915”(physical association)	0.560
ECE1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	ECE1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	ECE1	psi-mi:“MI:0915”(physical association)	0.560
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
NPB	CST4	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530

BioGRID (158): ECE1 (Two-hybrid), KRTAP10-1 (Two-hybrid), KRTAP10-5 (Two-hybrid), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Biochemical Activity), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Affinity Capture-MS), ECE1 (Two-hybrid)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391, Q8IS64, Q8T062, Q9JHL3, Q9JLI3, Q9JMI0, Q9W436, Q9W5Y0, W4VS99, P23276, Q9EQF2, P19621, A5PK19, A5WVX1, P0DPD7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ETS1	“up-regulates quantity by expression”	ECE1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	13	4.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

179 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	100
Likely benign	30
Benign	14

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
9133	NM_001397.3(ECE1):c.2260C>T (p.Arg754Cys)	Pathogenic
1172769	NM_001397.3(ECE1):c.1966G>A (p.Gly656Arg)	Likely pathogenic
599418	NM_001397.3(ECE1):c.1067T>G (p.Phe356Cys)	Likely pathogenic
599419	NM_001397.3(ECE1):c.1879C>T (p.Arg627Trp)	Likely pathogenic

SpliceAI

3186 predictions. Top by Δscore:

Variant	Effect	Δscore
1:21221742:CTCA:C	donor_loss	1.0000
1:21221743:TCA:T	donor_loss	1.0000
1:21221744:CA:C	donor_loss	1.0000
1:21221745:A:AT	donor_loss	1.0000
1:21221746:C:A	donor_loss	1.0000
1:21221841:GCC:G	acceptor_loss	1.0000
1:21221842:CCT:C	acceptor_loss	1.0000
1:21221843:C:CC	acceptor_gain	1.0000
1:21221843:CTGGG:C	acceptor_loss	1.0000
1:21225244:TCTCA:T	donor_loss	1.0000
1:21225245:CTCA:C	donor_loss	1.0000
1:21225246:TCACC:T	donor_loss	1.0000
1:21225247:CA:C	donor_loss	1.0000
1:21225248:A:AC	donor_gain	1.0000
1:21225248:A:C	donor_loss	1.0000
1:21225248:AC:A	donor_gain	1.0000
1:21225249:C:CC	donor_gain	1.0000
1:21225249:C:G	donor_loss	1.0000
1:21225249:CC:C	donor_gain	1.0000
1:21225264:TGAG:T	donor_gain	1.0000
1:21225436:CCGTC:C	acceptor_gain	1.0000
1:21225437:CGTC:C	acceptor_gain	1.0000
1:21225437:CGTCC:C	acceptor_gain	1.0000
1:21225439:TC:T	acceptor_gain	1.0000
1:21225439:TCCTG:T	acceptor_loss	1.0000
1:21225440:CC:C	acceptor_gain	1.0000
1:21225440:CCT:C	acceptor_loss	1.0000
1:21225441:C:CA	acceptor_loss	1.0000
1:21225441:C:CC	acceptor_gain	1.0000
1:21225442:T:G	acceptor_loss	1.0000

AlphaMissense

5098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:21225286:G:C	N668K	1.000
1:21225286:G:T	N668K	1.000
1:21227177:G:C	H611D	1.000
1:21227964:A:G	L583P	1.000
1:21227971:C:A	G581W	1.000
1:21228038:C:A	W558C	1.000
1:21228038:C:G	W558C	1.000
1:21228040:A:G	W558R	1.000
1:21228040:A:T	W558R	1.000
1:21235902:C:T	G505E	1.000
1:21236782:C:A	W484C	1.000
1:21236782:C:G	W484C	1.000
1:21236784:A:G	W484R	1.000
1:21236784:A:T	W484R	1.000
1:21238218:G:C	C435W	1.000
1:21238219:C:G	C435S	1.000
1:21238219:C:T	C435Y	1.000
1:21238220:A:G	C435R	1.000
1:21238220:A:T	C435S	1.000
1:21238227:C:A	W432C	1.000
1:21238227:C:G	W432C	1.000
1:21272803:C:T	C130Y	1.000
1:21220069:G:C	S733R	0.999
1:21220069:G:T	S733R	0.999
1:21220071:T:G	S733R	0.999
1:21220074:G:C	H732D	0.999
1:21220123:G:C	C715W	0.999
1:21220124:C:G	C715S	0.999
1:21220124:C:T	C715Y	0.999
1:21220125:A:G	C715R	0.999

dbSNP variants (sampled 300 via entrez): RS1000028387 (1:21234725 C>A,T), RS1000080400 (1:21234968 A>T), RS1000082917 (1:21336191 G>A,T), RS1000094481 (1:21288876 G>A), RS1000095013 (1:21295992 A>G), RS1000146650 (1:21274012 A>G), RS1000167862 (1:21256452 A>G), RS1000170024 (1:21310932 C>A), RS1000177154 (1:21258295 T>C), RS1000221770 (1:21218312 G>T), RS1000235193 (1:21285445 T>A,C), RS1000256460 (1:21244343 G>A), RS1000274632 (1:21324288 C>T), RS1000305896 (1:21261900 A>G), RS1000322112 (1:21240198 A>T)

Disease associations

OMIM: gene MIM:600423 | disease phenotypes: MIM:613870, MIM:145500, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
Hirschsprung disease, cardiac defects, and autonomic dysfunction	Limited	Autosomal dominant
essential hypertension, genetic	No Known Disease Relationship	Unknown

Mondo (3): Hirschsprung disease, cardiac defects, and autonomic dysfunction (MONDO:0013473), essential hypertension, genetic (MONDO:0007781), Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000358	Posteriorly rotated ears
HP:0000378	Cupped ear
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000713	Agitation
HP:0000822	Hypertension
HP:0001182	Tapered finger
HP:0001371	Flexion contracture
HP:0001426	Non-Mendelian inheritance
HP:0001510	Growth delay
HP:0001531	Failure to thrive in infancy
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001649	Tachycardia
HP:0001795	Hyperconvex nail
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002133	Status epilepticus
HP:0002251	Aganglionic megacolon
HP:0003196	Short nose
HP:0003270	Abdominal distention
HP:0003577	Congenital onset
HP:0004322	Short stature

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001762_455	Obesity-related traits	6.000000e-06
GCST002647_6	Height	5.000000e-12
GCST006950_43	Feeling worry	3.000000e-08
GCST007565_22	Morning person	3.000000e-18
GCST008152_124	Weight	5.000000e-06
GCST008158_73	Body mass index	1.000000e-06
GCST008158_80	Body mass index	1.000000e-06
GCST008600_4	Longevity (age >90th survival percentile)	2.000000e-07
GCST010989_168	Body size at age 10	1.000000e-09
GCST90000025_903	Appendicular lean mass	4.000000e-29

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009589	worry measurement
EFO:0008328	chronotype measurement
EFO:0004338	body weight
EFO:0004340	body mass index
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
C563939	Hirschsprung Disease, Cardiac Defects, and Autonomic Dysfunction (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4791 (SINGLE PROTEIN), CHEMBL5465380 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 91,089 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200976	IDARUBICIN HYDROCHLORIDE	4	26,567
CHEMBL4084119	LIRAGLUTIDE	4	10,473
CHEMBL2354444	PIRARUBICIN	3	50,520
CHEMBL42583	SAMPATRILAT	2	3,529

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M13: Neprilysin

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
SM19712	Inhibition	7.38	pIC50
compound 22 [PMID: 19899765]	Inhibition	5.92	pKi
KC-12615	Inhibition	5.8	pIC50
PD159790	Inhibition	5.64	pKi

Binding affinities (BindingDB)

1 measured of 2 human assays (31 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
SM19712	IC50	5 nM

ChEMBL bioactivities

398 potent at pChembl≥5 of 430 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL66284
9.70	IC50	0.2	nM	CHEMBL66967
9.60	IC50	0.25	nM	CHEMBL303159
9.10	IC50	0.8	nM	PHOSPHORAMIDON
8.92	IC50	1.2	nM	CHEMBL63317
8.92	Ki	1.2	nM	CHEMBL571153
8.59	IC50	2.6	nM	CHEMBL147964
8.52	IC50	3	nM	CHEMBL304939
8.32	IC50	4.8	nM	CHEMBL303892
8.22	IC50	6	nM	CHEMBL148056
8.19	IC50	6.4	nM	CHEMBL147157
8.17	IC50	6.8	nM	CHEMBL67000
8.16	IC50	6.9	nM	CHEMBL191879
8.11	Ki	7.7	nM	CHEMBL567628
8.10	IC50	8	nM	KELATORPHAN
8.10	IC50	8	nM	THIORPHAN
8.10	IC50	8	nM	CHEMBL147847
8.10	Ki	8	nM	CHEMBL577754
8.02	IC50	9.5	nM	CHEMBL317472
8.01	IC50	9.795	nM	CHEMBL102527
8.01	IC50	9.8	nM	CHEMBL102527
8.00	Ki	10	nM	CHEMBL60439
8.00	Ki	10	nM	CHEMBL305388
7.98	IC50	10.4	nM	CHEMBL194651
7.97	Ki	10.8	nM	CHEMBL285619
7.96	IC50	11	nM	CHEMBL293024
7.96	IC50	11	nM	CHEMBL292748
7.96	IC50	11	nM	CHEMBL2372437
7.96	IC50	11.02	nM	CHEMBL2297562
7.96	IC50	10.99	nM	CHEMBL2297552
7.92	IC50	12	nM	CHEMBL367315
7.89	IC50	13	nM	CHEMBL357226
7.89	IC50	13	nM	CHEMBL37052
7.85	IC50	14	nM	CHEMBL359024
7.85	Ki	14	nM	CHEMBL570953
7.85	Ki	14	nM	CHEMBL570843
7.85	IC50	14	nM	CHEMBL39828
7.80	IC50	16	nM	CHEMBL192441
7.77	IC50	17	nM	CHEMBL68128
7.77	IC50	17	nM	CHEMBL285619
7.77	IC50	17	nM	PHOSPHORAMIDON
7.77	IC50	17	nM	CHEMBL10251
7.75	Ki	18	nM	CHEMBL301646
7.72	IC50	19	nM	CHEMBL61269
7.72	IC50	19.01	nM	CHEMBL2297556
7.72	IC50	19	nM	CHEMBL423751
7.66	Ki	22	nM	CHEMBL305089
7.66	IC50	22	nM	CHEMBL146936
7.66	IC50	22	nM	CHEMBL342962
7.64	IC50	23.01	nM	CHEMBL319463

PubChem BioAssay actives

324 with measured affinity, of 501 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[[2-(hydroxycarbamoyl)-3-methylbutanoyl]amino]propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	<0.0001	uM
2-[[2-(hydroxycarbamoyl)-3-methylbutanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0002	uM
2-[[2-(hydroxycarbamoyl)-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0003	uM
(2S)-2-[[(2S)-2-[[hydroxy-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0008	uM
N-[1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-N’-hydroxy-2-propan-2-ylpropanediamide	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0012	uM
(2S)-2-[[2-benzyl-3-[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0012	uM
[1-[[(1S)-2-dibenzofuran-3-yl-1-(2H-tetrazol-5-yl)ethyl]amino]-3-naphthalen-1-ylpropyl]phosphonic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0026	uM
4-amino-2-[[2-(hydroxycarbamoyl)-3-methylbutanoyl]amino]-4-oxobutanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0030	uM
N-[1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-N’-hydroxy-2-(2-methylpropyl)propanediamide	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0048	uM
[[2-dibenzofuran-3-yl-1-(2H-tetrazol-5-yl)ethyl]amino]methylphosphonic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0060	uM
(2S)-3-dibenzofuran-3-yl-2-[[(2S)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoyl]amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0064	uM
2-[[2-(hydroxycarbamoyl)-3-methylbutanoyl]amino]acetic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0068	uM
2,3-dihydro-1,4-benzodioxin-5-yl (2S,4R)-4-acetylsulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-1-carboxylate	241703: Inhibitory concentration against human ECE-1 by RIA	ic50	0.0069	uM
(2S)-2-[[(2R)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-phenylpropanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0077	uM
(2S)-2-[[(2S)-2-[[(2S)-5-(2,4-difluorophenyl)-2-(phosphonomethylamino)pent-4-ynoyl]amino]-4-methylpentanoyl]amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0080	uM
(2S)-2-[[(2R)-2-benzyl-4-(hydroxyamino)-4-oxobutanoyl]amino]propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0080	uM
2-[(2-benzyl-3-sulfanylpropanoyl)amino]acetic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0080	uM
(2S)-2-[[(2R)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0080	uM
(2S)-2-[[1-[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]cyclopentanecarbonyl]amino]-3-(6-thiophen-2-yl-3-pyridinyl)propanoic acid	67195: In vitro inhibition of Endothelin-converting enzyme 1.	ic50	0.0095	uM
2-[[1-[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]cyclopentanecarbonyl]amino]-3-(6-thiophen-3-yl-3-pyridinyl)propanoic acid	67195: In vitro inhibition of Endothelin-converting enzyme 1.	ic50	0.0098	uM
(2S)-3-(1H-indol-3-yl)-2-[[(2R)-2-[(1R)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-3-sulfanylpropanoyl]amino]propanoic acid	67039: In vitro inhibition of endothelin converting enzyme.	ki	0.0100	uM
(2S)-3-(1H-indol-3-yl)-2-[[(2R)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-3-sulfanylpropanoyl]amino]propanoic acid	254285: Inhibition constant against endothelin converting enzyme 1	ki	0.0100	uM
(3R)-5-[[(2,5-difluorophenyl)methylamino]methyl]-1-(5-propylpyrimidin-2-yl)pyrrolidine-3-thiol	241703: Inhibitory concentration against human ECE-1 by RIA	ic50	0.0104	uM
[3-naphthalen-1-yl-1-[[(1S)-2-(4-phenylphenyl)-1-(2H-tetrazol-5-yl)ethyl]amino]propyl]phosphonic acid	1798102: In Vitro Inhibition of NEP from Article 10.1021/jm0005454: “Toward an optimal joint recognition of the S1’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP).”	ki	0.0108	uM
(2S)-3-(4-phenylphenyl)-2-[[1-[[(2S)-2-sulfanylpentanoyl]amino]cyclopentanecarbonyl]amino]propanoic acid	67040: In vitro inhibitory activity was tested against Endothelin converting enzyme 1	ic50	0.0110	uM
(2S)-2-[[1-[[(2S)-3-methoxy-2-sulfanylpropanoyl]amino]cyclopentanecarbonyl]amino]-3-(4-phenylphenyl)propanoic acid	67042: In vitro inhibition of human Endothelin converting Enzyme-1 activity	ic50	0.0110	uM
(2S)-N-[(2S)-1-[(2-amino-2-oxoethyl)amino]-1-oxopropan-2-yl]-N’-hydroxy-2-(2-methylpropyl)propanediamide	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0110	uM
2-morpholin-4-ylchromen-4-one	241703: Inhibitory concentration against human ECE-1 by RIA	ic50	0.0120	uM
(2S)-2-[[(2S)-5-(2-fluorophenyl)-2-(phosphonomethylamino)pent-4-ynoyl]amino]-3-(4-phenylphenyl)propanoic acid	67199: Inhibitory activity was assessed on CHO cells expressing recombinant human Endothelin-converting enzyme 1 (ECE-1).	ic50	0.0130	uM
2-[[(2S)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoyl]amino]-4-methylpentanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0130	uM
(2S)-3-(4-hydroxyphenyl)-2-[[(2R)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]propanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0140	uM
(2S)-3-cyclohexyl-2-[[(2S)-5-(2,4-difluorophenyl)-2-(phosphonomethylamino)pent-4-ynoyl]amino]propanoic acid	67199: Inhibitory activity was assessed on CHO cells expressing recombinant human Endothelin-converting enzyme 1 (ECE-1).	ic50	0.0140	uM
(2S)-3-dibenzofuran-3-yl-2-[(1-phosphono-3-quinolin-8-ylpropyl)amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0140	uM
(2S)-2-[[2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0140	uM
propan-2-yl (4R)-2-[[(2,5-difluorophenyl)methylamino]methyl]-4-sulfanylpyrrolidine-1-carboxylate	241703: Inhibitory concentration against human ECE-1 by RIA	ic50	0.0160	uM
2-[[4-(hydroxyamino)-4-oxo-2-propan-2-ylbutanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	67194: Inhibitory activity against human bronchiolar smooth muscle Endothelin-converting enzyme 1	ic50	0.0170	uM
(2S)-2-[[(2R)-2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-3-sulfanylpropanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	67039: In vitro inhibition of endothelin converting enzyme.	ki	0.0180	uM
(2S)-2-[[1-[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]cyclopentanecarbonyl]amino]-3-(4-phenylphenyl)propanoic acid	67042: In vitro inhibition of human Endothelin converting Enzyme-1 activity	ic50	0.0190	uM
(2S)-3-dibenzofuran-3-yl-2-[[3-(2,3-dimethoxyphenyl)-1-phosphonopropyl]amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0190	uM
3-(1H-indol-3-yl)-2-[[2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-3-sulfanylpropanoyl]amino]propanoic acid	67039: In vitro inhibition of endothelin converting enzyme.	ki	0.0220	uM
(2S)-3-dibenzofuran-3-yl-2-[[1-phosphono-3-(3,4,5-trimethoxyphenyl)propyl]amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0220	uM
(2S)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0220	uM
2-[[1-[[(2S)-3-cyclohexyl-2-sulfanylpropanoyl]amino]cyclopentanecarbonyl]amino]-3-(6-thiophen-3-yl-3-pyridinyl)propanoic acid	67195: In vitro inhibition of Endothelin-converting enzyme 1.	ic50	0.0230	uM
2-[[(2S)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoyl]amino]-3-phenylpropanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0230	uM
2-[[1-[[(2S)-2-sulfanylhexanoyl]amino]cyclopentanecarbonyl]amino]-3-(6-thiophen-3-yl-3-pyridinyl)propanoic acid	67195: In vitro inhibition of Endothelin-converting enzyme 1.	ic50	0.0240	uM
(2S)-3-dibenzofuran-3-yl-2-[(3-naphthalen-1-yl-1-phosphonopropyl)amino]propanoic acid	228593: In Vitro inhibition of recombinant human endothelin converting enzyme-1	ic50	0.0240	uM
(2S)-2-[[(2S)-5-(2-fluorophenyl)-2-(phosphonomethylamino)pent-4-ynoyl]amino]-3-naphthalen-2-ylpropanoic acid	67199: Inhibitory activity was assessed on CHO cells expressing recombinant human Endothelin-converting enzyme 1 (ECE-1).	ic50	0.0250	uM
(2S)-2-[[(2R)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]-3-sulfanylpropanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1798102: In Vitro Inhibition of NEP from Article 10.1021/jm0005454: “Toward an optimal joint recognition of the S1’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP).”	ki	0.0260	uM
(2S)-2-[[(2S)-2-[[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444548: Inhibition of human somatic ECE1	ki	0.0260	uM
2-[[1-[[(2S)-2-sulfanylpentanoyl]amino]cyclopentanecarbonyl]amino]-3-(6-thiophen-3-yl-3-pyridinyl)propanoic acid	67195: In vitro inhibition of Endothelin-converting enzyme 1.	ic50	0.0270	uM

CTD chemical–gene interactions

66 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression	6
Benzo(a)pyrene	affects cotreatment, affects expression, increases methylation, affects methylation	3
Estradiol	increases expression, decreases reaction	3
Fulvestrant	decreases expression, affects cotreatment, increases methylation	2
Acetaminophen	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
benzo(b)fluoranthene	affects cotreatment, affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
deoxynivalenol	decreases expression	1
fluoranthene	affects cotreatment, affects expression	1
4,4’-dihydroxystilbene	decreases expression, decreases activity	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
1-methylphenanthrene	affects cotreatment, affects expression	1
dibenzo(a,l)pyrene	affects cotreatment, affects expression	1
epigallocatechin gallate	increases expression, affects cotreatment	1
CGS 26303	decreases activity	1
entinostat	increases expression	1

ChEMBL screening assays

80 unique, capped per target: 78 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011713	Binding	Inhibition of ECE-1 at 10 uM	Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors. — Bioorg Med Chem
CHEMBL4617715	ADMET	Inhibition of mammalian ECE-1 (unknown origin) using MCA-RPPGFSAFK(DNP)-OH as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins	Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases. — J Med Chem
CHEMBL676082	Functional	Concentration required to inhibit conversion of big Endothelin-converting enzyme to Endothelin-converting enzyme after deprotection and purification by reverse-phase HPLC	Synthesis of a phostone glycomimetic of the endothelin converting enzyme inhibitor phosphoramidon. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6JA	U-87MG ATCC ECE1 KO	Cancer cell line	Male
CVCL_D1S8	Abcam U-87MG ECE1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

53 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00671684	PHASE1/PHASE2	UNKNOWN	Endoscopic Mucosal Resection (EMR) for Diagnosis of Hirschsprung’s Disease
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03406741	Not specified	COMPLETED	Neuropsychological Development and Functional Outcome Sin Children With Hirschsprung Disease at School Age
NCT03626350	Not specified	ACTIVE_NOT_RECRUITING	Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04713085	Not specified	COMPLETED	Sacral Neuromodulation in Children and Adolescents
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies