Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN4RQK8)

• DOT Name: Acetyl-coenzyme A thioesterase (ACOT12)
• Synonyms: EC 3.1.2.1; Acyl-CoA thioester hydrolase 12; Acyl-coenzyme A thioesterase 12; Acyl-CoA thioesterase 12; Cytoplasmic acetyl-CoA hydrolase 1; CACH-1; hCACH-1; START domain-containing protein 15; StARD15
• Gene Name: ACOT12
• Related Disease:
  Leukodystrophy
  Leukoencephalopathy with vanishing white matter
  Liver cancer
  Hepatocellular carcinoma
• UniProt ID: ACO12_HUMAN
• PDB ID: 3B7K; 4MOB; 4MOC
• EC Number: 3.1.2.1
• Pfam ID: PF03061 ; PF01852
• Sequence:
  MERPAPGEVVMSQAIQPAHATARGELSAGQLLKWIDTTACLAAEKHAGVSCVTASVDDIQ
  FEETARVGQVITIKAKVTRAFSTSMEISIKVMVQDMLTGIEKLVSVAFSTFVAKPVGKEK
  IHLKPVTLLTEQDHVEHNLAAERRKVRLQHEDTFNNLMKESSKFDDLIFDEEEGAVSTRG
  TSVQSIELVLPPHANHHGNTFGGQIMAWMETVATISASRLCWAHPFLKSVDMFKFRGPST
  VGDRLVFTAIVNNTFQTCVEVGVRVEAFDCQEWAEGRGRHINSAFLIYNAADDKENLITF
  PRIQPISKDDFRRYRGAIARKRIRLGRKYVISHKEEVPLCIHWDISKQASLSDSNVEALK
  KLAAKRGWEVTSTVEKIKIYTLEEHDVLSVWVEKHVGSPAHLAYRLLSDFTKRPLWDPHF
  VSCEVIDWVSEDDQLYHITCPILNDDKPKDLVVLVSRRKPLKDGNTYTVAVKSVILPSVP
  PSPQYIRSEIICAGFLIHAIDSNSCIVSYFNHMSASILPYFAGNLGGWSKSIEETAASCI
  QFLENPPDDGFVSTF
• Function: Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Preferentially hydrolyzes acetyl-CoA.
• KEGG Pathway:
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Mitochondrial Fatty Acid Beta-Oxidation (R-HSA-77289)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukodystrophy	DISVY1TT	Strong	Biomarker	[1]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[4]

7 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 Acetyl-coenzyme A thioesterase (ACOT12).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[6]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[8]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[8]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Acetyl-coenzyme A thioesterase (ACOT12).	[8]

References

• [1] Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.PLoS One. 2009 Dec 15;4(12):e8318. doi: 10.1371/journal.pone.0008318.
• [2] Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients.BMC Neurol. 2010 Oct 19;10:94. doi: 10.1186/1471-2377-10-94.
• [3] The biphasic change of cytosolic acetyl-CoA hydrolase in rat liver during 3'-methyl-4-dimethylaminoazobenzene hepatocarcinogenesis.Jpn J Cancer Res. 1989 Feb;80(2):132-5. doi: 10.1111/j.1349-7006.1989.tb02280.x.
• [4] ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition.Cell Metab. 2019 Apr 2;29(4):886-900.e5. doi: 10.1016/j.cmet.2018.12.019. Epub 2019 Jan 22.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.