Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3L9XO3)

• DOT Name: Long-chain-fatty-acid--CoA ligase 5 (ACSL5)
• Synonyms: EC 6.2.1.3; Arachidonate--CoA ligase; EC 6.2.1.15; Long-chain acyl-CoA synthetase 5; LACS 5
• Gene Name: ACSL5
• Related Disease:
  Advanced cancer
  Epithelial neoplasm
  Adenocarcinoma
  Astrocytoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Coeliac disease
  Colorectal carcinoma
  Congestive heart failure
  Fatty liver disease
  Glioblastoma multiforme
  Glioma
  Hyperlipidemia
  Neoplasm
  Obesity
  Systemic lupus erythematosus
  Acute coronary syndrome
  Acute erythroid leukemia
  Acute myelogenous leukaemia
  Childhood myelodysplastic syndrome
  Diarrhea 13
  Lung cancer
  Migraine disorder
  Myelodysplastic syndrome
  Myocardial infarction
• UniProt ID: ACSL5_HUMAN
• EC Number: 6.2.1.15; 6.2.1.3
• Pfam ID: PF00501
• Sequence:
  MLFIFNFLFSPLPTPALICILTFGAAIFLWLITRPQPVLPLLDLNNQSVGIEGGARKGVS
  QKNNDLTSCCFSDAKTMYEVFQRGLAVSDNGPCLGYRKPNQPYRWLSYKQVSDRAEYLGS
  CLLHKGYKSSPDQFVGIFAQNRPEWIISELACYTYSMVAVPLYDTLGPEAIVHIVNKADI
  AMVICDTPQKALVLIGNVEKGFTPSLKVIILMDPFDDDLKQRGEKSGIEILSLYDAENLG
  KEHFRKPVPPSPEDLSVICFTSGTTGDPKGAMITHQNIVSNAAAFLKCVEHAYEPTPDDV
  AISYLPLAHMFERIVQAVVYSCGARVGFFQGDIRLLADDMKTLKPTLFPAVPRLLNRIYD
  KVQNEAKTPLKKFLLKLAVSSKFKELQKGIIRHDSFWDKLIFAKIQDSLGGRVRVIVTGA
  APMSTSVMTFFRAAMGCQVYEAYGQTECTGGCTFTLPGDWTSGHVGVPLACNYVKLEDVA
  DMNYFTVNNEGEVCIKGTNVFKGYLKDPEKTQEALDSDGWLHTGDIGRWLPNGTLKIIDR
  KKNIFKLAQGEYIAPEKIENIYNRSQPVLQIFVHGESLRSSLVGVVVPDTDVLPSFAAKL
  GVKGSFEELCQNQVVREAILEDLQKIGKESGLKTFEQVKAIFLHPEPFSIENGLLTPTLK
  AKRGELSKYFRTQIDSLYEHIQD
• Function: Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage. Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids. It was suggested that it may also stimulate fatty acid oxidation. At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells.
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Fatty acid degradation (hsa00071)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  PPAR sig.ling pathway (hsa03320)
  Peroxisome (hsa04146)
  Ferroptosis (hsa04216)
  Thermogenesis (hsa04714)
  Adipocytokine sig.ling pathway (hsa04920)
• Reactome Pathway: Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
• BioCyc Pathway: MetaCyc:HS01349-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Epithelial neoplasm	DIS0T594	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Coeliac disease	DISIY60C	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[9]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Genetic Variation	[14]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[15]
Acute coronary syndrome	DIS7DYEW	Limited	Biomarker	[16]
Acute erythroid leukemia	DISZFC1O	Limited	Genetic Variation	[17]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[17]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[17]
Diarrhea 13	DIST251K	Limited	Unknown	[18]
Lung cancer	DISCM4YA	Limited	Altered Expression	[19]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[20]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[17]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[27]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[28]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[29]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[30]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[31]
Tolcapone	DM8MNVO	Approved	Tolcapone decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[32]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[33]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[37]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[38]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Long-chain-fatty-acid--CoA ligase 5 (ACSL5).	[39]

References

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• [2] Impaired expression of acyl-CoA-synthetase 5 in epithelial tumors of the small intestine.Hum Pathol. 2003 Oct;34(10):1048-52. doi: 10.1053/s0046-8177(03)00431-3.
• [3] Low acyl-CoA synthetase 5 expression in colorectal carcinomas is prognostic for early tumour recurrence.Pathol Res Pract. 2017 Mar;213(3):261-266. doi: 10.1016/j.prp.2016.09.002. Epub 2016 Sep 26.
• [4] Splice-site variant in ACSL5: a marker promoting opposing effect on cell viability and protein expression.Eur J Hum Genet. 2019 Dec;27(12):1836-1844. doi: 10.1038/s41431-019-0414-5. Epub 2019 May 3.
• [5] Association of long-chain acyl-coenzyme A synthetase5 expression in human breast cancer by estrogen receptor status and its clinical significance.Oncol Rep. 2017 Jun;37(6):3253-3260. doi: 10.3892/or.2017.5610. Epub 2017 Apr 28.
• [6] Levels of acyl-coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation.Histol Histopathol. 2013 Mar;28(3):353-64. doi: 10.14670/HH-28.353.
• [7] Coeliac disease is associated with impaired expression of acyl-CoA-synthetase 5.Int J Colorectal Dis. 2006 Mar;21(2):130-4. doi: 10.1007/s00384-004-0738-6. Epub 2005 Apr 5.
• [8] Acyl-CoA Synthetase 5 Promotes the Growth and Invasion of Colorectal Cancer Cells.Can J Gastroenterol Hepatol. 2017;2017:7615736. doi: 10.1155/2017/7615736. Epub 2017 Jul 20.
• [9] Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial).Am J Cardiol. 2018 Dec 1;122(11):1896-1901. doi: 10.1016/j.amjcard.2018.08.034. Epub 2018 Sep 7.
• [10] Lipid-induced up-regulation of human acyl-CoA synthetase 5 promotes hepatocellular apoptosis.Biochim Biophys Acta. 2010 Sep;1801(9):1025-35. doi: 10.1016/j.bbalip.2010.04.010. Epub 2010 May 12.
• [11] Fatty acid induced glioma cell growth is mediated by the acyl-CoA synthetase 5 gene located on chromosome 10q25.1-q25.2, a region frequently deleted in malignant gliomas.Oncogene. 2000 Nov 30;19(51):5919-25. doi: 10.1038/sj.onc.1203981.
• [12] Transcriptional activation of hepatic ACSL3 and ACSL5 by oncostatin m reduces hypertriglyceridemia through enhanced beta-oxidation.Arterioscler Thromb Vasc Biol. 2007 Oct;27(10):2198-205. doi: 10.1161/ATVBAHA.107.148429. Epub 2007 Aug 30.
• [13] Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion.Oncotarget. 2017 Feb 28;8(9):15014-15022. doi: 10.18632/oncotarget.14788.
• [14] Acyl-CoA synthetase long-chain 5 genotype is associated with body composition changes in response to lifestyle interventions in postmenopausal women with overweight and obesity: a genetic association study on cohorts Montral-Ottawa New Emerging Team, and Complications Associated with Obesity.BMC Med Genet. 2016 Aug 11;17(1):56. doi: 10.1186/s12881-016-0320-4.
• [15] High ACSL5 transcript levels associate with systemic lupus erythematosus and apoptosis in Jurkat T lymphocytes and peripheral blood cells.PLoS One. 2011;6(12):e28591. doi: 10.1371/journal.pone.0028591. Epub 2011 Dec 6.
• [16] Rivaroxaban: A New Treatment Paradigm in the Setting of Vascular Protection?.Thromb Haemost. 2018 May;118(S 01):S12-S22. doi: 10.1055/s-0038-1636530. Epub 2018 Mar 22.
• [17] Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13).Genes Chromosomes Cancer. 1999 Nov;26(3):192-202. doi: 10.1002/(sici)1098-2264(199911)26:3<192::aid-gcc2>3.0.co;2-e.
• [18] Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset. Clin Genet. 2021 Mar;99(3):376-383. doi: 10.1111/cge.13883. Epub 2020 Nov 25.
• [19] Systematic Analysis of Gene Expression Alterations and Clinical Outcomes for Long-Chain Acyl-Coenzyme A Synthetase Family in Cancer.PLoS One. 2016 May 12;11(5):e0155660. doi: 10.1371/journal.pone.0155660. eCollection 2016.
• [20] A splice variant in the ACSL5 gene relates migraine with fatty acid activation in mitochondria.Eur J Hum Genet. 2016 Nov;24(11):1572-1577. doi: 10.1038/ejhg.2016.54. Epub 2016 May 18.
• [21] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [22] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [23] 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.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] 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.
• [27] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [28] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [29] 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.
• [30] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [31] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [32] Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018 Aug 1;164(2):477-488.
• [33] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [34] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [35] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [36] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [37] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [38] Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. Cell Biol Toxicol. 2021 Feb;37(1):15-34. doi: 10.1007/s10565-020-09520-w. Epub 2020 Apr 28.
• [39] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.