Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43V4UN)

• DOT Name: 3-oxoacyl- reductase (CBR4)
• Synonyms: EC 1.1.1.100; 3-ketoacyl- reductase beta subunit; KAR beta subunit; Carbonyl reductase family member 4; CBR4; Quinone reductase CBR4; EC 1.6.5.10; Short chain dehydrogenase/reductase family 45C member 1
• Gene Name: CBR4
• Related Disease: Tuberculosis
• UniProt ID: CBR4_HUMAN
• PDB ID: 4CQL; 4CQM
• EC Number: 1.1.1.100; 1.6.5.10
• Pfam ID: PF13561
• Sequence:
  MDKVCAVFGGSRGIGRAVAQLMARKGYRLAVIARNLEGAKAAAGDLGGDHLAFSCDVAKE
  HDVQNTFEELEKHLGRVNFLVNAAGINRDGLLVRTKTEDMVSQLHTNLLGSMLTCKAAMR
  TMIQQQGGSIVNVGSIVGLKGNSGQSVYSASKGGLVGFSRALAKEVARKKIRVNVVAPGF
  VHTDMTKDLKEEHLKKNIPLGRFGETIEVAHAVVFLLESPYITGHVLVVDGGLQLIL
• Function: Component of the heterotetramer complex KAR (3-ketoacyl-[acyl carrier protein] reductase or 3-ketoacyl-[ACP] reductase) that forms part of the mitochondrial fatty acid synthase (mtFAS). Beta-subunit of the KAR heterotetramer complex, responsible for the 3-ketoacyl-ACP reductase activity of the mtFAS, reduces 3-oxoacyl-[ACP] to (3R)-hydroxyacyl-[ACP] in a NADPH-dependent manner with no chain length preference, thereby participating in mitochondrial fatty acid biosynthesis. The homotetramer has NADPH-dependent quinone reductase activity (in vitro), hence could play a role in protection against cytotoxicity of exogenous quinones. As a heterotetramer, it can also reduce 9,10-phenanthrenequinone, 1,4-benzoquinone and various other o-quinones and p-quinones (in vitro).
• Tissue Specificity: Detected in liver and kidney (at protein level) . Displays the highest expression in neuronal and muscle tissues .
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)
• BioCyc Pathway: MetaCyc:ENSG00000145439-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
Tuberculosis	DIS2YIMD	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 3-oxoacyl- reductase (CBR4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-oxoacyl- reductase (CBR4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-oxoacyl- reductase (CBR4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 3-oxoacyl- reductase (CBR4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of 3-oxoacyl- reductase (CBR4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-oxoacyl- reductase (CBR4).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 3-oxoacyl- reductase (CBR4).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of 3-oxoacyl- reductase (CBR4).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 3-oxoacyl- reductase (CBR4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of 3-oxoacyl- reductase (CBR4).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 3-oxoacyl- reductase (CBR4).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 3-oxoacyl- reductase (CBR4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3-oxoacyl- reductase (CBR4).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 3-oxoacyl- reductase (CBR4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 3-oxoacyl- reductase (CBR4).	[8]

References

• [1] Secretome profile analysis of multidrug-resistant, monodrug-resistant and drug-susceptible Mycobacterium tuberculosis.Arch Microbiol. 2018 Mar;200(2):299-309. doi: 10.1007/s00203-017-1448-0. Epub 2017 Nov 8.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] 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.
• [11] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.