Inulavosin and its benzo-derivatives, melanogenesis inhibitors, target the copper loading mechanism to the active site of tyrosinase
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
nationality International
journal PIGMENT CELL & MELANOMA RESEARCH
author keywords B16 melanoma cells; copper chaperon; lysosomes; melanogenesis; melanosomes; tyrosinase
keywords SKIN PIGMENTATION; MELANOSOME BIOGENESIS; MELANIN SYNTHESIS; PROTEINS; PATHWAY; DEGRADATION; MELANOCYTES; LYSOSOMES; TRANSPORT; BINDING
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.
publisher WILEY-BLACKWELL
issn 1755-1471
year published 2014
volume 27
issue 3
beginning page 376
ending page 386
digital object identifier (doi) 10.1111/pcmr.12225
web of science category Oncology; Cell Biology; Dermatology
subject category Oncology; Cell Biology; Dermatology
unique article identifier WOS:000334170900009
link 24479607
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5 year journal impact factor 4.833
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