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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.

SUBMITTER: Deri B

PROVIDER: S-EPMC5057104 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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The unravelling of the complex pattern of tyrosinase inhibition.

Deri Batel B Kanteev Margarita M Goldfeder Mor M Lecina Daniel D Guallar Victor V Adir Noam N Fishman Ayelet A

Scientific reports 20161011

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 ...[more]

PMID: 27725765

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Project description:When exposed to ultraviolet radiation, the human skin produces profuse reactive oxygen species (ROS), which in turn activate a variety of biological responses. Mounting ROS levels activate tyrosinase by mobilizing ?-melanocyte-stimulating hormone in the epidermis and finally stimulates the melanocytes to produce melanin. Meanwhile, the Keap1-Nrf2/ARE pathway, which removes ROS, is activated at increased ROS levels, and antioxidant compounds facilitates the dissociation of Nrf2. In this study, we explored the possible suppressing effects of antioxidant compounds and tyrosine inhibitors on melanin formation and the promotory effects of these compounds on ROS scavenging. The antioxidant activity of glabridin (GLA), resveratrol (RES), oxyresveratrol (OXYR), and phenylethylresorcinol (PR) were investigated via the stable free radical 2,2-diphenyl-1-picrylhydrazyl method. The inhibitory effects of the four compounds and their mixtures on tyrosinase were evaluated. l-Tyrosine or 3-(3,4-dihydroxyphenyl)-l-alanine (l-DOPA) was used as a substrate. The results showed that all mixtures did not exhibit synergistic effects with the l-tyrosine as a substrate, suggesting that l-tyrosine is not suitable as a substrate. However, the mixtures of "GLA:RES," "GLA:OXYR," "OXYR:RES," and "PR:RES" demonstrated synergistic effects (CI < 0.9, p < 0.05), whereas "GLA:RES" and "PR:OXYR" indicated an additive effect (0.9 ditive1, p < 0.05). Furthermore, we used a molecular docking strategy to study the interactions of the four compounds with tyrosinase and l-DOPA. The molecular docking result is consistent with that of the experiment. Finally, we selected RES + OXYR and used PIG1 cells to verify whether OXYR synergistically promotes RES activity on tyrosinase. The two agents had a synergistic inhibitory effect on tyrosinase activity. These results provided a novel synergistic strategy for antioxidants and tyrosinase inhibitors, and this strategy is useful in skin injury treatment.

Project description:Background:Unravelling the genetic basis of polymorphic characters is central to our understanding of the origins and diversification of living organisms. Recently, supergenes have been implicated in a wide range of complex polymorphisms, from adaptive colouration in butterflies and fish to reproductive strategies in birds and plants. The concept of a supergene is now a hot topic in biology, and identification of its functional elements is needed to shed light on the evolution of highly divergent adaptive traits. Here, we apply different gene expression analyses to study the supergene P that controls polymorphism of mimetic wing colour patterns in the neotropical butterfly Heliconius numata. Results:We performed de novo transcriptome assembly and differential expression analyses using high-throughput Illumina RNA sequencing on developing wing discs of different H. numata morphs. Within the P interval, 30 and 17 of the 191 transcripts were expressed differentially in prepupae and day-1 pupae, respectively. Among these is the gene cortex, known to play a role in wing pattern formation in Heliconius and other Lepidoptera. Our in situ hybridization experiments confirmed the relationship between cortex expression and adult wing patterns. Conclusions:This study found the majority of genes in the P interval to be expressed in the developing wing discs during the critical stages of colour pattern formation, and detect drastic changes in expression patterns in multiple genes associated with structural variants. The patterns of expression of cortex only partially recapitulate the variation in adult phenotype, suggesting that the remaining phenotypic variation could be controlled by other genes within the P interval. Although functional studies on cortex are now needed to determine its exact developmental role, our results are in accordance with the classical supergene hypothesis, whereby several genes inherited together due to tight linkage control a major developmental switch.

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The unravelling of the complex pattern of tyrosinase inhibition.

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The unravelling of the complex pattern of tyrosinase inhibition.

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