Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS0593S)

• DOT Name: Enoyl-CoA hydratase, mitochondrial (ECHS1)
• Synonyms: mECH; mECH1; EC 4.2.1.17; EC 5.3.3.8; Enoyl-CoA hydratase 1; ECHS1; Short-chain enoyl-CoA hydratase; SCEH
• Gene Name: ECHS1
• Related Disease:
  Advanced cancer
  Hepatocellular carcinoma
  Leigh syndrome
  Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
  Overnutrition
  3-hydroxyisobutyryl-CoA hydrolase deficiency
  Adult glioblastoma
  Alcohol dependence
  Childhood onset GLUT1 deficiency syndrome 2
  Gastric neoplasm
  Glioblastoma multiforme
  Hepatitis
  Hepatitis A virus infection
  Hereditary diffuse gastric adenocarcinoma
  Inborn error of metabolism
  Lactic acidosis
  Metabolic disorder
  Neoplasm
  Obesity
  Paroxysmal dyskinesia
  Periventricular leukomalacia
  Pyruvate dehydrogenase complex deficiency
  Sensorineural hearing loss disorder
  Stomach cancer
  3-methylglutaconic aciduria
  Breast cancer
  Breast carcinoma
  Obsolete Leigh syndrome with leukodystrophy
  Carcinoma of liver and intrahepatic biliary tract
  Cardiomyopathy
  Clear cell renal carcinoma
  Gastric cancer
  Liver cancer
• UniProt ID: ECHM_HUMAN
• PDB ID: 2HW5
• EC Number: 4.2.1.17; 5.3.3.8
• Pfam ID: PF00378
• Sequence:
  MAALRVLLSCVRGPLRPPVRCPAWRPFASGANFEYIIAEKRGKNNTVGLIQLNRPKALNA
  LCDGLIDELNQALKTFEEDPAVGAIVLTGGDKAFAAGADIKEMQNLSFQDCYSSKFLKHW
  DHLTQVKKPVIAAVNGYAFGGGCELAMMCDIIYAGEKAQFAQPEILIGTIPGAGGTQRLT
  RAVGKSLAMEMVLTGDRISAQDAKQAGLVSKICPVETLVEEAIQCAEKIASNSKIVVAMA
  KESVNAAFEMTLTEGSKLEKKLFYSTFATDDRKEGMTAFVEKRKANFKDQ
• 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).
• Tissue Specificity: Liver, fibroblast, muscle. Barely detectable in spleen and kidney.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  beta-Alanine metabolism (hsa00410)
  Propanoate metabolism (hsa00640)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA (R-HSA-77310)
  Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA (R-HSA-77346)
  Beta oxidation of octanoyl-CoA to hexanoyl-CoA (R-HSA-77348)
  Beta oxidation of hexanoyl-CoA to butanoyl-CoA (R-HSA-77350)
  Beta oxidation of butanoyl-CoA to acetyl-CoA (R-HSA-77352)
  Branched-chain amino acid catabolism (R-HSA-70895)
• BioCyc Pathway: MetaCyc:HS05132-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[3]
Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	DISC4EXW	Definitive	Autosomal recessive	[3]
Overnutrition	DISGAJIG	Definitive	Biomarker	[1]
3-hydroxyisobutyryl-CoA hydrolase deficiency	DISB4WD7	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[6]
Childhood onset GLUT1 deficiency syndrome 2	DISXPRXM	Strong	Biomarker	[7]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[5]
Hepatitis	DISXXX35	Strong	Biomarker	[9]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[9]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[8]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[10]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[11]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[12]
Paroxysmal dyskinesia	DIS5XVXE	Strong	Biomarker	[7]
Periventricular leukomalacia	DIS152XL	Strong	Genetic Variation	[13]
Pyruvate dehydrogenase complex deficiency	DIS8RZP9	Strong	Biomarker	[14]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[16]
3-methylglutaconic aciduria	DIS8G1WP	moderate	Biomarker	[10]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[17]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[17]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[18]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[19]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[20]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[21]
Gastric cancer	DISXGOUK	Limited	Biomarker	[16]
Liver cancer	DISDE4BI	Limited	Biomarker	[19]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[38]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[30]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[31]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[32]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[33]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[36]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[39]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[33]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Enoyl-CoA hydratase, mitochondrial (ECHS1).	[40]

References

• [1] Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.Nat Commun. 2017 Sep 6;8(1):464. doi: 10.1038/s41467-017-00489-5.
• [2] Enoyl-coenzyme A hydratase short chain 1 silencing attenuates the proliferation of hepatocellular carcinoma by inhibiting epidermal growth factor signaling in vitro and in vivo.Mol Med Rep. 2015 Jul;12(1):1421-8. doi: 10.3892/mmr.2015.3453. Epub 2015 Mar 9.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome.Hum Genet. 2015 Sep;134(9):981-91. doi: 10.1007/s00439-015-1577-y. Epub 2015 Jun 23.
• [5] Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells.Antiviral Res. 2007 Aug;75(2):152-8. doi: 10.1016/j.antiviral.2007.02.002. Epub 2007 Mar 16.
• [6] Multifactorial comparative proteomic study of cytochrome P450 2E1 function in chronic alcohol administration.PLoS One. 2014 Mar 21;9(3):e92504. doi: 10.1371/journal.pone.0092504. eCollection 2014.
• [7] Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.Mov Disord. 2016 Jul;31(7):1041-8. doi: 10.1002/mds.26610. Epub 2016 Apr 19.
• [8] Two-dimensional differential in-gel electrophoresis for identification of gastric cancer-specific protein markers.Oncol Rep. 2009 Jun;21(6):1429-37. doi: 10.3892/or_00000371.
• [9] ECHS1 acts as a novel HBsAg-binding protein enhancing apoptosis through the mitochondrial pathway in HepG2 cells.Cancer Lett. 2013 Mar 1;330(1):67-73. doi: 10.1016/j.canlet.2012.11.030. Epub 2012 Nov 23.
• [10] Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.Am J Med Genet A. 2018 May;176(5):1115-1127. doi: 10.1002/ajmg.a.38658. Epub 2018 Mar 25.
• [11] A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.Clin Genet. 2017 Apr;91(4):629-633. doi: 10.1111/cge.12891. Epub 2016 Nov 30.
• [12] Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers.J Physiol Biochem. 2011 Mar;67(1):15-26. doi: 10.1007/s13105-010-0044-4. Epub 2010 Sep 30.
• [13] Distinguishing Encephaloclastic Lesions Resulting From Primary or Secondary Pyruvate Dehydrogenase Deficiency From Other Neonatal or Infantile Cavitary Brain Lesions.Pediatr Dev Pathol. 2020 May-Jun;23(3):189-196. doi: 10.1177/1093526619876448. Epub 2019 Sep 22.
• [14] Clinical and biochemical characterization of four patients with mutations in ECHS1.Orphanet J Rare Dis. 2015 Jun 18;10:79. doi: 10.1186/s13023-015-0290-1.
• [15] A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet Med. 2016 Nov;18(11):1090-1096. doi: 10.1038/gim.2016.1. Epub 2016 Mar 3.
• [16] Attenuation of enoyl coenzyme A hydratase short chain 1 expression in gastric cancer cells inhibits cell proliferation and migration in vitro.Cell Mol Biol Lett. 2014 Dec;19(4):576-89. doi: 10.2478/s11658-014-0213-5. Epub 2014 Oct 23.
• [17] MiR-548-3p functions as an anti-oncogenic regulator in breast cancer.Biomed Pharmacother. 2015 Oct;75:111-6. doi: 10.1016/j.biopha.2015.07.027. Epub 2015 Aug 18.
• [18] ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. 2015 Feb;36(2):232-9. doi: 10.1002/humu.22730.
• [19] Attenuation of enoyl coenzyme A hydratase 1 expression in colorectal cancer cells using small interfering RNA inhibits cell proliferation and migration.Mol Med Rep. 2015 Jul;12(1):470-4. doi: 10.3892/mmr.2015.3418. Epub 2015 Mar 4.
• [20] Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis.Metab Brain Dis. 2016 Oct;31(5):1189-92. doi: 10.1007/s11011-016-9842-x. Epub 2016 May 25.
• [21] Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.Cancer Res. 2020 Jan 15;80(2):319-333. doi: 10.1158/0008-5472.CAN-19-1023. Epub 2019 Nov 5.
• [22] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [23] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [24] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] Arsenic modulates posttranslational S-nitrosylation and translational proteome in keratinocytes. ScientificWorldJournal. 2014;2014:360153.
• [29] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [30] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [31] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [32] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [33] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [34] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [35] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [36] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [37] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [38] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [39] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [40] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.