Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2NT4MV)

• DOT Name: Very-long-chain enoyl-CoA reductase (TECR)
• Synonyms: EC 1.3.1.93; Synaptic glycoprotein SC2; Trans-2,3-enoyl-CoA reductase; TER
• Gene Name: TECR
• Related Disease:
  Cardiac disease
  Dyskeratosis congenita
  Endometriosis
  Pneumothorax
  Influenza
  Autosomal recessive non-syndromic intellectual disability
  Intellectual disability
  Intellectual disability, autosomal recessive 14
• UniProt ID: TECR_HUMAN
• PDB ID: 2DZJ
• EC Number: 1.3.1.93
• Pfam ID: PF02544 ; PF21696
• Sequence:
  MKHYEVEILDAKTREKLCFLDKVEPHATIAEIKNLFTKTHPQWYPARQSLRLDPKGKSLK
  DEDVLQKLPVGTTATLYFRDLGAQISWVTVFLTEYAGPLFIYLLFYFRVPFIYGHKYDFT
  SSRHTVVHLACICHSFHYIKRLLETLFVHRFSHGTMPLRNIFKNCTYYWGFAAWMAYYIN
  HPLYTPPTYGAQQVKLALAIFVICQLGNFSIHMALRDLRPAGSKTRKIPYPTKNPFTWLF
  LLVSCPNYTYEVGSWIGFAIMTQCLPVALFSLVGFTQMTIWAKGKHRSYLKEFRDYPPLR
  MPIIPFLL
• Function: Involved in both the production of very long-chain fatty acids for sphingolipid synthesis and the degradation of the sphingosine moiety in sphingolipids through the sphingosine 1-phosphate metabolic pathway. Catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme reduces the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Catalyzes the saturation step of the sphingosine 1-phosphate metabolic pathway, the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA.
• Tissue Specificity: Expressed in most tissues tested. Highly expressed in skeletal muscle.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
• BioCyc Pathway: MetaCyc:ENSG00000099797-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac disease	DISVO1I5	Strong	Altered Expression	[1]
Dyskeratosis congenita	DISSXV0K	Strong	Altered Expression	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Pneumothorax	DISP86H1	Strong	Biomarker	[3]
Influenza	DIS3PNU3	moderate	Biomarker	[4]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[6]
Intellectual disability, autosomal recessive 14	DISCSYIQ	Limited	Autosomal recessive	[7]

2 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 Very-long-chain enoyl-CoA reductase (TECR).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Very-long-chain enoyl-CoA reductase (TECR).	[11]

10 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 Very-long-chain enoyl-CoA reductase (TECR).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Very-long-chain enoyl-CoA reductase (TECR).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Very-long-chain enoyl-CoA reductase (TECR).	[19]

References

• [1] Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study.J Pediatr. 1989 Jan;114(1):79-86. doi: 10.1016/s0022-3476(89)80605-5.
• [2] Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts.Aging Cell. 2007 Jun;6(3):383-94. doi: 10.1111/j.1474-9726.2007.00288.x. Epub 2007 Mar 23.
• [3] Clinical presentation and treatment of catameinal pneumothorax and endometriosis-related pneumothorax.Expert Rev Respir Med. 2018 Dec;12(12):1031-1036. doi: 10.1080/17476348.2018.1551133. Epub 2018 Nov 27.
• [4] Alterations in sialic-acid O-acetylation glycoforms during murine erythrocyte development.Glycobiology. 2019 Mar 1;29(3):222-228. doi: 10.1093/glycob/cwy110.
• [5] Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum Mol Genet. 2011 Apr 1;20(7):1285-9. doi: 10.1093/hmg/ddq569. Epub 2011 Jan 6.
• [6] 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.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] 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.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] 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.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.