title: The unravelling of the complex pattern of tyrosinase inhibition.
abstract: Tyrosinases are responsible for melanin formation in all life domains. Tyrosinase inhibitors are used for the prevention of severe skin diseases, in skin-whitening creams and to avoid fruit browning, however continued use of many such inhibitors is considered unsafe. In this study we provide conclusive evidence of the inhibition mechanism of two well studied tyrosinase inhibitors, KA (kojic acid) and HQ (hydroquinone), which are extensively used in hyperpigmentation treatment. KA is reported in the literature with contradicting inhibition mechanisms, while HQ is described as both a tyrosinase inhibitor and a substrate. By visualization of KA and HQ in the active site of TyrBm crystals, together with molecular modeling, binding constant analysis and kinetic experiments, we have elucidated their mechanisms of inhibition, which was ambiguous for both inhibitors. We confirm that while KA acts as a mixed inhibitor, HQ can act both as a TyrBm substrate and as an inhibitor.
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
authors.forename: Batel
authors.initials: B
authors.lastname: Deri
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
authors.forename: Margarita
authors.initials: M
authors.lastname: Kanteev
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Goldfeder
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lecina
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Guallar
authors.affiliation: Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Adir
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Fishman
mesh_terms: D001410:Bacillus megaterium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006873:Hydroquinones / Q000378:metabolism; D017495:Hyperpigmentation / Q000378:metabolism; D007700:Kinetics; D008543:Melanins / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D011753:Pyrones / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006873:Hydroquinones; D008543:Melanins; D011753:Pyrones; C011890:kojic acid; D014442:Monophenol Monooxygenase; C031927:hydroquinone