Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIDTQ8R)

• DOT Name: Very long chain fatty acid elongase 1 (ELOVL1)
• Synonyms: EC 2.3.1.199; 3-keto acyl-CoA synthase ELOVL1; ELOVL fatty acid elongase 1; ELOVL FA elongase 1; Elongation of very long chain fatty acids protein 1; Very long chain 3-ketoacyl-CoA synthase 1; Very long chain 3-oxoacyl-CoA synthase 1
• Gene Name: ELOVL1
• Related Disease:
  Hyperglycemia
  Adrenoleukodystrophy
  Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features
  Neoplasm
  Triple negative breast cancer
  Adrenomyeloneuropathy
  Keratoconjunctivitis sicca
• UniProt ID: ELOV1_HUMAN
• EC Number: 2.3.1.199
• Pfam ID: PF01151
• Sequence:
  MEAVVNLYQEVMKHADPRIQGYPLMGSPLLMTSILLTYVYFVLSLGPRIMANRKPFQLRG
  FMIVYNFSLVALSLYIVYEFLMSGWLSTYTWRCDPVDYSNSPEALRMVRVAWLFLFSKFI
  ELMDTVIFILRKKDGQVTFLHVFHHSVLPWSWWWGVKIAPGGMGSFHAMINSSVHVIMYL
  YYGLSAFGPVAQPYLWWKKHMTAIQLIQFVLVSLHISQYYFMSSCNYQYPVIIHLIWMYG
  TIFFMLFSNFWYHSYTKGKRLPRALQQNGAPGIAKVKAN
• Function: Catalyzes the first and rate-limiting reaction of the four reactions that constitute 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. Condensing enzyme that exhibits activity toward saturated and monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. May participate in the production of both saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Important for saturated C24:0 and monounsaturated C24:1 sphingolipid synthesis. Indirectly inhibits RPE65 via production of VLCFAs.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
  Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
  Linoleic acid (LA) metabolism (R-HSA-2046105)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[1]
Adrenoleukodystrophy	DISTUD1F	Strong	Biomarker	[2]
Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features	DISOYL0V	Strong	Autosomal dominant	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Adrenomyeloneuropathy	DISPTS3P	Limited	Biomarker	[5]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[6]

1 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 fatty acid elongase 1 (ELOVL1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[19]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[20]
CITCO	DM0N634	Investigative	CITCO increases the expression of Very long chain fatty acid elongase 1 (ELOVL1).	[20]

References

• [1] Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration.J Biomed Sci. 2018 May 2;25(1):40. doi: 10.1186/s12929-018-0437-1.
• [2] Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis.Biochim Biophys Acta. 2015 Feb;1851(2):231-7. doi: 10.1016/j.bbalip.2014.12.005. Epub 2014 Dec 11.
• [3] De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy. J Med Genet. 2019 Mar;56(3):164-175. doi: 10.1136/jmedgenet-2018-105711. Epub 2018 Nov 28.
• [4] Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer.BMC Cancer. 2017 Aug 29;17(1):589. doi: 10.1186/s12885-017-3554-4.
• [5] MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy.Mol Neurobiol. 2017 Mar;54(2):1392-1403. doi: 10.1007/s12035-016-9746-0. Epub 2016 Feb 3.
• [6] Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice.FASEB J. 2018 Jun;32(6):2966-2978. doi: 10.1096/fj.201700947R. Epub 2018 Jan 17.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] 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.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [14] 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.
• [15] Nervonoylceramide (C24:1Cer), a lipid biomarker for ocular irritants released from the 3D reconstructed human cornea-like epithelium, MCTT HCE?. Toxicol In Vitro. 2018 Mar;47:94-102. doi: 10.1016/j.tiv.2017.11.008. Epub 2017 Nov 15.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.