Inulavosin and its benzo‐derivatives,melanogenesis inhibitors,target the copper loading mechanism to the active site of tyrosinase |
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| Authors: | Sérgio M Santos Sadaki Yokota Shrivallabh P Kamat José A S Cavaleiro Tomonori Motokawa Tomomi Kato Mayu Mochizuki Toshiyuki Fujiwara Yuki Fujii Yoshitaka Tanaka |
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| Institution: | 1. Department of Chemistry and CICECO, University of Aveiro, , Aveiro, Portugal;2. Section of Functional Morphology, Faculty of Pharmaceutical Sciences, Nagasaki International University, , Nagasaki, Japan;3. Department of Chemistry, Goa University, , Taleigao, Goa, India;4. Department of Chemistry and QOPNA, University of Aveiro, , Aveiro, Portugal;5. Skin Research Department, POLA Chemical Industries, Inc., , Totsuka‐ku, Yokohama, Japan;6. Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, , Fukuoka, Japan;7. Organelle Homeostasis Research Center, Kyushu University, , Fukuoka, Japan |
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| Abstract: | Tyrosinase, a melanosomal membrane protein containing copper, is a key enzyme for melanin synthesis in melanocytes. Inulavosin inhibits melanogenesis by enhancing a degradation of tyrosinase in lysosomes. However, the mechanism by which inulavosin redirects tyrosinase to lysosomes is yet unknown. The analyses of structure–activity relationship of inulavosin and its benzo‐derivatives reveal that the hydroxyl and the methyl groups play a critical role in their inhibitory activity. Intriguingly, the docking studies to tyrosinase suggest that the compounds showing inhibitory activity bind through hydrophobic interactions to the cavity of tyrosinase below which the copper‐binding sites are located. This cavity is proposed to be required for the association with a chaperon that assists in copper loading to tyrosinase in Streptomyces antibioticus. Inulavosin and its benzo‐derivatives may compete with the copper chaperon and result in a lysosomal mistargeting of apo‐tyrosinase that has a conformational defect. |
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| Keywords: | B16 melanoma cells copper chaperon lysosomes melanogenesis melanosomes tyrosinase |
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