Inulavosin and its benzo-derivatives, melanogenesis inhibitors, target the copper loading mechanism to the active site of tyrosinase

Hideaki Fujita, José C.J.M.D.S. Menezes, Sérgio M. Santos, Sadaki Yokota, Shrivallabh P. Kamat, José A.S. Cavaleiro, Tomonori Motokawa, Tomomi Kato, Mayu Mochizuki, Toshiyuki Fujiwara, Yuki Fujii, Yoshitaka Tanaka

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)376-386
Number of pages11
JournalPigment Cell and Melanoma Research
Volume27
Issue number3
DOIs
Publication statusPublished - May 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

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