Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRK49R4)

• DOT Name: 5,6-dihydroxyindole-2-carboxylic acid oxidase
• Synonyms: DHICA oxidase; EC 1.14.18.-; Catalase B; Glycoprotein 75; Melanoma antigen gp75; Tyrosinase-related protein 1; TRP; TRP-1; TRP1
• Gene Name: TYRP1
• Related Disease: Oculocutaneous albinism type 3
• UniProt ID: TYRP1_HUMAN
• PDB ID: 5M8L; 5M8M; 5M8N; 5M8O; 5M8P; 5M8Q; 5M8R; 5M8S; 5M8T
• EC Number: 1.14.18.-
• Pfam ID: PF00264
• Sequence:
  MSAPKLLSLGCIFFPLLLFQQARAQFPRQCATVEALRSGMCCPDLSPVSGPGTDRCGSSS
  GRGRCEAVTADSRPHSPQYPHDGRDDREVWPLRFFNRTCHCNGNFSGHNCGTCRPGWRGA
  ACDQRVLIVRRNLLDLSKEEKNHFVRALDMAKRTTHPLFVIATRRSEEILGPDGNTPQFE
  NISIYNYFVWTHYYSVKKTFLGVGQESFGEVDFSHEGPAFLTWHRYHLLRLEKDMQEMLQ
  EPSFSLPYWNFATGKNVCDICTDDLMGSRSNFDSTLISPNSVFSQWRVVCDSLEDYDTLG
  TLCNSTEDGPIRRNPAGNVARPMVQRLPEPQDVAQCLEVGLFDTPPFYSNSTNSFRNTVE
  GYSDPTGKYDPAVRSLHNLAHLFLNGTGGQTHLSPNDPIFVLLHTFTDAVFDEWLRRYNA
  DISTFPLENAPIGHNRQYNMVPFWPPVTNTEMFVTAPDNLGYTYEIQWPSREFSVPEIIA
  IAVVGALLLVALIFGTASYLIRARRSMDEANQPLLTDQYQCYAEEYEKLQNPNQSVV
• Function: Plays a role in melanin biosynthesis. Catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into indole-5,6-quinone-2-carboxylic acid in the presence of bound Cu(2+) ions, but not in the presence of Zn(2+). May regulate or influence the type of melanin synthesized. Also to a lower extent, capable of hydroxylating tyrosine and producing melanin.
• Tissue Specificity: Pigment cells.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
  Melanogenesis (hsa04916)
• Reactome Pathway: Melanin biosynthesis (R-HSA-5662702)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oculocutaneous albinism type 3	DISDEWS5	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	5,6-dihydroxyindole-2-carboxylic acid oxidase affects the response to substance of Etoposide.	[19]

21 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 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[8]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[9]
Vemurafenib	DM62UG5	Approved	Vemurafenib increases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[11]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[12]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[12]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[13]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[16]
Manganese	DMKT129	Investigative	Manganese decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[17]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[11]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[12]
CyPPA	DM64L9I	Investigative	CyPPA decreases the expression of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5,6-dihydroxyindole-2-carboxylic acid oxidase.	[15]

References

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• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [7] Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact. 2017 Aug 1;273:107-114. doi: 10.1016/j.cbi.2017.06.005. Epub 2017 Jun 7.
• [8] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [9] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [10] PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
• [11] Post-transcriptional regulation of melanin biosynthetic enzymes by cAMP and resveratrol in human melanocytes. J Invest Dermatol. 2007 Sep;127(9):2216-27. doi: 10.1038/sj.jid.5700840. Epub 2007 Apr 26.
• [12] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [13] 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.
• [14] Emodin isolated from Polygoni Multiflori Ramulus inhibits melanogenesis through the liver X receptor-mediated pathway. Chem Biol Interact. 2016 Apr 25;250:78-84. doi: 10.1016/j.cbi.2016.03.014. Epub 2016 Mar 10.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [18] The ion channel activator CyPPA inhibits melanogenesis via the GSK3/-catenin pathway. Chem Biol Interact. 2019 Feb 25;300:1-7. doi: 10.1016/j.cbi.2018.12.014. Epub 2018 Dec 28.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.