Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAKUO27)

• DOT Name: Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2)
• Synonyms: Acyl-CoA thioesterase 2; EC 3.1.2.2; Acyl-coenzyme A thioester hydrolase 2a; CTE-Ia; Long-chain acyl-CoA thioesterase 2; ZAP128
• Gene Name: ACOT2
• UniProt ID: ACOT2_HUMAN
• PDB ID: 3HLK
• EC Number: 3.1.2.2
• Pfam ID: PF08840 ; PF04775
• Sequence:
  MSNKLLSPHPHSVVLRSEFKMASSPAVLRASRLYQWSLKSSAQFLGSPQLRQVGQIIRVP
  ARMAATLILEPAGRCCWDEPVRIAVRGLAPEQPVTLRASLRDEKGALFQAHARYRADTLG
  ELDLERAPALGGSFAGLEPMGLLWALEPEKPLVRLVKRDVRTPLAVELEVLDGHDPDPGR
  LLCQTRHERYFLPPGVRREPVRVGRVRGTLFLPPEPGPFPGIVDMFGTGGGLLEYRASLL
  AGKGFAVMALAYYNYEDLPKTMETLHLEYFEEAMNYLLSHPEVKGPGVGLLGISKGGELC
  LSMASFLKGITAAVVINGSVANVGGTLHYKGETLPPVGVNRNRIKVTKDGYADIVDVLNS
  PLEGPDQKSFIPVERAESTFLFLVGQDDHNWKSEFYANEACKRLQAHGRRKPQIICYPET
  GHYIEPPYFPLCRASLHALVGSPIIWGGEPRAHAMAQVDAWKQLQTFFHKHLGGHEGTIP
  SKV
• Function: Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Displays higher activity toward long chain acyl CoAs (C14-C20). The enzyme is involved in enhancing the hepatic fatty acid oxidation in mitochondria.
• Tissue Specificity: Strongest expression in heart, liver, muscle and kidney. Weak in placenta and pancreas.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Mitochondrial Fatty Acid Beta-Oxidation (R-HSA-77289)
• BioCyc Pathway: MetaCyc:HS04318-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2) affects the response to substance of Mitomycin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[5]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[6]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[7]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[8]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[11]

1 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 increases the methylation of Acyl-coenzyme A thioesterase 2, mitochondrial (ACOT2).	[10]

References

• [1] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] 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.
• [6] Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes. Toxicol Appl Pharmacol. 2022 May 1;442:115991. doi: 10.1016/j.taap.2022.115991. Epub 2022 Mar 23.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [10] 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.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] 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.