Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7L16DY)

• DOT Name: Acyl-CoA-binding domain-containing protein 5 (ACBD5)
• Gene Name: ACBD5
• Related Disease:
  Retinal dystrophy with leukodystrophy
  Inherited retinal dystrophy
  Peroxisomal disorder
  Acyl-CoA binding domain containing protein 5 deficiency
  Neoplasm
  Thyroid gland papillary carcinoma
• UniProt ID: ACBD5_HUMAN
• PDB ID: 3FLV
• Pfam ID: PF00887
• Sequence:
  MFQFHAGSWESWCCCCLIPADRPWDRGQHWQLEMADTRSVHETRFEAAVKVIQSLPKNGS
  FQPTNEMMLKFYSFYKQATEGPCKLSRPGFWDPIGRYKWDAWSSLGDMTKEEAMIAYVEE
  MKKIIETMPMTEKVEELLRVIGPFYEIVEDKKSGRSSDITSVRLEKISKCLEDLGNVLTS
  TPNAKTVNGKAESSDSGAESEEEEAQEEVKGAEQSDNDKKMMKKSADHKNLEVIVTNGYD
  KDGFVQDIQNDIHASSSLNGRSTEEVKPIDENLGQTGKSAVCIHQDINDDHVEDVTGIQH
  LTSDSDSEVYCDSMEQFGQEESLDSFTSNNGPFQYYLGGHSSQPMENSGFREDIQVPPGN
  GNIGNMQVVAVEGKGEVKHGGEDGRNNSGAPHREKRGGETDEFSNVRRGRGHRMQHLSEG
  TKGRQVGSGGDGERWGSDRGSRGSLNEQIALVLMRLQEDMQNVLQRLQKLETLTALQAKS
  STSTLQTAPQPTSQRPSWWPFEMSPGVLTFAIIWPFIAQWLVYLYYQRRRRKLN
• Function: Acyl-CoA binding protein which acts as the peroxisome receptor for pexophagy but is dispensable for aggrephagy and nonselective autophagy. Binds medium- and long-chain acyl-CoA esters.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  Peroxisomal lipid metabolism (R-HSA-390918)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinal dystrophy with leukodystrophy	DISXRT54	Definitive	Autosomal recessive	[1]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[1]
Peroxisomal disorder	DISV185U	Strong	Biomarker	[2]
Acyl-CoA binding domain containing protein 5 deficiency	DIS7CMWR	Moderate	Autosomal recessive	[3]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[4]

3 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 Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[15]

11 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 Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[10]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[16]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Acyl-CoA-binding domain-containing protein 5 (ACBD5).	[17]

References

• [1] ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J Med Genet. 2017 May;54(5):330-337. doi: 10.1136/jmedgenet-2016-104132. Epub 2016 Oct 31.
• [2] Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal -Oxidation of Very-long-chain Fatty Acids.J Biol Chem. 2017 Jan 13;292(2):691-705. doi: 10.1074/jbc.M116.760090. Epub 2016 Nov 29.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] A novel RET rearrangement (ACBD5/RET) by pericentric inversion, inv(10)(p12.1;q11.2), in papillary thyroid cancer from an atomic bomb survivor exposed to high-dose radiation.Oncol Rep. 2014 Nov;32(5):1809-14. doi: 10.3892/or.2014.3449. Epub 2014 Aug 29.
• [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] 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.
• [8] 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.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] 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.
• [17] Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci. 2014 Jan 9;15(1):905-26. doi: 10.3390/ijms15010905.