Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHY684G)

• DOT Name: Acyl-coenzyme A thioesterase 8 (ACOT8)
• Synonyms: Acyl-CoA thioesterase 8; EC 3.1.2.1; EC 3.1.2.11; EC 3.1.2.2; EC 3.1.2.3; EC 3.1.2.5; Choloyl-coenzyme A thioesterase; EC 3.1.2.27; HIV-Nef-associated acyl-CoA thioesterase; Peroxisomal acyl-CoA thioesterase 2; PTE-2; Peroxisomal acyl-coenzyme A thioester hydrolase 1; PTE-1; Peroxisomal long-chain acyl-CoA thioesterase 1; Thioesterase II; hACTE-III; hACTEIII; hTE
• Gene Name: ACOT8
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Hepatocellular carcinoma
  HIV infectious disease
  Hypophosphatemia
  Non-small-cell lung cancer
  Psoriasis
  Thiel-Behnke corneal dystrophy
• UniProt ID: ACOT8_HUMAN
• EC Number: 3.1.2.1; 3.1.2.11; 3.1.2.2; 3.1.2.27; 3.1.2.3; 3.1.2.5
• Pfam ID: PF13622 ; PF02551
• Sequence:
  MSSPQAPEDGQGCGDRGDPPGDLRSVLVTTVLNLEPLDEDLFRGRHYWVPAKRLFGGQIV
  GQALVAAAKSVSEDVHVHSLHCYFVRAGDPKLPVLYQVERTRTGSSFSVRSVKAVQHGKP
  IFICQASFQQAQPSPMQHQFSMPTVPPPEELLDCETLIDQYLRDPNLQKRYPLALNRIAA
  QEVPIEIKPVNPSPLSQLQRMEPKQMFWVRARGYIGEGDMKMHCCVAAYISDYAFLGTAL
  LPHQWQHKVHFMVSLDHSMWFHAPFRADHWMLYECESPWAGGSRGLVHGRLWRQDGVLAV
  TCAQEGVIRVKPQVSESKL
• Function: Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Displays no strong substrate specificity with respect to the carboxylic acid moiety of Acyl-CoAs. Hydrolyzes medium length (C2 to C20) straight-chain, saturated and unsaturated acyl-CoAS but is inactive towards substrates with longer aliphatic chains. Moreover, it catalyzes the hydrolysis of CoA esters of bile acids, such as choloyl-CoA and chenodeoxycholoyl-CoA and competes with bile acid CoA:amino acid N-acyltransferase (BAAT). Is also able to hydrolyze CoA esters of dicarboxylic acids. It is involved in the metabolic regulation of peroxisome proliferation ; (Microbial infection) May mediate Nef-induced down-regulation of CD4 cell-surface expression.
• Tissue Specificity: Detected in a T-cell line (at protein level). Ubiquitous .
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)
  Beta-oxidation of very long chain fatty acids (R-HSA-390247)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS02282-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
HIV infectious disease	DISO97HC	Strong	Biomarker	[4]
Hypophosphatemia	DIS9DZYF	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Altered Expression	[7]
Thiel-Behnke corneal dystrophy	DIS3GK26	Strong	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[11]
Orlistat	DMRJSP8	Approved	Orlistat decreases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[11]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Acyl-coenzyme A thioesterase 8 (ACOT8).	[14]

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 8 (ACOT8).	[13]

References

• [1] Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital.J Clin Microbiol. 2010 Dec;48(12):4519-24. doi: 10.1128/JCM.01648-10. Epub 2010 Oct 13.
• [2] Isolation of hNap1BP which interacts with human Nap1 (NCKAP1) whose expression is down-regulated in Alzheimer's disease.Gene. 2001 Jun 27;271(2):159-69. doi: 10.1016/s0378-1119(01)00521-2.
• [3] Fatty acid metabolic enzyme acyl-CoA thioesterase8 promotes the development of hepatocellular carcinoma.Oncol Rep. 2014 Jun;31(6):2797-803. doi: 10.3892/or.2014.3155. Epub 2014 Apr 24.
• [4] Physiological relevance of ACOT8-Nef interaction in HIV infection.Rev Med Virol. 2019 Sep;29(5):e2057. doi: 10.1002/rmv.2057. Epub 2019 Jun 9.
• [5] Phosphatonin washout in Hyp mice proximal tubules: evidence for posttranscriptional regulation.Am J Physiol Renal Physiol. 2005 Feb;288(2):F363-70. doi: 10.1152/ajprenal.00217.2004. Epub 2004 Sep 28.
• [6] Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.J Exp Clin Cancer Res. 2019 Mar 11;38(1):122. doi: 10.1186/s13046-019-1124-0.
• [7] Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ.J Invest Dermatol. 1991 Jul;97(1):73-9. doi: 10.1111/1523-1747.ep12478128.
• [8] Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.PLoS One. 2017 Jan 26;12(1):e0170640. doi: 10.1371/journal.pone.0170640. eCollection 2017.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Orlistat Displays Antitumor Activity and Enhances the Efficacy of Paclitaxel in Human Hepatoma Hep3B Cells. Chem Res Toxicol. 2019 Feb 18;32(2):255-264. doi: 10.1021/acs.chemrestox.8b00269. Epub 2019 Jan 22.
• [12] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.