Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0TT8P8)

• DOT Name: Long-chain-fatty-acid--CoA ligase 6 (ACSL6)
• Synonyms: EC 6.2.1.3; Arachidonate--CoA ligase; EC 6.2.1.15; Long-chain acyl-CoA synthetase 6; LACS 6
• Gene Name: ACSL6
• Related Disease:
  Neoplasm
  Alzheimer disease
  Congestive heart failure
  Male infertility
  Mental disorder
  Polycythemia vera
  Female hypogonadism
  Acute coronary syndrome
  Acute erythroid leukemia
  Acute myelogenous leukaemia
  Childhood myelodysplastic syndrome
  Myelodysplastic syndrome
  Myocardial infarction
  Osteoarthritis
• UniProt ID: ACSL6_HUMAN
• EC Number: 6.2.1.15; 6.2.1.3
• Pfam ID: PF00501
• Sequence:
  MQTQEILRILRLPELGDLGQFFRSLSATTLVSMGALAAILAYWFTHRPKALQPPCNLLMQ
  SEEVEDSGGARRSVIGSGPQLLTHYYDDARTMYQVFRRGLSISGNGPCLGFRKPKQPYQW
  LSYQEVADRAEFLGSGLLQHNCKACTDQFIGVFAQNRPEWIIVELACYTYSMVVVPLYDT
  LGPGAIRYIINTADISTVIVDKPQKAVLLLEHVERKETPGLKLIILMDPFEEALKERGQK
  CGVVIKSMQAVEDCGQENHQAPVPPQPDDLSIVCFTSGTTGNPKGAMLTHGNVVADFSGF
  LKVTEKVIFPRQDDVLISFLPLAHMFERVIQSVVYCHGGRVGFFQGDIRLLSDDMKALCP
  TIFPVVPRLLNRMYDKIFSQANTPLKRWLLEFAAKRKQAEVRSGIIRNDSIWDELFFNKI
  QASLGGCVRMIVTGAAPASPTVLGFLRAALGCQVYEGYGQTECTAGCTFTTPGDWTSGHV
  GAPLPCNHIKLVDVEELNYWACKGEGEICVRGPNVFKGYLKDPDRTKEALDSDGWLHTGD
  IGKWLPAGTLKIIDRKKHIFKLAQGEYVAPEKIENIYIRSQPVAQIYVHGDSLKAFLVGI
  VVPDPEVMPSWAQKRGIEGTYADLCTNKDLKKAILEDMVRLGKESGLHSFEQVKAIHIHS
  DMFSVQNGLLTPTLKAKRPELREYFKKQIEELYSISM
• Function: Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation. Plays an important role in fatty acid metabolism in brain and the acyl-CoAs produced may be utilized exclusively for the synthesis of the brain lipid.
• Tissue Specificity: Expressed predominantly in erythrocyte precursors, in particular in reticulocytes, fetal blood cells derived from fetal liver, hemopoietic stem cells from cord blood, bone marrow and brain.
• 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:HS15193-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[3]
Male infertility	DISY3YZZ	Strong	Biomarker	[4]
Mental disorder	DIS3J5R8	Strong	Biomarker	[5]
Polycythemia vera	DISB5FPO	Strong	Genetic Variation	[6]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[7]
Acute coronary syndrome	DIS7DYEW	Limited	Biomarker	[8]
Acute erythroid leukemia	DISZFC1O	Limited	Genetic Variation	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[10]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[9]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[9]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[8]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Long-chain-fatty-acid--CoA ligase 6 (ACSL6) affects the response to substance of Methamphetamine.	[22]

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 Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[17]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Long-chain-fatty-acid--CoA ligase 6 (ACSL6).	[21]

References

• [1] Dithiolethiones inhibit NF-B activity via covalent modification in human estrogen receptor-negative breast cancer.Cancer Res. 2012 May 1;72(9):2394-404. doi: 10.1158/0008-5472.CAN-11-3115. Epub 2012 Mar 21.
• [2] A novel Alzheimer disease locus located near the gene encoding tau protein.Mol Psychiatry. 2016 Jan;21(1):108-17. doi: 10.1038/mp.2015.23. Epub 2015 Mar 17.
• [3] 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.
• [4] Acyl-CoA synthetase 6 regulates long-chain polyunsaturated fatty acid composition of membrane phospholipids in spermatids and supports normal spermatogenic processes in mice.FASEB J. 2019 Dec;33(12):14194-14203. doi: 10.1096/fj.201901074R. Epub 2019 Oct 25.
• [5] DNA pooling: a comprehensive, multi-stage association analysis of ACSL6 and SIRT5 polymorphisms in schizophrenia.Genes Brain Behav. 2007 Apr;6(3):229-39. doi: 10.1111/j.1601-183X.2006.00251.x. Epub 2006 Jul 10.
• [6] t(5;12)(q23-31;p13) with ETV6-ACSL6 gene fusion in polycythemia vera.Leukemia. 2006 Jun;20(6):1175-8. doi: 10.1038/sj.leu.2404194.
• [7] Acyl-CoA synthetase long-chain family member 6 is associated with premature ovarian failure.Fertil Steril. 2009 Apr;91(4 Suppl):1339-43. doi: 10.1016/j.fertnstert.2008.03.035. Epub 2008 Jun 13.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] The lncRNA, Nespas, Is Associated with Osteoarthritis Progression and Serves as a Potential New Prognostic Biomarker.Cartilage. 2019 Apr;10(2):148-156. doi: 10.1177/1947603517725566. Epub 2017 Aug 13.
• [12] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [18] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [21] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [22] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.