Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGPB0SM)

• DOT Name: Acyl-coenzyme A thioesterase 11 (ACOT11)
• Synonyms: Acyl-CoA thioesterase 11; EC 3.1.2.-; Acyl-CoA thioester hydrolase 11; Adipose-associated thioesterase; Brown fat-inducible thioesterase; BFIT; Palmitoyl-coenzyme A thioesterase; EC 3.1.2.2
• Gene Name: ACOT11
• Related Disease:
  Neoplasm
  Central nervous system neoplasm
  Fatty liver disease
  Glioma
  Lung adenocarcinoma
  Obesity
  Type-1/2 diabetes
• UniProt ID: ACO11_HUMAN
• PDB ID: 3FO5; 6VVQ
• EC Number: 3.1.2.-; 3.1.2.2
• Pfam ID: PF03061 ; PF01852
• Sequence:
  MIQNVGNHLRRGLASVFSNRTSRKSALRAGNDSAMADGEGYRNPTEVQMSQLVLPCHTNQ
  RGELSVGQLLKWIDTTACLSAERHAGCPCVTASMDDIYFEHTISVGQVVNIKAKVNRAFN
  SSMEVGIQVASEDLCSEKQWNVCKALATFVARREITKVKLKQITPRTEEEKMEHSVAAER
  RRMRLVYADTIKDLLANCAIQGDLESRDCSRMVPAEKTRVESVELVLPPHANHQGNTFGG
  QIMAWMENVATIAASRLCRAHPTLKAIEMFHFRGPSQVGDRLVLKAIVNNAFKHSMEVGV
  CVEAYRQEAETHRRHINSAFMTFVVLDADDQPQLLPWIRPQPGDGERRYREASARKKIRL
  DRKYIVSCKQTEVPLSVPWDPSNQVYLSYNNVSSLKMLVAKDNWVLSSEISQVRLYTLED
  DKFLSFHMEMVVHVDAAQAFLLLSDLRQRPEWDKHYRSVELVQQVDEDDAIYHVTSPALG
  GHTKPQDFVILASRRKPCDNGDPYVIALRSVTLPTHRETPEYRRGETLCSGFCLWREGDQ
  LTKCCWVRVSLTELVSASGFYSWGLESRSKGRRSDGWNGKLAGGHLSTLKAIPVAKINSR
  FGYLQDT
• Function: Has an acyl-CoA thioesterase activity with a preference for the long chain fatty acyl-CoA thioesters hexadecanoyl-CoA/palmitoyl-CoA and tetradecanoyl-CoA/myristoyl-CoA which are the main substrates in the mitochondrial beta-oxidation pathway.
• Tissue Specificity: Isoform 1 is predominantly expressed in skeletal muscle, liver, testis, stomach, spleen, lung and brain. Isoform 2 is predominantly expressed in kidney, uterus, hibernoma and white adipose tissue.
• Reactome Pathway: Mitochondrial Fatty Acid Beta-Oxidation (R-HSA-77289)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[2]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Acyl-coenzyme A thioesterase 11 (ACOT11).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Acyl-coenzyme A thioesterase 11 (ACOT11).	[15]

References

• [1] Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers.Clin Cancer Res. 2011 Sep 1;17(17):5582-92. doi: 10.1158/1078-0432.CCR-10-2659. Epub 2011 Jul 25.
• [2] Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.Nat Genet. 2009 Aug;41(8):905-8. doi: 10.1038/ng.408. Epub 2009 Jul 5.
• [3] Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1.J Lipid Res. 2018 Feb;59(2):368-379. doi: 10.1194/jlr.M081455. Epub 2017 Dec 5.
• [4] Overexpression and proliferation dependence of acyl-CoA thioesterase 11 and 13 in lung adenocarcinoma.Oncol Lett. 2017 Sep;14(3):3647-3656. doi: 10.3892/ol.2017.6594. Epub 2017 Jul 18.
• [5] BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity.Biochem J. 2001 Nov 15;360(Pt 1):135-42. doi: 10.1042/bj3600135.
• [6] Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial.Lancet. 2017 Jun 3;389(10085):2204-2213. doi: 10.1016/S0140-6736(17)31373-9.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.