Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6ZORKP)

• DOT Name: Tyrosine 3-monooxygenase (TH)
• Synonyms: EC 1.14.16.2; Tyrosine 3-hydroxylase; TH
• Gene Name: TH
• Related Disease:
  TH-deficient dopa-responsive dystonia
  Tyrosine hydroxylase deficiency
• UniProt ID: TY3H_HUMAN
• PDB ID: 2XSN; 4J6S; 6ZN2; 6ZVP; 6ZZU; 7A2G; 7PIM
• EC Number: 1.14.16.2
• Pfam ID: PF00351 ; PF21417 ; PF12549
• Sequence:
  MPTPDATTPQAKGFRRAVSELDAKQAEAIMVRGQGAPGPSLTGSPWPGTAAPAASYTPTP
  RSPRFIGRRQSLIEDARKEREAAVAAAAAAVPSEPGDPLEAVAFEEKEGKAVLNLLFSPR
  ATKPSALSRAVKVFETFEAKIHHLETRPAQRPRAGGPHLEYFVRLEVRRGDLAALLSGVR
  QVSEDVRSPAGPKVPWFPRKVSELDKCHHLVTKFDPDLDLDHPGFSDQVYRQRRKLIAEI
  AFQYRHGDPIPRVEYTAEEIATWKEVYTTLKGLYATHACGEHLEAFALLERFSGYREDNI
  PQLEDVSRFLKERTGFQLRPVAGLLSARDFLASLAFRVFQCTQYIRHASSPMHSPEPDCC
  HELLGHVPMLADRTFAQFSQDIGLASLGASDEEIEKLSTLYWFTVEFGLCKQNGEVKAYG
  AGLLSSYGELLHCLSEEPEIRAFDPEAAAVQPYQDQTYQSVYFVSESFSDAKDKLRSYAS
  RIQRPFSVKFDPYTLAIDVLDSPQAVRRSLEGVQDELDTLAHALSAIG
• Function: Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of cathecolamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa. In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity. Positively regulates the regression of retinal hyaloid vessels during postnatal development; [Isoform 5]: Lacks catalytic activity; [Isoform 6]: Lacks catalytic activity.
• Tissue Specificity: Mainly expressed in the brain and adrenal glands.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Dopaminergic sy.pse (hsa04728)
  Prolactin sig.ling pathway (hsa04917)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway: Catecholamine biosynthesis (R-HSA-209905)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
TH-deficient dopa-responsive dystonia	DISLE7HP	Definitive	Autosomal recessive	[1]
Tyrosine hydroxylase deficiency	DISSQ831	Definitive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Tyrosine 3-monooxygenase (TH) affects the response to substance of Hydrogen peroxide.	[24]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dopamine	DMPGUCF	Approved	Tyrosine 3-monooxygenase (TH) increases the chemical synthesis of Dopamine.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Tyrosine 3-monooxygenase (TH).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine 3-monooxygenase (TH).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine 3-monooxygenase (TH).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine 3-monooxygenase (TH).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tyrosine 3-monooxygenase (TH).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Tyrosine 3-monooxygenase (TH).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tyrosine 3-monooxygenase (TH).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Tyrosine 3-monooxygenase (TH).	[11]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Tyrosine 3-monooxygenase (TH).	[12]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Tyrosine 3-monooxygenase (TH).	[13]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of Tyrosine 3-monooxygenase (TH).	[14]
Lovastatin	DM9OZWQ	Approved	Lovastatin increases the expression of Tyrosine 3-monooxygenase (TH).	[15]
Piperazine	DMTY9LU	Approved	Piperazine decreases the expression of Tyrosine 3-monooxygenase (TH).	[16]
Zonisamide	DM0DTF7	Approved	Zonisamide increases the expression of Tyrosine 3-monooxygenase (TH).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tyrosine 3-monooxygenase (TH).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine 3-monooxygenase (TH).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine 3-monooxygenase (TH).	[6]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Tyrosine 3-monooxygenase (TH).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Tyrosine 3-monooxygenase (TH).	[21]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Tyrosine 3-monooxygenase (TH).	[22]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Tyrosine 3-monooxygenase (TH).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Tyrosine 3-monooxygenase (TH).	[4]

References

• [1] A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum Genet. 1995 Jan;95(1):123-5. doi: 10.1007/BF00225091.
• [2] 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.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] A not cytotoxic nickel concentration alters the expression of neuronal differentiation markers in NT2 cells. Neurotoxicology. 2015 Mar;47:47-53. doi: 10.1016/j.neuro.2015.01.001. Epub 2015 Jan 19.
• [6] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [7] Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro. Biochem Biophys Res Commun. 2000 Oct 14;277(1):179-85. doi: 10.1006/bbrc.2000.3651.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] A DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, exacerbates neurotoxicity and upregulates Parkinson's disease-related genes in dopaminergic neurons. CNS Neurosci Ther. 2013 Mar;19(3):183-90. doi: 10.1111/cns.12059.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol. 2007 Jun 15;221(3):261-7. doi: 10.1016/j.taap.2007.04.002. Epub 2007 Apr 12.
• [12] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [13] Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro. Toxicology. 2023 Mar 15;487:153461. doi: 10.1016/j.tox.2023.153461. Epub 2023 Feb 16.
• [14] Immunohistochemical investigation of dopaminergic terminal markers and caspase-3 activation in the striatum of human methamphetamine users. Int J Legal Med. 2007 May;121(3):163-8. doi: 10.1007/s00414-006-0087-9. Epub 2006 Apr 19.
• [15] Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP. Mol Cell Biochem. 2010 Dec;345(1-2):1-11. doi: 10.1007/s11010-010-0553-z. Epub 2010 Aug 9.
• [16] Comparing the dopaminergic neurotoxic effects of benzylpiperazine and benzoylpiperazine. Toxicol Mech Methods. 2018 Mar;28(3):177-186. doi: 10.1080/15376516.2017.1376024. Epub 2017 Sep 28.
• [17] [The discovery of an antiparkinsonian drug, zonisamide]. Rinsho Shinkeigaku. 2010 Feb;50(2):67-73. doi: 10.5692/clinicalneurol.50.67.
• [18] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [19] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [21] Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells. Environ Toxicol Pharmacol. 2015 Nov;40(3):895-900. doi: 10.1016/j.etap.2015.09.019. Epub 2015 Oct 3.
• [22] Phenolic-rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb-induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve-like cells. Environ Toxicol. 2022 Mar;37(3):660-676. doi: 10.1002/tox.23433. Epub 2021 Dec 12.
• [23] Gene-Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres. Environ Health Perspect. 2021 Jul;129(7):77001. doi: 10.1289/EHP8580. Epub 2021 Jul 14.
• [24] Expression of tyrosine hydroxylase increases the resistance of human neuroblastoma cells to oxidative insults. Toxicol Sci. 2010 Jan;113(1):150-7. doi: 10.1093/toxsci/kfp245. Epub 2009 Oct 8.