Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX54MAA)

• DOT Name: Tyrosinase
• Synonyms: EC 1.14.18.1; LB24-AB; Monophenol monooxygenase; SK29-AB; Tumor rejection antigen AB
• Gene Name: TYR
• Related Disease:
  Oculocutaneous albinism type 1
  Oculocutaneous albinism type 1A
  Minimal pigment oculocutaneous albinism type 1
  Oculocutaneous albinism type 1B
  Temperature-sensitive oculocutaneous albinism type 1
• UniProt ID: TYRO_HUMAN
• PDB ID: 7RK7
• EC Number: 1.14.18.1
• Pfam ID: PF00264
• Sequence:
  MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILL
  SNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCTERRLLVR
  RNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLFVWMH
  YYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENFTIPYWDWRD
  AEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTPEGPLRRN
  PGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIADASQS
  SMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPIGH
  NRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLG
  AAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQPLLMEKEDYHSLYQSHL
• Function: This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the initial and rate limiting step in the cascade of reactions leading to melanin production from tyrosine. In addition to hydroxylating tyrosine to DOPA (3,4-dihydroxyphenylalanine), also catalyzes the oxidation of DOPA to DOPA-quinone, and possibly the oxidation of DHI (5,6-dihydroxyindole) to indole-5,6 quinone.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
  Melanogenesis (hsa04916)
• Reactome Pathway: Melanin biosynthesis (R-HSA-5662702)
• BioCyc Pathway: MetaCyc:HS01248-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oculocutaneous albinism type 1	DISBKTWY	Definitive	Autosomal recessive	[1]
Oculocutaneous albinism type 1A	DIS9AICT	Definitive	Autosomal recessive	[2]
Minimal pigment oculocutaneous albinism type 1	DIS2U2VO	Supportive	Autosomal recessive	[3]
Oculocutaneous albinism type 1B	DISD1HF3	Supportive	Autosomal recessive	[3]
Temperature-sensitive oculocutaneous albinism type 1	DIS8V501	Supportive	Autosomal recessive	[3]

This DOT Affected the Biotransformations of 9 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin C	DMXJ7O8	Approved	Tyrosinase increases the oxidation of Vitamin C.	[23]
Levodopa	DMN3E57	Approved	Tyrosinase increases the oxidation of Levodopa.	[24]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	Tyrosinase increases the oxidation of 3,4-Dihydroxycinnamic Acid.	[23]
Ferulic Acid	DMJC7NF	Patented	Tyrosinase increases the oxidation of Ferulic Acid.	[23]
Chlorogenic acid	DM2Y3P4	Investigative	Tyrosinase increases the oxidation of Chlorogenic acid.	[23]
P-Coumaric Acid	DMGJSVD	Investigative	Tyrosinase increases the oxidation of P-Coumaric Acid.	[23]
Caffeic acid phenethyl ester	DMRJKIV	Investigative	Tyrosinase increases the oxidation of Caffeic acid phenethyl ester.	[23]
Nicotinamide-Adenine-Dinucleotide	DM9LRKB	Investigative	Tyrosinase increases the oxidation of Nicotinamide-Adenine-Dinucleotide.	[23]
Cinnamic acid	DM340FH	Investigative	Tyrosinase increases the oxidation of Cinnamic acid.	[23]

19 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 Tyrosinase.	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the activity of Tyrosinase.	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Tyrosinase.	[7]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Tyrosinase.	[8]
Nicotinamide	DMUPE07	Approved	Nicotinamide increases the expression of Tyrosinase.	[9]
Vemurafenib	DM62UG5	Approved	Vemurafenib increases the expression of Tyrosinase.	[10]
Amikacin	DM5PDRB	Approved	Amikacin decreases the activity of Tyrosinase.	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Tyrosinase.	[12]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Tyrosinase.	[13]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the activity of Tyrosinase.	[14]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha decreases the expression of Tyrosinase.	[15]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Tyrosinase.	[16]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Tyrosinase.	[8]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the activity of Tyrosinase.	[17]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Tyrosinase.	[18]
PD98059	DMZC90M	Investigative	PD98059 decreases the expression of Tyrosinase.	[19]
H-89	DM4RVGO	Investigative	H-89 decreases the activity of Tyrosinase.	[20]
AMENTOFLAVONE	DMLRNV2	Investigative	AMENTOFLAVONE decreases the activity of Tyrosinase.	[21]
Beta-ionone	DM6QV8A	Investigative	Beta-ionone increases the expression of Tyrosinase.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Tyrosinase.	[6]

References

• [1] 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.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Oculocutaneous Albinism Type 1 C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2000 Jan 19 [updated 2013 May 16]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] Quercetin enhances melanogenesis by increasing the activity and synthesis of tyrosinase in human melanoma cells and in normal human melanocytes. Pigment Cell Res. 2004 Feb;17(1):66-73. doi: 10.1046/j.1600-0749.2003.00113.x.
• [6] 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.
• [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] 9-cis retinoic acid is the ALDH1A1 product that stimulates melanogenesis. Exp Dermatol. 2013 Mar;22(3):202-9. doi: 10.1111/exd.12099.
• [9] Examining the impact of skin lighteners in vitro. Oxid Med Cell Longev. 2013;2013:702120. doi: 10.1155/2013/702120. Epub 2013 Apr 28.
• [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] Modulation of melanogenesis and antioxidant defense system in melanocytes by amikacin. Toxicol In Vitro. 2013 Apr;27(3):1102-8.
• [12] 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.
• [13] Melanogenesis and antioxidant defense system in normal human melanocytes cultured in the presence of chlorpromazine. Toxicol In Vitro. 2015 Feb;29(1):221-7.
• [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] The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. J Biol Chem. 2009 Feb 13;284(7):4343-53. doi: 10.1074/jbc.M805570200. Epub 2008 Dec 18.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Anti-melanogenic effects of resorcinol are mediated by suppression of cAMP signaling and activation of p38 MAPK signaling. Biosci Biotechnol Biochem. 2018 Jul;82(7):1188-1196. doi: 10.1080/09168451.2018.1459176. Epub 2018 Apr 5.
• [18] Galvanic zinc-copper microparticles inhibit melanogenesis via multiple pigmentary pathways. Arch Dermatol Res. 2014 Jan;306(1):27-35. doi: 10.1007/s00403-013-1369-y. Epub 2013 May 23.
• [19] Melanogenesis in uveal melanoma cells: Effect of argan oil. Int J Mol Med. 2017 Oct;40(4):1277-1284. doi: 10.3892/ijmm.2017.3104. Epub 2017 Aug 23.
• [20] p44/42 MAPK signaling is a prime target activated by phenylethyl resorcinol in its anti-melanogenic action. Phytomedicine. 2019 May;58:152877. doi: 10.1016/j.phymed.2019.152877. Epub 2019 Feb 26.
• [21] New constituent from Podocarpus macrophyllus var. macrophyllus shows anti-tyrosinase effect and regulates tyrosinase-related proteins and mRNA in human epidermal melanocytes. Chem Pharm Bull (Tokyo). 2007 May;55(5):757-61. doi: 10.1248/cpb.55.757.
• [22] Functional Characterization of the Odorant Receptor 51E2 in Human Melanocytes. J Biol Chem. 2016 Aug 19;291(34):17772-86. doi: 10.1074/jbc.M116.734517. Epub 2016 May 18.
• [23] Biochemical mechanism of caffeic acid phenylethyl ester (CAPE) selective toxicity towards melanoma cell lines. Chem Biol Interact. 2010 Oct 6;188(1):1-14. doi: 10.1016/j.cbi.2010.05.018. Epub 2010 Jun 4.
• [24] Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Mol Pharmacol. 2013 Jan;83(1):85-94. doi: 10.1124/mol.112.079798. Epub 2012 Oct 10.