Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJC60Q7)

• DOT Name: Acetyl-CoA acetyltransferase, mitochondrial (ACAT1)
• Synonyms: EC 2.3.1.9; Acetoacetyl-CoA thiolase; T2
• Gene Name: ACAT1
• Related Disease: Beta-ketothiolase deficiency
• UniProt ID: THIL_HUMAN
• PDB ID: 2F2S; 2IB7; 2IB8; 2IB9; 2IBU; 2IBW; 2IBY
• EC Number: 2.3.1.9
• Pfam ID: PF02803 ; PF00108
• Sequence:
  MAVLAALLRSGARSRSPLLRRLVQEIRYVERSYVSKPTLKEVVIVSATRTPIGSFLGSLS
  LLPATKLGSIAIQGAIEKAGIPKEEVKEAYMGNVLQGGEGQAPTRQAVLGAGLPISTPCT
  TINKVCASGMKAIMMASQSLMCGHQDVMVAGGMESMSNVPYVMNRGSTPYGGVKLEDLIV
  KDGLTDVYNKIHMGSCAENTAKKLNIARNEQDAYAINSYTRSKAAWEAGKFGNEVIPVTV
  TVKGQPDVVVKEDEEYKRVDFSKVPKLKTVFQKENGTVTAANASTLNDGAAALVLMTADA
  AKRLNVTPLARIVAFADAAVEPIDFPIAPVYAASMVLKDVGLKKEDIAMWEVNEAFSLVV
  LANIKMLEIDPQKVNINGGAVSLGHPIGMSGARIVGHLTHALKQGEYGLASICNGGGGAS
  AMLIQKL
• Function: This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA. Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms. The activity of the enzyme is reversible and it can also catalyze the condensation of two acetyl-CoA molecules into acetoacetyl-CoA. Thereby, it plays a major role in ketone body metabolism.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  Pyruvate metabolism (hsa00620)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Butanoate metabolism (hsa00650)
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Fatty acid metabolism (hsa01212)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Utilization of Ketone Bodies (R-HSA-77108)
  Synthesis of Ketone Bodies (R-HSA-77111)
  Branched-chain amino acid catabolism (R-HSA-70895)
• BioCyc Pathway: MetaCyc:HS01167-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beta-ketothiolase deficiency	DIS7NWEJ	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Acetyl-CoA acetyltransferase, mitochondrial (ACAT1) increases the response to substance of Irinotecan.	[22]

21 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-CoA acetyltransferase, mitochondrial (ACAT1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[13]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[12]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[14]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[18]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[19]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[20]
Serotonin	DMOFCRY	Investigative	Serotonin increases the expression of Acetyl-CoA acetyltransferase, mitochondrial (ACAT1).	[21]

References

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• [12] Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation. Biochem Biophys Res Commun. 2004 Oct 22;323(3):782-8.
• [13] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [14] 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.
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• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [20] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [21] Serotonin acts as an up-regulator of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-macrophages. Atherosclerosis. 2006 Jun;186(2):275-81. doi: 10.1016/j.atherosclerosis.2005.08.007. Epub 2005 Sep 12.
• [22] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.