Affiliation:
1. Université Grenoble Alpes CNRS Department of Molecular Chemistry (DCM UMR 5250) 38058 Grenoble Cedex 9 France
2. Structural Biology Group, European Synchrotron Radiation Facility (ESRF) 38053 Grenoble France
3. Aix Marseille Université, CNRS, Centrale Marseille, iSm2 Marseille France).
4. IRIG-BGE U1038 INSERM Univ. Grenoble Alpes, Biomics 38054 Grenoble France
Abstract
AbstractThe pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments’ precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo‐ and hyper‐pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT‐1 cells, and X‐ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L–DOPA, namely (S)‐3‐amino‐tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.
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