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.
keywords
SKIN PIGMENTATION; MELANOSOME BIOGENESIS; MELANIN SYNTHESIS; PROTEINS; PATHWAY; DEGRADATION; MELANOCYTES; LYSOSOMES; TRANSPORT; BINDING
subject category
Oncology; Cell Biology; Dermatology
authors
Fujita, H; Menezes, JCJMDS; Santos, SM; Yokota, S; Kamat, SP; Cavaleiro, JAS; Motokawa, T; Kato, T; Mochizuki, M; Fujiwara, T; Fujii, Y; Tanaka, Y
our authors
Sérgio Miguel Fernandes dos Santos
Assistant Researcheracknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan. We acknowledge University of Aveiro and Goa University for providing necessary laboratory facilities. Thanks are due to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal), European Union, QREN, FEDER, and COMPETE for funding the QOPNA research unit (project PEst-C/QUI/UI0062/2013). JCJMDS Menezes thanks QOPNA for a research grant and S. M. Santos acknowledges FCT for the postdoc grant SFRH/BPD/64752/2009.