Details of Drug Off-Target (DOT)

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

DOT Name 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2)
Synonyms
EC 2.3.1.16; Acetyl-CoA acetyltransferase; EC 2.3.1.9; Acetyl-CoA acyltransferase; Acyl-CoA hydrolase, mitochondrial; EC 3.1.2.-, EC 3.1.2.1, EC 3.1.2.2; Beta-ketothiolase; Mitochondrial 3-oxoacyl-CoA thiolase; T1
Gene Name ACAA2
UniProt ID
THIM_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4C2J; 4C2K
EC Number
2.3.1.16; 2.3.1.9; 3.1.2.-; 3.1.2.1; 3.1.2.2
Pfam ID
PF02803 ; PF00108
Sequence
MALLRGVFVVAAKRTPFGAYGGLLKDFTATDLSEFAAKAALSAGKVSPETVDSVIMGNVL
QSSSDAIYLARHVGLRVGIPKETPALTINRLCGSGFQSIVNGCQEICVKEAEVVLCGGTE
SMSQAPYCVRNVRFGTKLGSDIKLEDSLWVSLTDQHVQLPMAMTAENLAVKHKISREECD
KYALQSQQRWKAANDAGYFNDEMAPIEVKTKKGKQTMQVDEHARPQTTLEQLQKLPPVFK
KDGTVTAGNASGVADGAGAVIIASEDAVKKHNFTPLARIVGYFVSGCDPSIMGIGPVPAI
SGALKKAGLSLKDMDLVEVNEAFAPQYLAVERSLDLDISKTNVNGGAIALGHPLGGSGSR
ITAHLVHELRRRGGKYAVGSACIGGGQGIAVIIQSTA
Function
In the production of energy from fats, 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 (Probable). Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain unbranched 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms (Probable). Also catalyzes the condensation of two acetyl-CoA molecules into acetoacetyl-CoA and could be involved in the production of ketone bodies (Probable). Also displays hydrolase activity on various fatty acyl-CoAs. Thereby, could be responsible for the production of acetate in a side reaction to beta-oxidation (Probable). Abolishes BNIP3-mediated apoptosis and mitochondrial damage.
KEGG Pathway
Fatty acid elongation (hsa00062 )
Fatty acid degradation (hsa00071 )
Valine, leucine and isoleucine degradation (hsa00280 )
Metabolic pathways (hsa01100 )
Fatty acid metabolism (hsa01212 )
Reactome Pathway
Mitochondrial Fatty Acid Beta-Oxidation (R-HSA-77289 )
BioCyc Pathway
MetaCyc:HS09539-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 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, mitochondrial (ACAA2). [1]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [21]
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25 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, mitochondrial (ACAA2). [2]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [3]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [4]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [5]
Quercetin DM3NC4M Approved Quercetin decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [6]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [7]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [8]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [9]
Selenium DM25CGV Approved Selenium increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [10]
Phenobarbital DMXZOCG Approved Phenobarbital decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [11]
Isotretinoin DM4QTBN Approved Isotretinoin decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [12]
Obeticholic acid DM3Q1SM Approved Obeticholic acid increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [13]
Fenofibrate DMFKXDY Approved Fenofibrate increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [14]
Acocantherin DM7JT24 Approved Acocantherin affects the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [15]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [16]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [17]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [10]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [18]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [19]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [20]
Oleic acid DM54O1Z Investigative Oleic acid increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [22]
GW7647 DM9RD0C Investigative GW7647 increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [22]
Benzoquinone DMNBA0G Investigative Benzoquinone decreases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [23]
Farnesol DMV2X1B Investigative Farnesol increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [22]
Flavone DMEQH6J Investigative Flavone increases the expression of 3-ketoacyl-CoA thiolase, mitochondrial (ACAA2). [24]
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⏷ Show the Full List of 25 Drug(s)

References

1 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.
2 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.
3 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.
4 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
5 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.
6 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
7 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
8 Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
9 The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
10 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.
11 Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
12 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.
13 Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
14 Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
15 Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
16 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
17 A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
18 Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potencies. Carcinogenesis. 2006 Mar;27(3):646-55.
19 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.
20 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
21 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
22 Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
23 l-Carnitine protects against 1,4-benzoquinone-induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells. Environ Toxicol. 2020 Oct;35(10):1033-1042. doi: 10.1002/tox.22939. Epub 2020 Jun 1.
24 Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.