Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVKRET0)

• DOT Name: 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1)
• Synonyms: EC 2.3.1.16; Acetyl-CoA C-myristoyltransferase; EC 2.3.1.155; Acetyl-CoA acyltransferase; EC 2.3.1.9; Beta-ketothiolase; Peroxisomal 3-oxoacyl-CoA thiolase
• Gene Name: ACAA1
• Related Disease:
  Allergic asthma
  Beta-ketothiolase deficiency
  Colorectal carcinoma
  Hepatocellular carcinoma
  Non-hodgkin lymphoma
  Adrenoleukodystrophy
  Asthma
  Non-insulin dependent diabetes
• UniProt ID: THIK_HUMAN
• PDB ID: 2IIK
• EC Number: 2.3.1.155; 2.3.1.16; 2.3.1.9
• Pfam ID: PF02803 ; PF00108
• Sequence:
  MQRLQVVLGHLRGPADSGWMPQAAPCLSGAPQASAADVVVVHGRRTAICRAGRGGFKDTT
  PDELLSAVMTAVLKDVNLRPEQLGDICVGNVLQPGAGAIMARIAQFLSDIPETVPLSTVN
  RQCSSGLQAVASIAGGIRNGSYDIGMACGVESMSLADRGNPGNITSRLMEKEKARDCLIP
  MGITSENVAERFGISREKQDTFALASQQKAARAQSKGCFQAEIVPVTTTVHDDKGTKRSI
  TVTQDEGIRPSTTMEGLAKLKPAFKKDGSTTAGNSSQVSDGAAAILLARRSKAEELGLPI
  LGVLRSYAVVGVPPDIMGIGPAYAIPVALQKAGLTVSDVDIFEINEAFASQAAYCVEKLR
  LPPEKVNPLGGAVALGHPLGCTGARQVITLLNELKRRGKRAYGVVSMCIGTGMGAAAVFE
  YPGN
• Function: Responsible for the thiolytic cleavage of straight chain 3-keto fatty acyl-CoAs (3-oxoacyl-CoAs). Plays an important role in fatty acid peroxisomal beta-oxidation. Catalyzes the cleavage of short, medium, long, and very long straight chain 3-oxoacyl-CoAs.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  alpha-Linolenic acid metabolism (hsa00592)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  PPAR sig.ling pathway (hsa03320)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Beta-oxidation of very long chain fatty acids (R-HSA-390247)
  Neutrophil degranulation (R-HSA-6798695)
  Peroxisomal protein import (R-HSA-9033241)
  TYSND1 cleaves peroxisomal proteins (R-HSA-9033500)
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
• BioCyc Pathway: MetaCyc:HS00752-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
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[1]
Beta-ketothiolase deficiency	DIS7NWEJ	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[5]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	3-ketoacyl-CoA thiolase, peroxisomal (ACAA1) increases the response to substance of Capecitabine.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[21]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of 3-ketoacyl-CoA thiolase, peroxisomal (ACAA1).	[22]

References

• [1] Transforming growth factor-beta(2) polymorphisms are associated with childhood atopic asthma.Clin Exp Allergy. 2007 Aug;37(8):1165-74. doi: 10.1111/j.1365-2222.2007.02768.x.
• [2] Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10?years' experience of a medical center in northern Vietnam. J Inherit Metab Dis. 2017 May;40(3):395-401. doi: 10.1007/s10545-017-0026-6. Epub 2017 Feb 20.
• [3] Functional TLR5 genetic variants affect human colorectal cancer survival.Cancer Res. 2013 Dec 15;73(24):7232-42. doi: 10.1158/0008-5472.CAN-13-1746. Epub 2013 Oct 23.
• [4] Identification of hepatocellular carcinoma-associated hub genes and pathways by integrated microarray analysis.Tumori. 2015 Mar-Apr;101(2):206-14. doi: 10.5301/tj.5000241. Epub 2015 Mar 13.
• [5] Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case-control study for gastric cancer risk.PLoS One. 2012;7(9):e45274. doi: 10.1371/journal.pone.0045274. Epub 2012 Sep 21.
• [6] Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.Proc Natl Acad Sci U S A. 1987 Mar;84(5):1425-8. doi: 10.1073/pnas.84.5.1425.
• [7] Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1.BMC Med Genet. 2011 Dec 8;12:158. doi: 10.1186/1471-2350-12-158.
• [8] Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes.Biochem Biophys Res Commun. 2008 Sep 12;374(1):101-5. doi: 10.1016/j.bbrc.2008.06.102. Epub 2008 Jul 9.
• [9] 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.
• [10] 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.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] 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.
• [17] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [22] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [23] 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.