Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies
Résumé
The 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 hyperpigmentations
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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