Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2M9W26)

• DOT Name: Very long chain fatty acid elongase 4 (ELOVL4)
• Synonyms: EC 2.3.1.199; 3-keto acyl-CoA synthase ELOVL4; ELOVL fatty acid elongase 4; ELOVL FA elongase 4; Elongation of very long chain fatty acids protein 4; Very long chain 3-ketoacyl-CoA synthase 4; Very long chain 3-oxoacyl-CoA synthase 4
• Gene Name: ELOVL4
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
  Neoplasm
  Stargardt disease 3
  Blindness
  Cerebellar ataxia
  Cone-rod dystrophy 7
  Erythrokeratodermia variabilis
  Glycogen storage disease type II
  Hepatocellular carcinoma
  Hereditary macular dystrophy
  Leber congenital amaurosis
  Macular degeneration
  Non-syndromic ichthyosis
  Retinitis pigmentosa
  Retinitis pigmentosa 25
  Severe early-childhood-onset retinal dystrophy
  Spinocerebellar ataxia type 34
  Cardiac arrest
  Stargardt disease
  Keratoconjunctivitis sicca
  Nervous system disease
  Type-1/2 diabetes
• UniProt ID: ELOV4_HUMAN
• EC Number: 2.3.1.199
• Pfam ID: PF01151
• Sequence:
  MGLLDSEPGSVLNVVSTALNDTVEFYRWTWSIADKRVENWPLMQSPWPTLSISTLYLLFV
  WLGPKWMKDREPFQMRLVLIIYNFGMVLLNLFIFRELFMGSYNAGYSYICQSVDYSNNVH
  EVRIAAALWWYFVSKGVEYLDTVFFILRKKNNQVSFLHVYHHCTMFTLWWIGIKWVAGGQ
  AFFGAQLNSFIHVIMYSYYGLTAFGPWIQKYLWWKRYLTMLQLIQFHVTIGHTALSLYTD
  CPFPKWMHWALIAYAISFIFLFLNFYIRTYKEPKKPKAGKTAMNGISANGVSKSEKQLMI
  ENGKKQKNGKAKGD
• 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 catalyzes the synthesis of very long chain saturated (VLC-SFA) and polyunsaturated (PUFA) fatty acids that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May play a critical role in early brain and skin development.
• Tissue Specificity: Expressed in the retina and at much lower level in the brain. Ubiquitous, highest expression in thymus, followed by testis, small intestine, ovary, and prostate. Little or no expression in heart, lung, liver, or leukocates.
• 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:ENSG00000118402-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Genetic Variation	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[1]
Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome	DISXXWAE	Definitive	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Stargardt disease 3	DIS7SKAQ	Definitive	Autosomal dominant	[4]
Blindness	DISTIM10	Strong	Genetic Variation	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[6]
Cone-rod dystrophy 7	DISVA5ZE	Strong	Biomarker	[7]
Erythrokeratodermia variabilis	DIS4BMUQ	Strong	Genetic Variation	[8]
Glycogen storage disease type II	DISXZPBC	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Hereditary macular dystrophy	DISEYSYY	Strong	Genetic Variation	[11]
Leber congenital amaurosis	DISMGH8F	Strong	Genetic Variation	[12]
Macular degeneration	DISLKKHD	Strong	Genetic Variation	[13]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[12]
Retinitis pigmentosa 25	DISTIKZB	Strong	Biomarker	[7]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Strong	Genetic Variation	[14]
Spinocerebellar ataxia type 34	DISACNLZ	Strong	Autosomal dominant	[15]
Cardiac arrest	DIS9DIA4	moderate	Genetic Variation	[8]
Stargardt disease	DISPXOTO	Supportive	Autosomal dominant	[16]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[17]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[18]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[23]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[25]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[26]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[33]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Very long chain fatty acid elongase 4 (ELOVL4).	[34]

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 affects the methylation of Very long chain fatty acid elongase 4 (ELOVL4).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Very long chain fatty acid elongase 4 (ELOVL4).	[32]

References

• [1] Clinical and genetic studies of an autosomal dominant cone-rod dystrophy with features of Stargardt disease.Ophthalmic Genet. 1999 Jun;20(2):71-81. doi: 10.1076/opge.20.2.71.2287.
• [2] Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet. 2011 Dec 9;89(6):745-50. doi: 10.1016/j.ajhg.2011.10.011. Epub 2011 Nov 17.
• [3] Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22.Oncogene. 2011 Mar 17;30(11):1290-301. doi: 10.1038/onc.2010.510. Epub 2010 Nov 8.
• [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] Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3).Sci Rep. 2018 Apr 13;8(1):5944. doi: 10.1038/s41598-018-24357-4.
• [6] Prevalence and clinicoradiological features of spinocerebellar ataxia type 34 in a Japanese ataxia cohort.Parkinsonism Relat Disord. 2019 Aug;65:238-242. doi: 10.1016/j.parkreldis.2019.05.019. Epub 2019 May 13.
• [7] Autosomal dominant macular atrophy at 6q14 excludes CORD7 and MCDR1/PBCRA loci. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):248-55.
• [8] A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.JAMA Neurol. 2015 Jul;72(7):797-805. doi: 10.1001/jamaneurol.2015.0610.
• [9] Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration.Arch Ophthalmol. 2007 Jan;125(1):49-54. doi: 10.1001/archopht.125.1.49.
• [10] Biosynthesis of very long-chain polyunsaturated fatty acids in hepatocytes expressing ELOVL4.Adv Exp Med Biol. 2014;801:631-6. doi: 10.1007/978-1-4614-3209-8_79.
• [11] ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function.Prog Retin Eye Res. 2019 Mar;69:137-158. doi: 10.1016/j.preteyeres.2018.10.004. Epub 2018 Oct 25.
• [12] Evaluation of the ELOVL4 gene in patients with autosomal recessive retinitis pigmentosa and Leber congenital amaurosis.Mol Vis. 2003 Feb 18;9:49-51.
• [13] Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 2014 Apr;71(4):470-5. doi: 10.1001/jamaneurol.2013.6337.
• [14] Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?.Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):843-857. doi: 10.1167/iovs.17-22962.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res. 2010 Oct;49(4):476-92. doi: 10.1016/j.plipres.2010.07.002. Epub 2010 Jul 13.
• [17] A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology.Invest Ophthalmol Vis Sci. 2014 May 1;55(5):2832-40. doi: 10.1167/iovs.13-13335.
• [18] Different Mutations in ELOVL4 Affect Very Long Chain Fatty Acid Biosynthesis to Cause Variable Neurological Disorders in Humans.Adv Exp Med Biol. 2016;854:129-35. doi: 10.1007/978-3-319-17121-0_18.
• [19] ELOVL4-Mediated Production of Very Long-Chain Ceramides Stabilizes Tight Junctions and Prevents Diabetes-Induced Retinal Vascular Permeability.Diabetes. 2018 Apr;67(4):769-781. doi: 10.2337/db17-1034. Epub 2018 Jan 23.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] 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.
• [25] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [26] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [27] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.