title: Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors.
abstract: Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, we searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50=6.97μM, monophenolase activity; IC50=36.3μM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, respectively. Analyses by in silico docking studies using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, we examined the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compound for the generation of novel tyrosinase inhibitors and provides a new insight into the molecular basis of tyrosinase catalytic mechanisms.
authors: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors: Takahiro
authors: T
authors: Oyama
authors: Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama, Kanagawa 226-8510, Japan.
authors: Satoshi
authors: S
authors: Takahashi
authors: Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama, Kanagawa 226-8510, Japan.
authors: Atsushi
authors: A
authors: Yoshimori
authors: Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama, Kanagawa 226-8510, Japan.
authors: Tetsuya
authors: T
authors: Yamamoto
authors: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Akira
authors: A
authors: Sato
authors: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors: Takanori
authors: T
authors: Kamiya
authors: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors: Hideaki
authors: H
authors: Abe
authors: Hinoki Shinyaku Co., Ltd, 9-6 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan.
authors: Takehiko
authors: T
authors: Abe
authors: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: tanuma@rs.noda.tus.ac.jp.
authors: Sei-Ichi
authors: SI
authors: Tanuma
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010084:Oxidation-Reduction
chemical_list: D001565:Benzoates; D004791:Enzyme Inhibitors; D014442:Monophenol Monooxygenase
keywords: Inhibitor; MM-GB/SA; Mushroom tyrosinase; Phenylbenzoic acid