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

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.

A polymethoxyflavone mixture extracted from orange peels, mainly containing nobiletin, 3,3’,4’,5,6,7,8-heptamethoxyflavone and tangeretin, suppresses melanogenesis through the acidification of cell organelles, including melanosomes

“…The translocation of tyrosinase to melanosomes proceeds through the endoplasmic reticulum and trans-Golgi network (TGN). It has been reported that mistransfer of tyrosinase in lysosomes is caused by mutation of the membrane trafficking related genes of Hermansky-Pudlak Syndrome at the post-TGN [24,25] and inulavosin which is a flavonid posseing methyl and hydroxyl groups, reduced melanin synthesis promoting the mistranslocation of tyrosinase in lysosomes in the post-TGN [20,26]. Regarding chemical structure, the PMF mixture could similarly induce the mistranlocation of tyrosinase to lysosomes in the post-TGN fashion and reduced melanin synthesis.…”

Biochemical effects of the flavanol‐rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species

“…Recently, inulavosin and its benzo-derivatives have been shown to interact with the active site of tyrosinase. 32 From the experiments using ROS-producing antimycin A, FRLFE as well as resveratrol was shown to exert anti-ROS activity in the NHEMa and SK-mel-24 melanoma cells ( Fig. 7).…”

“…It is necessary to examine whether resveratrol and FRLFE could interact with the enzymatic active site of tyrosinase and produce oxidative intermediates. Recently, inulavosin and its benzo‐derivatives have been shown to interact with the active site of tyrosinase …”

Inhibitory effects of (-)-epigallocatechin-3-gallate on melanogenesis in ultraviolet A-induced B16 murine melanoma cell

“…Tyrosinase (TRY), a melanosomal membrane protein containing copper, is a key enzyme for melanin synthesis in melanocytes. Inulavosin, a melanogenesis inhibitor isolated from Inula nervosa, was reported to inhibit melanogenesis by enhancing a degradation of TRY in lysosomes [15]. The analyses of structure-activity relationship of inulavosin and its benzo-derivatives revealed that the hydroxyl and the methyl groups played a critical role in their inhibitory activity.…”

“…This cavity of TRY is required for the association with a chaperon that assisted in copper loading to TRY. Inulavosin might compete with the copper chaperon and inhibit the copper loading processing in living melanocytes [15]. Green tea EGCG is a benzoderivative with 8 hydroxyl groups, which has strong antioxidant activity [8,16].…”