title: Exploring the interaction of N/S compounds with a dicopper center: tyrosinase inhibition and model studies.
abstract: Tyrosinase (Ty) is a copper-containing enzyme widely present in plants, bacteria, and humans, where it is involved in biosynthesis of melanin-type pigments. Development of Ty inhibitors is an important approach to control the production and the accumulation of pigments in living systems. In this paper, we focused our interest in phenylthiourea (PTU) and phenylmethylene thiosemicarbazone (PTSC) recognized as inhibitors of tyrosinase by combining enzymatic studies and coordination chemistry methods. Both are efficient inhibitors of mushroom tyrosinase and they can be considered mainly as competitive inhibitors. Computational studies verify that PTSC and PTU inhibitors interact with the metal center of the active site. The KIC value of 0.93 μM confirms that PTSC is a much more efficient inhibitor than PTU, for which a KIC value of 58 μM was determined. The estimation of the binding free energies inhibitors/Ty confirms the high inhibitor efficiency of PTSC. Binding studies of PTSC along with PTU to a dinuclear copper(II) complex ([Cu2(μ-BPMP)(μ-OH)](ClO4)2 (1); H-BPMP = 2,6-bis-[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) known to be a structural and functional model for the tyrosinase catecholase activity, have been performed. Interactions of the compounds with the dicopper model complex 1 were followed by spectrophotometry and electrospray ionization (ESI). The molecular structure of 1-PTSC and 1-PTU adducts were determined by single-crystal X-ray diffraction analysis showing for both an unusual bridging binding mode on the dicopper center. These results reflect their adaptable binding mode in relation to the geometry and chelate size of the dicopper center.
authors.affiliation: Université Grenoble Alpes, DCM, CNRS, F-38000 Grenoble, France.
authors.forename: Elina
authors.initials: E
authors.lastname: Buitrago
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vuillamy
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.forename: Gisèle
authors.initials: G
authors.lastname: Gellon
authors.forename: Renaud
authors.initials: R
authors.lastname: Hardré
authors.forename: Christian
authors.initials: C
authors.lastname: Philouze
authors.forename: Guy
authors.initials: G
authors.lastname: Serratrice
authors.forename: Hélène
authors.initials: H
authors.lastname: Jamet
authors.forename: Marius
authors.initials: M
authors.lastname: Réglier
authors.forename: Catherine
authors.initials: C
authors.lastname: Belle
mesh_terms: D000364:Agaricus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000378:metabolism; D008958:Models, Molecular; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010670:Phenylthiourea / Q000737:chemistry* / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D013882:Thiosemicarbazones; D007980:Levodopa; D010670:Phenylthiourea; D003300:Copper; D014442:Monophenol Monooxygenase