Inulavosin and its benzo-derivatives, melanogenesis inhibitors, target the copper loading mechanism to the active site of tyrosinase.
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.
Section of Functional Morphology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, Japan; Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
Hideaki
H
Fujita
José C J M D S
JC
Menezes
Sérgio M
SM
Santos
Sadaki
S
Yokota
Shrivallabh P
SP
Kamat
José A S
JA
Cavaleiro
Tomonori
T
Motokawa
Tomomi
T
Kato
Mayu
M
Mochizuki
Toshiyuki
T
Fujiwara
Yuki
Y
Fujii
Yoshitaka
Y
Tanaka
D000818:Animals; D001051:Apoenzymes / Q000187:drug effects / Q000378:metabolism; D001426:Bacterial Proteins / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D020134:Catalytic Domain; D003300:Copper / Q000378:metabolism*; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008247:Lysosomes / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000201:enzymology; D020460:Melanosomes / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013303:Streptomyces antibioticus / Q000201:enzymology; D013329:Structure-Activity Relationship
C541382:2'-hydroxy-2,4,4,7,4'-pentamethylflavan; D001051:Apoenzymes; D001426:Bacterial Proteins; D005419:Flavonoids; D008543:Melanins; D018832:Molecular Chaperones; D003300:Copper; D014442:Monophenol Monooxygenase
B16 melanoma cells; copper chaperon; lysosomes; melanogenesis; melanosomes; tyrosinase