title: Inhibition of tyrosinase by fumaric acid: Integration of inhibition kinetics with computational docking simulations.
abstract: Fumaric acid (FA), which is naturally found in organisms, is a well known intermediate of the citric acid cycle. We evaluated the effects of FA on tyrosinase activity and structure via enzyme kinetics and computational simulations. FA was found to be a reversible inhibitor of tyrosinase and its induced mechanism was the parabolic non-competitive inhibition type with IC50=13.7±0.25mM and Kislope=12.64±0.75mM. We newly established the equation for the dissociation constant (Kislope) for the parabolic inhibition type in this study. Kinetic measurements and spectrofluorimetry studies showed that FA induced regional changes in the active site of tyrosinase. One possible binding site for FA was identified under the condition without L-DOPA. The computational docking simulations further revealed that FA can interact with HIS263 and HIS85 at the active site. Furthermore, four important hydrogen bonds were found to be involved with the docking of FA on tyrosinase. Our study provides insight into the mechanism by which dicarboxylic acids such as FA inhibit tyrosinase. By inhibiting tyrosinase and its central role in pigment production, FA is a potential natural antipigmentation agent.
authors.affiliation: College of Biology and Science, Sichuan Agriculture University, Chengdu 611130, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Gou
authors.affiliation: Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea; Department of Nanobiotechnology and Bioinformatics, University of Sciences and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul 135-710, Republic of Korea.
authors.forename: Jun-Mo
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, PR China.
authors.forename: Yong-Doo
authors.initials: YD
authors.lastname: Park
authors.affiliation: Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, PR China.
authors.forename: Hai-Meng
authors.initials: HM
authors.lastname: Zhou
authors.affiliation: College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, PR China. Electronic address: zhanyi_1006@hotmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, PR China. Electronic address: lzr7899@163.com.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Lü
mesh_terms: D000363:Agaricales / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005650:Fumarates / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005650:Fumarates; C032005:fumaric acid; D014442:Monophenol Monooxygenase
keywords: Fumaric acid; Inhibition kinetics; Tyrosinase