Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJQ5XKQ)

• DOT Name: Enoyl- reductase, mitochondrial (MECR)
• Synonyms: EC 1.3.1.104; 2-enoyl thioester reductase; Nuclear receptor-binding factor 1; HsNrbf-1; NRBF-1
• Gene Name: MECR
• Related Disease:
  Colorectal carcinoma
  Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
  Schizophrenia
  Leigh syndrome
• UniProt ID: MECR_HUMAN
• PDB ID: 1ZSY; 2VCY; 7AYB; 7AYC
• EC Number: 1.3.1.104
• Pfam ID: PF08240 ; PF00107
• Sequence:
  MWVCSTLWRVRTPARQWRGLLPASGCHGPAASSYSASAEPARVRALVYGHHGDPAKVVEL
  KNLELAAVRGSDVRVKMLAAPINPSDINMIQGNYGFLPELPAVGGNEGVAQVVAVGSNVT
  GLKPGDWVIPANAGLGTWRTEAVFSEEALIQVPSDIPLQSAATLGVNPCTAYRMLMDFEQ
  LQPGDSVIQNASNSGVGQAVIQIAAALGLRTINVVRDRPDIQKLSDRLKSLGAEHVITEE
  ELRRPEMKNFFKDMPQPRLALNCVGGKSSTELLRQLARGGTMVTYGGMAKQPVVASVSLL
  IFKDLKLRGFWLSQWKKDHSPDQFKELILTLCDLIRRGQLTAPACSQVPLQDYQSALEAS
  MKPFISSKQILTM
• Function: Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II). Fatty acid chain elongation in mitochondria uses acyl carrier protein (ACP) as an acyl group carrier, but the enzyme accepts both ACP and CoA thioesters as substrates in vitro. Displays a preference for medium-chain over short- and long-chain substrates. May provide the octanoyl chain used for lipoic acid biosynthesis, regulating protein lipoylation and mitochondrial respiratory activity particularly in Purkinje cells.
• Tissue Specificity: Highly expressed in skeletal and heart muscle. Expressed at lower level in placenta, liver, kidney and pancreas. Weakly or not expressed in lung.
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Fatty acid elongation (hsa00062)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA (R-HSA-77346)
• BioCyc Pathway: MetaCyc:HS04010-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	DISBF3BV	Strong	Autosomal recessive	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Enoyl- reductase, mitochondrial (MECR).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Enoyl- reductase, mitochondrial (MECR).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Enoyl- reductase, mitochondrial (MECR).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Enoyl- reductase, mitochondrial (MECR).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Enoyl- reductase, mitochondrial (MECR).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Enoyl- reductase, mitochondrial (MECR).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Enoyl- reductase, mitochondrial (MECR).	[11]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Enoyl- reductase, mitochondrial (MECR).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Enoyl- reductase, mitochondrial (MECR).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Enoyl- reductase, mitochondrial (MECR).	[13]

References

• [1] Efficacy of triple therapies including ionising radiation, agonistic TRAIL antibodies and cisplatin.Oncol Rep. 2009 Jun;21(6):1455-60. doi: 10.3892/or_00000374.
• [2] MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder. Am J Hum Genet. 2016 Dec 1;99(6):1229-1244. doi: 10.1016/j.ajhg.2016.09.021. Epub 2016 Nov 3.
• [3] Genome-wide association study with the risk of schizophrenia in a Korean population.Am J Med Genet B Neuropsychiatr Genet. 2016 Mar;171B(2):257-65. doi: 10.1002/ajmg.b.32400. Epub 2015 Nov 4.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [9] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [10] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.