Please use this identifier to cite or link to this item: http://hdl.handle.net/10773/20484
Title: Inulavosin and its benzo-derivatives, melanogenesis inhibitors, target the copper loading mechanism to the active site of tyrosinase
Author: Fujita, Hideaki
Menezes, Jose C. J. M. D. S.
Santos, Sergio M.
Yokota, Sadaki
Kamat, Shrivallabh P.
Cavaleiro, Jose A. S.
Motokawa, Tomonori
Kato, Tomomi
Mochizuki, Mayu
Fujiwara, Toshiyuki
Fujii, Yuki
Tanaka, Yoshitaka
Keywords: SKIN PIGMENTATION
MELANOSOME BIOGENESIS
MELANIN SYNTHESIS
PROTEINS
PATHWAY
DEGRADATION
MELANOCYTES
LYSOSOMES
TRANSPORT
BINDING
Issue Date: 2014
Publisher: WILEY-BLACKWELL
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.
Peer review: yes
URI: http://hdl.handle.net/10773/20484
DOI: 10.1111/pcmr.12225
ISSN: 1755-1471
Publisher Version: 10.1111/pcmr.12225
Appears in Collections:CICECO - Artigos



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