Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5HKJ4)

• DOT Name: Tryptophan 2,3-dioxygenase (TDO2)
• Synonyms: TDO; EC 1.13.11.11; Tryptamin 2,3-dioxygenase; Tryptophan oxygenase; TO; TRPO; Tryptophan pyrrolase; Tryptophanase
• Gene Name: TDO2
• Related Disease: Familial hypertryptophanemia
• UniProt ID: T23O_HUMAN
• PDB ID: 4PW8; 5TI9; 5TIA; 6A4I; 6PYY; 6PYZ; 6UD5; 6VBN; 7LU7
• EC Number: 1.13.11.11
• Pfam ID: PF03301
• Sequence:
  MSGCPFLGNNFGYTFKKLPVEGSEEDKSQTGVNRASKGGLIYGNYLHLEKVLNAQELQSE
  TKGNKIHDEHLFIITHQAYELWFKQILWELDSVREIFQNGHVRDERNMLKVVSRMHRVSV
  ILKLLVQQFSILETMTALDFNDFREYLSPASGFQSLQFRLLENKIGVLQNMRVPYNRRHY
  RDNFKGEENELLLKSEQEKTLLELVEAWLERTPGLEPHGFNFWGKLEKNITRGLEEEFIR
  IQAKEESEEKEEQVAEFQKQKEVLLSLFDEKRHEHLLSKGERRLSYRALQGALMIYFYRE
  EPRFQVPFQLLTSLMDIDSLMTKWRYNHVCMVHRMLGSKAGTGGSSGYHYLRSTVSDRYK
  VFVDLFNLSTYLIPRHWIPKMNPTIHKFLYTAEYCDSSYFSSDESD
• Function: Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine. Catalyzes the oxidative cleavage of the indole moiety.
• KEGG Pathway:
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS07771-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
Familial hypertryptophanemia	DISDJM7Y	Supportive	Autosomal recessive	[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 Tryptophan 2,3-dioxygenase (TDO2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[13]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Tryptophan 2,3-dioxygenase (TDO2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tryptophan 2,3-dioxygenase (TDO2).	[14]

References

• [1] Hypertryptophanemia due to tryptophan 2,3-dioxygenase deficiency. Mol Genet Metab. 2017 Apr;120(4):317-324. doi: 10.1016/j.ymgme.2017.02.009. Epub 2017 Mar 1.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [6] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [7] Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] 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.
• [15] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.