Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP1L0BZ)

• DOT Name: Carotenoid-cleaving dioxygenase, mitochondrial (BCO2)
• Synonyms: EC 1.13.11.-; EC 1.13.11.71; B-diox-II; Beta,beta-carotene 9',10'-oxygenase; Beta-carotene dioxygenase 2
• Gene Name: BCO2
• Related Disease:
  Epilepsy
  Fatty liver disease
  Hepatocellular carcinoma
  Metabolic disorder
  Prostate cancer
  Prostate carcinoma
  Non-alcoholic fatty liver disease
  Vitamin A deficiency
  Advanced cancer
  Neoplasm
• UniProt ID: BCDO2_HUMAN
• EC Number: 1.13.11.-; 1.13.11.71
• Pfam ID: PF03055
• Sequence:
  MFFRVFLHFIRSHSATAVDFLPVMVHRLPVFKRYMGNTPQKKAVFGQCRGLPCVAPLLTT
  VEEAPRGISARVWGHFPKWLNGSLLRIGPGKFEFGKDKYNHWFDGMALLHQFRMAKGTVT
  YRSKFLQSDTYKANSAKNRIVISEFGTLALPDPCKNVFERFMSRFELPGKAAAMTDNTNV
  NYVRYKGDYYLCTETNFMNKVDIETLEKTEKVDWSKFIAVNGATAHPHYDLDGTAYNMGN
  SFGPYGFSYKVIRVPPEKVDLGETIHGVQVICSIASTEKGKPSYYHSFGMTRNYIIFIEQ
  PLKMNLWKIATSKIRGKAFSDGISWEPQCNTRFHVVEKRTGQLLPGRYYSKPFVTFHQIN
  AFEDQGCVIIDLCCQDNGRTLEVYQLQNLRKAGEGLDQVHNSAAKSFPRRFVLPLNVSLN
  APEGDNLSPLSYTSASAVKQADGTIWCSHENLHQEDLEKEGGIEFPQIYYDRFSGKKYHF
  FYGCGFRHLVGDSLIKVDVVNKTLKVWREDGFYPSEPVFVPAPGTNEEDGGVILSVVITP
  NQNESNFILVLDAKNFEELGRAEVPVQMPYGFHGTFIPI
• Function: Broad specificity mitochondrial dioxygenase that mediates the asymmetric oxidative cleavage of carotenoids. Cleaves carotenes (pure hydrocarbon carotenoids) such as all-trans-beta-carotene and lycopene as well as xanthophylls (oxygenated carotenoids) such as zeaxanthin, lutein and beta-cryptoxanthin at both the 9,10 and the 9',10' carbon-carbon double bond. Through its function in carotenoids metabolism regulates oxidative stress and the production of important signaling molecules.
• Tissue Specificity: Highly expressed in retinal pigment epithelium. Also expressed in stomach, small intestine, liver, testis, kidney, adrenal gland, pancreas, heart, skeletal muscle and prostate (at protein level).
• Reactome Pathway: Retinoid metabolism and transport (R-HSA-975634)
• BioCyc Pathway: MetaCyc:G66-33846-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Disputed	Biomarker	[6]
Vitamin A deficiency	DISBEPZO	Disputed	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

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 Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[14]

5 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 Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carotenoid-cleaving dioxygenase, mitochondrial (BCO2).	[15]

References

• [1] A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine.Epilepsia Open. 2019 Jan 17;4(1):102-109. doi: 10.1002/epi4.12297. eCollection 2019 Mar.
• [2] Tomato Powder Inhibits Hepatic Steatosis and Inflammation Potentially Through Restoring SIRT1 Activity and Adiponectin Function Independent of Carotenoid Cleavage Enzymes in Mice.Mol Nutr Food Res. 2018 Apr;62(8):e1700738. doi: 10.1002/mnfr.201700738. Epub 2018 Mar 22.
• [3] Comprehensive characterization of cancer genes in hepatocellular carcinoma genomes.Oncol Lett. 2018 Feb;15(2):1503-1510. doi: 10.3892/ol.2017.7521. Epub 2017 Dec 5.
• [4] Ablation of ,-carotene-9',10'-oxygenase 2 remodels the hypothalamic metabolome leading to metabolic disorders in mice.J Nutr Biochem. 2017 Aug;46:74-82. doi: 10.1016/j.jnutbio.2017.02.019. Epub 2017 Apr 12.
• [5] -Carotene 9',10' Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model.Cancer Prev Res (Phila). 2017 Feb;10(2):161-169. doi: 10.1158/1940-6207.CAPR-15-0402. Epub 2016 Nov 2.
• [6] Dietary -Cryptoxanthin Inhibits High-Refined Carbohydrate Diet-Induced Fatty Liver via Differential Protective Mechanisms Depending on Carotenoid Cleavage Enzymes in Male Mice.J Nutr. 2019 Sep 1;149(9):1553-1564. doi: 10.1093/jn/nxz106.
• [7] -apo-10'-carotenoids support normal embryonic development during vitamin A deficiency.Sci Rep. 2018 Jun 11;8(1):8834. doi: 10.1038/s41598-018-27071-3.
• [8] Mitochondrial -Carotene 9',10' Oxygenase Modulates Prostate Cancer Growth via NF-B Inhibition: A Lycopene-Independent Function.Mol Cancer Res. 2016 Oct;14(10):966-975. doi: 10.1158/1541-7786.MCR-16-0075. Epub 2016 Jul 12.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] 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.