Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT375W1Z)

• DOT Name: Very long chain fatty acid elongase 5 (ELOVL5)
• Synonyms: EC 2.3.1.199; 3-keto acyl-CoA synthase ELOVL5; ELOVL fatty acid elongase 5; ELOVL FA elongase 5; Elongation of very long chain fatty acids protein 5; Fatty acid elongase 1; hELO1; Very long chain 3-ketoacyl-CoA synthase 5; Very long chain 3-oxoacyl-CoA synthase 5
• Gene Name: ELOVL5
• Related Disease:
  Nephropathy
  Non-insulin dependent diabetes
  Adenocarcinoma
  Advanced cancer
  Cardiac arrest
  Cerebellar ataxia
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Fatty liver disease
  Major depressive disorder
  Obesity
  Prostate cancer
  Prostate carcinoma
  Retinitis pigmentosa 25
  Spinocerebellar ataxia type 38
  Triple negative breast cancer
  Hyperglycemia
  OPTN-related open angle glaucoma
  Type-1/2 diabetes
• UniProt ID: ELOV5_HUMAN
• EC Number: 2.3.1.199
• Pfam ID: PF01151
• Sequence:
  MEHFDASLSTYFKALLGPRDTRVKGWFLLDNYIPTFICSVIYLLIVWLGPKYMRNKQPFS
  CRGILVVYNLGLTLLSLYMFCELVTGVWEGKYNFFCQGTRTAGESDMKIIRVLWWYYFSK
  LIEFMDTFFFILRKNNHQITVLHVYHHASMLNIWWFVMNWVPCGHSYFGATLNSFIHVLM
  YSYYGLSSVPSMRPYLWWKKYITQGQLLQFVLTIIQTSCGVIWPCTFPLGWLYFQIGYMI
  SLIALFTNFYIQTYNKKGASRRKDHLKDHQNGSMAAVNGHTNSFSPLENNVKPRKLRKD
• 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 acts specifically toward polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA. May participate in the production of monounsaturated and of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. In conditions where the essential linoleic and alpha linoleic fatty acids are lacking it is also involved in the synthesis of Mead acid from oleic acid.
• Tissue Specificity: Ubiquitous. Highly expressed in the adrenal gland and testis. Weakly expressed in prostate, lung and brain. Expressed in the cerebellum.
• 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)
• BioCyc Pathway: MetaCyc:ENSG00000012660-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Posttranslational Modification	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[6]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[6]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[6]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[7]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[8]
Obesity	DIS47Y1K	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Retinitis pigmentosa 25	DISTIKZB	Strong	Biomarker	[10]
Spinocerebellar ataxia type 38	DISUC2CF	Strong	Autosomal dominant	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[13]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[14]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Very long chain fatty acid elongase 5 (ELOVL5) affects the response to substance of Fluorouracil.	[35]
Mitoxantrone	DMM39BF	Approved	Very long chain fatty acid elongase 5 (ELOVL5) affects the response to substance of Mitoxantrone.	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[20]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[23]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[25]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[28]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[31]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[33]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Very long chain fatty acid elongase 5 (ELOVL5).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Very long chain fatty acid elongase 5 (ELOVL5).	[30]

References

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• [2] Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus.Sci Rep. 2018 Oct 5;8(1):14862. doi: 10.1038/s41598-018-33238-9.
• [3] The Expression of HSD17B12 Is Associated with COX-2 Expression and Is Increased in High-Grade Epithelial Ovarian Cancer.Oncology. 2018;94(4):233-242. doi: 10.1159/000485624. Epub 2018 Jan 12.
• [4] SCA38 is rare in Mainland China.J Neurol Sci. 2015 Nov 15;358(1-2):333-4. doi: 10.1016/j.jns.2015.09.350. Epub 2015 Sep 15.
• [5] Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family.Front Genet. 2018 Mar 23;9:85. doi: 10.3389/fgene.2018.00085. eCollection 2018.
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• [8] Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder.J Affect Disord. 2011 Mar;129(1-3):359-63. doi: 10.1016/j.jad.2010.08.021. Epub 2010 Sep 21.
• [9] Maximizing RNA Loading for Gene Silencing Using Porous Silicon Nanoparticles.ACS Appl Mater Interfaces. 2019 Jul 3;11(26):22993-23005. doi: 10.1021/acsami.9b05577. Epub 2019 Jun 24.
• [10] Mutation screening of three candidate genes, ELOVL5, SMAP1 and GLULD1 in autosomal recessive retinitis pigmentosa.Int J Mol Med. 2005 Dec;16(6):1163-7.
• [11] Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res. 2009 Mar;50(3):412-423. doi: 10.1194/jlr.M800383-JLR200. Epub 2008 Oct 6.
• [12] 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.
• [13] Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese C57BL/6J mice.J Lipid Res. 2010 Sep;51(9):2642-54. doi: 10.1194/jlr.M006080. Epub 2010 May 19.
• [14] Association between SRBD1 and ELOVL5 gene polymorphisms and primary open-angle glaucoma.Invest Ophthalmol Vis Sci. 2011 Jun 28;52(7):4626-9. doi: 10.1167/iovs.11-7382.
• [15] Identification of Shared and Unique Serum Lipid Profiles in Diabetes Mellitus and Myocardial Infarction.J Am Heart Assoc. 2016 Nov 29;5(12):e004503. doi: 10.1161/JAHA.116.004503.
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• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [21] 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.
• [22] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
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• [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] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [27] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [28] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
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• [30] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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• [32] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [34] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [35] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [36] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.