Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKEX4RK)

• DOT Name: Gamma-butyrobetaine dioxygenase (BBOX1)
• Synonyms: EC 1.14.11.1; Gamma-butyrobetaine hydroxylase; Gamma-BBH; Gamma-butyrobetaine,2-oxoglutarate dioxygenase
• Gene Name: BBOX1
• UniProt ID: BODG_HUMAN
• PDB ID: 3MS5; 3N6W; 3O2G; 4BG1; 4BGK; 4BGM; 4BHF; 4BHG; 4BHI; 4C5W; 4C8R; 4CWD
• EC Number: 1.14.11.1
• Pfam ID: PF06155 ; PF02668
• Sequence:
  MACTIQKAEALDGAHLMQILWYDEEESLYPAVWLRDNCPCSDCYLDSAKARKLLVEALDV
  NIGIKGLIFDRKKVYITWPDEHYSEFQADWLKKRCFSKQARAKLQRELFFPECQYWGSEL
  QLPTLDFEDVLRYDEHAYKWLSTLKKVGIVRLTGASDKPGEVSKLGKRMGFLYLTFYGHT
  WQVQDKIDANNVAYTTGKLSFHTDYPALHHPPGVQLLHCIKQTVTGGDSEIVDGFNVCQK
  LKKNNPQAFQILSSTFVDFTDIGVDYCDFSVQSKHKIIELDDKGQVVRINFNNATRDTIF
  DVPVERVQPFYAALKEFVDLMNSKESKFTFKMNPGDVITFDNWRLLHGRRSYEAGTEISR
  HLEGAYADWDVVMSRLRILRQRVENGN
• Function: Catalyzes the formation of L-carnitine from gamma-butyrobetaine.
• Tissue Specificity: Highly expressed in kidney; moderately expressed in liver; very low expression in brain.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Carnitine synthesis (R-HSA-71262)
• BioCyc Pathway: MetaCyc:HS05246-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Levacecarnine HCL	DMJBOCR	Approved	Gamma-butyrobetaine dioxygenase (BBOX1) increases the chemical synthesis of Levacecarnine HCL.	[7]

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 Gamma-butyrobetaine dioxygenase (BBOX1).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-butyrobetaine dioxygenase (BBOX1).	[13]

14 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 Gamma-butyrobetaine dioxygenase (BBOX1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[8]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[9]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[10]
Aluminium	DM6ECN9	Approved	Aluminium decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A affects the expression of Gamma-butyrobetaine dioxygenase (BBOX1).	[10]

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] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [7] The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipidemia in human astrocytic and hepatic cells. Toxicol Lett. 2011 Jun 24;203(3):219-26. doi: 10.1016/j.toxlet.2011.03.019. Epub 2011 Mar 23.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [10] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] 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.
• [13] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [14] The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipidemia in human astrocytic and hepatic cells. Toxicol Lett. 2011 Jun 24;203(3):219-26. doi: 10.1016/j.toxlet.2011.03.019. Epub 2011 Mar 23.