ECHS1

Summary

ECHS1 (enoyl-CoA hydratase, short chain 1, HGNC:3151) is a protein-coding gene on chromosome 10q26.3, encoding Enoyl-CoA hydratase, mitochondrial (P30084). Converts unsaturated trans-2-enoyl-CoA species ((2E)-enoyl-CoA) to the corresponding (3S)-3hydroxyacyl-CoA species through addition of a water molecule to the double bond.

The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature.

Source: NCBI Gene 1892 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 408 total — 27 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_004092

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3151
Approved symbol	ECHS1
Name	enoyl-CoA hydratase, short chain 1
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	SCEH
Ensembl gene	ENSG00000127884
Ensembl biotype	protein_coding
OMIM	602292
Entrez	1892

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000368547, ENST00000857564, ENST00000857565, ENST00000857566, ENST00000857567, ENST00000857568, ENST00000857569, ENST00000857570, ENST00000857571, ENST00000857572, ENST00000857573, ENST00000857574, ENST00000935006, ENST00000935007, ENST00000935008, ENST00000970368

RefSeq mRNA: 1 — MANE Select: NM_004092 NM_004092

CCDS: CCDS7681

Canonical transcript exons

ENST00000368547 — 8 exons

Exon	Start	End
ENSE00000729180	133369904	133370031
ENSE00000729184	133368923	133369022
ENSE00000729187	133366889	133366993
ENSE00000729191	133365976	133366095
ENSE00000729194	133364658	133364725
ENSE00000987622	133370560	133370757
ENSE00001447393	133362485	133362933
ENSE00001447396	133373246	133373354

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.4018 / max 530.2442, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112127	44.4018	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.60	gold quality
nephron tubule	UBERON:0001231	99.52	gold quality
parotid gland	UBERON:0001831	99.45	gold quality
adult mammalian kidney	UBERON:0000082	99.34	gold quality
liver	UBERON:0002107	99.31	gold quality
adult organism	UBERON:0007023	99.26	gold quality
kidney epithelium	UBERON:0004819	99.23	gold quality
mucosa of transverse colon	UBERON:0004991	99.14	gold quality
jejunal mucosa	UBERON:0000399	99.06	gold quality
renal medulla	UBERON:0000362	99.05	gold quality
renal glomerulus	UBERON:0000074	98.87	gold quality
apex of heart	UBERON:0002098	98.80	gold quality
metanephric glomerulus	UBERON:0004736	98.70	gold quality
duodenum	UBERON:0002114	98.66	gold quality
heart right ventricle	UBERON:0002080	98.64	gold quality
heart left ventricle	UBERON:0002084	98.60	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.60	gold quality
cardiac ventricle	UBERON:0002082	98.59	gold quality
kidney	UBERON:0002113	98.57	gold quality
right adrenal gland cortex	UBERON:0035827	98.53	gold quality
right adrenal gland	UBERON:0001233	98.49	gold quality
middle temporal gyrus	UBERON:0002771	98.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.36	gold quality
cortex of kidney	UBERON:0001225	98.35	gold quality
jejunum	UBERON:0002115	98.33	gold quality
left adrenal gland	UBERON:0001234	98.25	gold quality
metanephros	UBERON:0000081	98.23	gold quality
ileal mucosa	UBERON:0000331	98.23	gold quality
colonic mucosa	UBERON:0000317	98.18	gold quality
gastrocnemius	UBERON:0001388	98.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	115.48
E-MTAB-10553	yes	39.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting ECHS1, 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-3605-5P	99.96	67.12	932
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4438	97.96	63.70	947
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-34A-3P	96.80	67.70	805

Literature-anchored findings (GeneRIF, showing 26)

• Expression of mitochondrial short chain enoyl-CoA hydratase (ECHS)was significantly down-modulated in virus infected glioblastoma cells and ECHS knockdown (siRNA) impaired virus replication and cytopathic effects. (PMID:17395278)
• The coexistence of HBs and ECHS1 enhances HepG2 cell apoptosis, affects ECHS1 localization in the mitochondria and induces apoptosis by decreasing the mitochondrial membrane potential (MMP). (PMID:23178449)
• The results confirmed that small hepatitis B surface antigen (SHBs) interacted with ECHS1. (PMID:23275097)
• ECHS1 specifically represses STAT3 activity and negatively regulates the expression of several target genes of STAT3 through inhibiting STAT3 phosphorylation. (PMID:23416296)
• ECHS1 knockdown reduced cell viability and enhanced cisplatin-induced apoptosis in hepatocellular carcinoma cells. (PMID:23879543)
• The study demonstrated that ECHS1 mutations result in ECHS1 deficiency and are another cause of Leigh disease in two siblings. (PMID:25125611)
• ECHS1 may play important roles in gastric cancer cell proliferation and migration through PKB- and GSK3b-related signaling pathways. (PMID:25338767)
• ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. (PMID:25393721)
• In conclusion, the results of the present study suggested that ECHS1 may have an important role in colorectal cancer cell proliferation and migration (PMID:25739098)
• These results suggested that ECHS1 may promote cell proliferation in hepatocellular carcinoma in an EGFR-dependent manner. (PMID:25760819)
• identification of four additional patients with mutations in ECHS1 highlights the importance of the valine degradation pathway in Leigh syndrome (PMID:26099313)
• Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA (PMID:26251176)
• ECHS1 mutations phenotype might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. (PMID:27090768)
• This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis (PMID:27905109)
• Whole exome sequencing identified heterozygous ECHS1 mutations c.836T>C (novel) and c.8C>A for short-chain enoyl-CoA hydratase (SCEH) deficiency of which 1/2 of the cases are associated with secondary lymphocyte pyruvate dehydrogenase complex deficiency.[review] (PMID:28202214)
• Due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency. (PMID:28409271)
• exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation (PMID:28878358)
• In clear cell renal cell carcinoma (ccRCC) ECHS1 downregulation induced fatty acid (FA) and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis and promoted cell proliferation. GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. (PMID:31690668)
• ECHS1 suppresses renal cell carcinoma development through inhibiting mTOR signaling activation. (PMID:31891870)
• Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene. (PMID:32677093)
• Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report. (PMID:32677908)
• Paroxysmal and non-paroxysmal dystonia in 3 patients with biallelic ECHS1 variants: Expanding the neurological spectrum and therapeutic approaches. (PMID:32858208)
• ECHS1 disease in two unrelated families of Samoan descent: Common variant - rare disorder. (PMID:33112498)
• Differentially expressed genes PCCA, ECHS1, and HADH are potential prognostic biomarkers for gastric cancer. (PMID:33881965)
• ECHS1, an interacting protein of LASP1, induces sphingolipid-metabolism imbalance to promote colorectal cancer progression by regulating ceramide glycosylation. (PMID:34615856)
• Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity. (PMID:38363494)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	echs1	ENSDARG00000001578
mus_musculus	Echs1	ENSMUSG00000025465
rattus_norvegicus	Echs1	ENSRNOG00000064647
drosophila_melanogaster	Echs1	FBGN0033879
caenorhabditis_elegans		WBGENE00001155
caenorhabditis_elegans	ech-7	WBGENE00001156

Paralogs (13): ECHDC1 (ENSG00000093144), ECH1 (ENSG00000104823), ECHDC2 (ENSG00000121310), CDY2B (ENSG00000129873), ECHDC3 (ENSG00000134463), AUH (ENSG00000148090), CDYL (ENSG00000153046), CDYL2 (ENSG00000166446), ECI1 (ENSG00000167969), CDY1 (ENSG00000172288), CDY1B (ENSG00000172352), CDY2A (ENSG00000182415), HIBCH (ENSG00000198130)

Protein

Protein identifiers

Enoyl-CoA hydratase, mitochondrial — P30084 (reviewed: P30084)

Alternative names: Enoyl-CoA hydratase 1, Short-chain enoyl-CoA hydratase

All UniProt accessions (1): P30084

UniProt curated annotations — full annotation on UniProt →

Function. Converts unsaturated trans-2-enoyl-CoA species ((2E)-enoyl-CoA) to the corresponding (3S)-3hydroxyacyl-CoA species through addition of a water molecule to the double bond. Catalyzes the hydration of medium- and short-chained fatty enoyl-CoA thioesters from 4 carbons long (C4) up to C16. Has high substrate specificity for crotonyl-CoA ((2E)-butenoyl-CoA) and moderate specificity for acryloyl-CoA, 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA) and methacrylyl-CoA ((2E)-2-methylpropenoyl-CoA). Can bind tiglyl-CoA (2-methylcrotonoyl-CoA), but hydrates only a small amount of this substrate. Plays a key role in the beta-oxidation spiral of short- and medium-chain fatty acid oxidation. At a lower rate than the hydratase reaction, catalyzes the isomerase reaction of trans-3-enoyl-CoA species (such as (3E)-hexenoyl-CoA) to trans-2-enoyl-CoA species (such as (2E)-hexenoyl-CoA), which are subsequently hydrated to 3(S)-3-hydroxyacyl-CoA species (such as (3S)-hydroxyhexanoyl-CoA).

Subunit / interactions. Homohexamer; dimer of trimers.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Liver, fibroblast, muscle. Barely detectable in spleen and kidney.

Disease relevance. Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) [MIM:616277] A severe, autosomal recessive inborn error affecting valine metabolism. Disease features include brain lesions in the basal ganglia, neurodegeneration, delayed psychomotor development, hypotonia, spasticity, and increased lactic acid in serum and cerebral serum fluid. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; fatty acid beta-oxidation.

Similarity. Belongs to the enoyl-CoA hydratase/isomerase family.

RefSeq proteins (1): NP_004083* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001753	Enoyl-CoA_hydra/iso	Domain
IPR014748	Enoyl-CoA_hydra_C	Homologous_superfamily
IPR018376	Enoyl-CoA_hyd/isom_CS	Conserved_site
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily

Pfam: PF00378

Enzyme classification (BRENDA):

• EC 4.2.1.17 — enoyl-CoA hydratase (BRENDA: 26 organisms, 124 substrates, 26 inhibitors, 61 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

21 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CROTONYL-COA	0.003–0.45	14
TRANS-2-DECENOYL-COA	0.0025–0.0063	7
TRANS-2-HEXENOYL-COA	0.0143–0.027	7
(S)-3-HYDROXYBUTYRYL-COA	0.034–1.31	4
ACRYLOYL-COA	0.037–0.71	4
METHACRYLYL-COA	0.14–2.19	4
3-HYDROXYPROPANOYL-COA	0.16–0.35	3
(E)-OCTENOYL-COA	0.048–0.18	2
3-OXO-CHOL-4,22-DIENE-24-OYL-COA	0.0058–0.008	2
(Z)-2-BUTENOYL-COA	0.05	1
2-DECENOYL-COA	0.008	1
3’-DEPHOSPHOCROTONYL-COA	0.118	1
CROTONOYL-COA	0.07	1
DEC-2-ENOYL-COA	0.029	1
DODEC-2-ENOYL-COA	0.03	1

Catalyzed reactions (Rhea), 10 shown:

• a (3S)-3-hydroxyacyl-CoA = a (2E)-enoyl-CoA + H2O (RHEA:16105)
• 3-hydroxypropanoyl-CoA = acryloyl-CoA + H2O (RHEA:26518)
• (3S)-3-hydroxybutanoyl-CoA = (2E)-butenoyl-CoA + H2O (RHEA:26558)
• (3S)-hydroxyhexanoyl-CoA = (2E)-hexenoyl-CoA + H2O (RHEA:30547)
• 3-hydroxyisovaleryl-CoA = 3-methylbut-2-enoyl-CoA + H2O (RHEA:31079)
• 2-methylpropenoyl-CoA + H2O = (S)-3-hydroxyisobutanoyl-CoA (RHEA:31175)
• (3S)-hydroxydecanoyl-CoA = (2E)-decenoyl-CoA + H2O (RHEA:31191)
• a (3E)-enoyl-CoA = a 4-saturated (2E)-enoyl-CoA (RHEA:45228)
• 3-hydroxybutanoyl-CoA = (2E)-butenoyl-CoA + H2O (RHEA:45584)
• (3E)-hexenoyl-CoA = (2E)-hexenoyl-CoA (RHEA:45736)

UniProt features (66 total): sequence variant 18, helix 16, strand 10, modified residue 9, sequence conflict 5, turn 3, binding site 2, transit peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8ZRU	ELECTRON MICROSCOPY	2.18
8ZRY	ELECTRON MICROSCOPY	2.23
8ZRX	ELECTRON MICROSCOPY	2.27
8ZRW	ELECTRON MICROSCOPY	2.29
2HW5	X-RAY DIFFRACTION	2.55
8ZRV	ELECTRON MICROSCOPY	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30084-F1	91.54	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 (1): 164 (important for catalytic activity)

Ligand- & substrate-binding residues (2): 98–101; 141

Post-translational modifications (9): 115, 118, 204, 211, 46, 101, 101, 114, 115

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-77310	Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA
R-HSA-77346	Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA
R-HSA-77348	Beta oxidation of octanoyl-CoA to hexanoyl-CoA
R-HSA-77350	Beta oxidation of hexanoyl-CoA to butanoyl-CoA
R-HSA-77352	Beta oxidation of butanoyl-CoA to acetyl-CoA
R-HSA-9916720	Mitochondrial short-chain enoyl-CoA hydratase deficiency 1

MSigDB gene sets: 267 (showing top): GOBP_LIPID_MODIFICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_FATTY_ACID_CATABOLIC_PROCESS, PAL_PRMT5_TARGETS_UP, GNF2_GSTM1, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, HSIAO_HOUSEKEEPING_GENES, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GERY_CEBP_TARGETS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (4): fatty acid beta-oxidation (GO:0006635), branched-chain amino acid catabolic process (GO:0009083), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (9): delta(3)-delta(2)-enoyl-CoA isomerase activity (GO:0004165), enoyl-CoA hydratase activity (GO:0004300), 3-hydroxypropionyl-CoA dehydratase activity (GO:0043956), (2E)-butenoyl-CoA hydratase activity (GO:0120092), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829), isomerase activity (GO:0016853), 3-hydroxyacyl-CoA dehydratase activity (GO:0018812)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
mitochondrial fatty acid beta-oxidation of saturated fatty acids	5
Metabolism of amino acids and derivatives	1
Diseases of branched-chain amino acid catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enoyl-CoA hydratase activity	2
catalytic activity	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
intramolecular oxidoreductase activity, transposing C=C bonds	1
hydro-lyase activity	1
3-hydroxyacyl-CoA dehydratase activity	1
molecular_function	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ECHS1	HADHB	P55084	981
ECHS1	HADH	Q16836	964
ECHS1	ACAA1	P09110	940
ECHS1	ACAA2	P42765	927
ECHS1	ACOX1	Q15067	926
ECHS1	HSD17B4	P51659	881
ECHS1	ACOX3	O15254	839
ECHS1	CS	O75390	748
ECHS1	ACADS	P16219	743
ECHS1	ACADM	P11310	712
ECHS1	PPARA	Q07869	678
ECHS1	ACADSB	P45954	668
ECHS1	ACADVL	P49748	656
ECHS1	AASDH	Q4L235	645
ECHS1	ALDH6A1	Q02252	645

IntAct

105 interactions, top by confidence:

A	B	Type	Score
CUL9	TP53	psi-mi:“MI:0914”(association)	0.920
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
LRRK2	ECHS1	psi-mi:“MI:0407”(direct interaction)	0.710
ECHS1	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.710
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
ECHS1	DBT	psi-mi:“MI:0914”(association)	0.530
ECHS1	Stat3	psi-mi:“MI:0915”(physical association)	0.520
YPEL5	SYNCRIP	psi-mi:“MI:0914”(association)	0.510
ECHS1	STAT3	psi-mi:“MI:0915”(physical association)	0.510
STAT3	ECHS1	psi-mi:“MI:0915”(physical association)	0.510
LRRK1	ECHS1	psi-mi:“MI:0407”(direct interaction)	0.440
ZNF157	ECHS1	psi-mi:“MI:0915”(physical association)	0.400
SLMAP	ECHS1	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	ECHS1	psi-mi:“MI:0915”(physical association)	0.400
SAV1	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
ECHS1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
ECHS1	FXR2	psi-mi:“MI:0915”(physical association)	0.370
CYP2E1	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
UBA1	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
CLDN12	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
ECHS1	ECHS1	psi-mi:“MI:0915”(physical association)	0.370
ECHS1	SERPINA1	psi-mi:“MI:0915”(physical association)	0.370
TRIM63	ECHS1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (291): ECHS1 (Affinity Capture-RNA), ECHS1 (Affinity Capture-RNA), ECHS1 (Affinity Capture-MS), CAMK2D (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), DBT (Affinity Capture-MS), USP15 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), ATPAF2 (Affinity Capture-MS), ECHS1 (Affinity Capture-MS), ADI1 (Co-fractionation), AHCYL1 (Co-fractionation), AKR1A1 (Co-fractionation), ALDOA (Co-fractionation), CTBP1 (Co-fractionation)

ESM2 similar proteins: A2VDC2, A3KP37, F1NB38, F1R6N4, F1RAX8, O35459, P00341, P14604, P23965, P28492, P30084, P33571, P34559, P40939, P42125, P42126, Q0P5G4, Q13011, Q28C91, Q2HJD5, Q2KIL4, Q3MIE0, Q58DM8, Q58FK9, Q5HZQ8, Q5R4W0, Q5R646, Q5RFG0, Q5ZJ60, Q62651, Q64323, Q68FU7, Q6AYG5, Q6DF46, Q6GM82, Q6NVY1, Q71RI9, Q7T3E5, Q8BGT5, Q8BH95

Diamond homologs: A0A481WNM8, A0KEL1, A0KV76, A1ADI8, A1JK30, A1RI92, A1S7L6, A3D684, A3QFP3, A4TM82, A4WCW6, A4Y897, A4YI89, A5F2P2, A5WH99, A6WQ25, A7FGK1, A7ZPF8, A8A2L0, A8ADP2, A9N453, B0TL21, B1IXA5, B1LME7, B1X9L4, B2TWV4, B4SZR0, B4TCA8, B4TQC2, B5EZR9, B5FPN1, B5R3R9, B5RCL3, B5XVW2, B5YXY4, B6I6Q4, B7LBJ5, B7LLD0, B7M6M2, B7MGV7

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
ECHS1	“down-regulates quantity”	trans-dodec-2-enoyl-CoA(4-)	“chemical modification”
ECHS1	“down-regulates quantity”	water	“chemical modification”
ECHS1	“up-regulates quantity”	(S)-3-hydroxylauroyl-CoA	“chemical modification”
ECHS1	“down-regulates quantity”	trans-dec-2-enoyl-CoA	“chemical modification”
ECHS1	“up-regulates quantity”	(S)-3-hydroxydecanoyl-CoA	“chemical modification”
ECHS1	“down-regulates quantity”	trans-oct-2-enoyl-CoA(4-)	“chemical modification”
ECHS1	“up-regulates quantity”	(S)-3-hydroxyoctanoyl-CoA	“chemical modification”
ECHS1	“down-regulates quantity”	trans-hex-2-enoyl-CoA(4-)	“chemical modification”
ECHS1	“up-regulates quantity”	(S)-3-hydroxyhexanoyl-CoA	“chemical modification”
ECHS1	“down-regulates quantity”	crotonoyl-CoA(4-)	“chemical modification”
ECHS1	“up-regulates quantity”	(S)-3-hydroxybutanoyl-CoA	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	24
Uncertain significance	111
Likely benign	150
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1328252	NM_004092.4(ECHS1):c.563C>T (p.Ala188Val)	Pathogenic
1382291	NM_004092.4(ECHS1):c.1A>G (p.Met1Val)	Pathogenic
1456449	NM_004092.4(ECHS1):c.121dup (p.Arg41fs)	Pathogenic
1511772	NC_000010.10:g.(?135176372)(135180517_?)del	Pathogenic
156434	NM_004092.4(ECHS1):c.5C>T (p.Ala2Val)	Pathogenic
1685760	NM_004092.4(ECHS1):c.250G>A (p.Ala84Thr)	Pathogenic
1691714	NM_004092.4(ECHS1):c.673T>C (p.Cys225Arg)	Pathogenic
1806267	NM_004092.4(ECHS1):c.601C>T (p.Gln201Ter)	Pathogenic
187859	NM_004092.4(ECHS1):c.473C>A (p.Ala158Asp)	Pathogenic
187860	NM_004092.4(ECHS1):c.414+3G>C	Pathogenic
1903474	NM_004092.4(ECHS1):c.2T>C (p.Met1Thr)	Pathogenic
1992780	NM_004092.4(ECHS1):c.3G>C (p.Met1Ile)	Pathogenic
2032134	NM_004092.4(ECHS1):c.370dup (p.Thr124fs)	Pathogenic
2032860	NM_004092.4(ECHS1):c.619+1del	Pathogenic
218891	NM_004092.4(ECHS1):c.413C>T (p.Ala138Val)	Pathogenic
3244966	NC_000010.10:g.(?135186730)(135186837_?)del	Pathogenic
3616765	NM_004092.4(ECHS1):c.533_536dup (p.Arg181fs)	Pathogenic
3617392	NM_004092.4(ECHS1):c.362del (p.Asp121fs)	Pathogenic
3726858	NM_004092.4(ECHS1):c.198del (p.Ile66fs)	Pathogenic
397547	NC_000010.10:g.(?135175966)(135180498_135182426)del	Pathogenic
4714449	NM_004092.4(ECHS1):c.414+2T>C	Pathogenic
4734651	NM_004092.4(ECHS1):c.211C>T (p.Gln71Ter)	Pathogenic
488496	NM_004092.4(ECHS1):c.856_857dup (p.Asn286fs)	Pathogenic
488500	NM_004092.4(ECHS1):c.74G>C (p.Arg25Pro)	Pathogenic
802642	NM_004092.4(ECHS1):c.161G>A (p.Arg54His)	Pathogenic
972720	NM_004092.4(ECHS1):c.229G>C (p.Glu77Gln)	Pathogenic
981051	NM_004092.4(ECHS1):c.467A>G (p.Glu156Gly)	Pathogenic
1194776	NM_004092.4(ECHS1):c.582_589delinsCGGTGACT (p.Arg197Trp)	Likely pathogenic
1203134	NM_004092.4(ECHS1):c.832G>A (p.Ala278Thr)	Likely pathogenic
1521152	NM_004092.4(ECHS1):c.161G>T (p.Arg54Leu)	Likely pathogenic

SpliceAI

1836 predictions. Top by Δscore:

Variant	Effect	Δscore
10:133364575:A:AC	donor_gain	1.0000
10:133364576:A:C	donor_gain	1.0000
10:133364656:A:AC	donor_gain	1.0000
10:133364657:C:CC	donor_gain	1.0000
10:133366006:C:CT	donor_gain	1.0000
10:133366007:T:TT	donor_gain	1.0000
10:133366095:CCTGA:C	acceptor_loss	1.0000
10:133366096:C:CC	acceptor_gain	1.0000
10:133366097:T:C	acceptor_loss	1.0000
10:133369902:A:AC	donor_gain	1.0000
10:133369903:C:CC	donor_gain	1.0000
10:133369903:CGG:C	donor_gain	1.0000
10:133370028:CCAG:C	acceptor_gain	1.0000
10:133370029:CAG:C	acceptor_gain	1.0000
10:133370029:CAGC:C	acceptor_gain	1.0000
10:133370032:C:CC	acceptor_gain	1.0000
10:133370032:CTAGC:C	acceptor_loss	1.0000
10:133370036:C:CT	acceptor_gain	1.0000
10:133370037:A:T	acceptor_gain	1.0000
10:133370555:CGTA:C	donor_loss	1.0000
10:133370558:A:C	donor_loss	1.0000
10:133370613:T:TA	donor_gain	1.0000
10:133370758:CTGG:C	acceptor_loss	1.0000
10:133362930:CATC:C	acceptor_gain	0.9900
10:133362932:TC:T	acceptor_gain	0.9900
10:133362933:CC:C	acceptor_gain	0.9900
10:133362934:C:CC	acceptor_gain	0.9900
10:133362934:CT:C	acceptor_loss	0.9900
10:133362935:T:A	acceptor_loss	0.9900
10:133362938:C:CT	acceptor_gain	0.9900

AlphaMissense

1905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:133370589:A:T	V86D	0.997
10:133368958:A:G	F160S	0.996
10:133368988:T:A	D150V	0.996
10:133369923:G:T	A132D	0.996
10:133369917:A:T	V134D	0.995
10:133362904:A:C	F279L	0.994
10:133362904:A:T	F279L	0.994
10:133362906:A:G	F279L	0.994
10:133365992:T:A	K241N	0.994
10:133365992:T:G	K241N	0.994
10:133366900:G:T	A203D	0.994
10:133366901:C:G	A203P	0.994
10:133368934:C:T	G168E	0.994
10:133370564:A:C	F94L	0.994
10:133370564:A:T	F94L	0.994
10:133370566:A:G	F94L	0.994
10:133366089:A:T	V209D	0.993
10:133369920:G:T	A133D	0.993
10:133368934:C:A	G168V	0.992
10:133366930:A:G	L193P	0.991
10:133368946:T:A	E164V	0.991
10:133368976:G:T	A154D	0.991
10:133368988:T:G	D150A	0.991
10:133368990:A:C	C149W	0.991
10:133368992:A:G	C149R	0.991
10:133369000:G:T	A146D	0.991
10:133370565:A:G	F94S	0.991
10:133370640:A:G	L69P	0.991
10:133369018:C:T	G140D	0.990
10:133370028:C:T	G97E	0.990

dbSNP variants (sampled 300 via entrez): RS1000142300 (10:133371920 C>T), RS1000251430 (10:133366448 G>A), RS1000382983 (10:133371613 C>G), RS1000516556 (10:133375233 G>T), RS1001231568 (10:133374623 T>C), RS1001301642 (10:133368663 A>G), RS1001384659 (10:133365358 G>A,C,T), RS1001661009 (10:133365368 C>T), RS1002019999 (10:133370346 G>A,C), RS1002118334 (10:133364855 C>T), RS1002355679 (10:133374443 C>T), RS1002370758 (10:133369226 G>A), RS1002655663 (10:133364146 T>A,C), RS1002687751 (10:133367746 T>C), RS1002706608 (10:133370092 T>A,C)

Disease associations

OMIM: gene MIM:602292 | disease phenotypes: MIM:616277, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	Definitive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	Definitive	AR

Mondo (3): mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency (MONDO:0014563), Leigh syndrome (MONDO:0009723), (MONDO:0016815)

Orphanet (3): Leigh syndrome with leukodystrophy (Orphanet:255241), Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (Orphanet:653880), Leigh syndrome (Orphanet:506)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001522	Death in infancy
HP:0001629	Ventricular septal defect
HP:0001639	Hypertrophic cardiomyopathy
HP:0001662	Bradycardia
HP:0002033	Poor suck
HP:0002104	Apnea
HP:0002151	Increased circulating lactate concentration
HP:0002490	Increased CSF lactate
HP:0002878	Respiratory failure
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex
HP:0003577	Congenital onset
HP:0007366	Atrophy/Degeneration affecting the brainstem
HP:0010544	Vertical nystagmus
HP:0011344	Severe global developmental delay
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0012707	Elevated brain lactate level by MRS
HP:0033725	Thin corpus callosum
HP:6000469	Elevated urine 2,3-dihydroxy-2-methylbutanoic acid level

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002846_3	Lifespan	3.000000e-10
GCST007250_1	Nonunion in individuals with fractures	2.000000e-08
GCST012020_581	Serum metabolite levels	3.000000e-12
GCST012021_98	Serum metabolite levels	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009707	fractures, ununited

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523211 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs140410716	Efficacy	3	aspirin;clopidogrel	Acute coronary syndrome;Major Adverse Cardiac Events (MACE)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs140410716	ECHS1	3	3.50	1	aspirin;clopidogrel

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.74	Kd	180.8	nM	CHEMBL5653589
6.74	ED50	180.8	nM	CHEMBL5653589
5.03	Kd	9237	nM	CHEMBL4462318

PubChem BioAssay actives

2 with measured affinity, of 3 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148280: Binding affinity to human ECHS1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1808	uM
2,6-difluoro-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]benzenesulfonamide	1573331: Binding affinity to ECHS1 in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	kd	9.2370	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects expression, affects cotreatment, decreases methylation	4
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Arsenic Trioxide	increases expression	2
Arsenic	affects methylation, decreases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Doxorubicin	affects response to substance, increases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
lasiocarpine	decreases expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
linalool	increases expression	1
gossypol acetic acid	decreases expression	1
cupric oxide	decreases expression	1
methacrylyl-coenzyme A	increases abundance	1
acryloyl-coenzyme A	increases abundance	1
microcystin RR	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
GW 4064	affects cotreatment, decreases expression	1
GW 7647	increases expression	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
LDN 193189	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4371461	Binding	Binding affinity to ECHS1 in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors. — J Med Chem

Cellosaurus cell lines

16 cell lines: 7 finite cell line, 5 cancer cell line, 3 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5K1	HAP1 ECHS1 (-) 2	Cancer cell line	Male
CVCL_B5K2	HAP1 ECHS1 (-) 3	Cancer cell line	Male
CVCL_B5K3	HAP1 ECHS1 (-) 4	Cancer cell line	Male
CVCL_B5K4	HAP1 ECHS1 (-) 5	Cancer cell line	Male
CVCL_D6XP	GM28472	Finite cell line	Female
CVCL_D6XQ	GM28473	Finite cell line	Female
CVCL_D6XR	GM28474	Finite cell line	Male
CVCL_F0U0	GM29095	Finite cell line	Female
CVCL_F0YT	GM29337	Transformed cell line	Male
CVCL_F0YV	GM29340	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells