Tyrosinase (Tyr) catalyzes the rate-limiting step of melanogenesis in human skin and is thus the main target for treating pigmentation disorders today. This has led to an increased research interest in Tyr inhibitors during the last decades, with a frequent focus on polyphenols. In the early stages of drug discovery, it is typical to avoid the high costs of human Tyr by using the more economic mushroom tyrosinase (mh-Tyr). Since some polyphenols are accepted as substrates by mh-Tyr, the present study aimed to more generally investigate this enzyme’s specificity toward polyphenols and to discuss its significance in the context of bioactivity-guided fractionation. Mh-Tyr substrates can change the sample color during an inhibition assay, leading to unreliable inhibition constants or to the discontinuation of a bioactivity-guided fractionation campaign. A data set of 56 natural products was investigated and classified into assay interferers (AIs) and noninterferers, using a spectrophotometric and an LC-ESIHRMS assay. Based on these experimental findings, structure–activity relationships defining AIs were deduced and implemented into an in silico tool that will allow for rapid prescreening in the future. We anticipate that these results will aid in the search for new Tyr inhibitors and contribute to the understanding of this enzyme, as well as its optimal use in pharmacological research.

Mayr, F.; Sturm, S.; Ganzera, M.; Waltenberger, B.; Martens, S.; Schwaiger, S.; Schuster, D.; Stuppner, H. (2019). Mushroom tyrosinase-based enzyme inhibition assays are not suitable for bioactivity-guided fractionation of extracts. JOURNAL OF NATURAL PRODUCTS, 82 (1): 136-147. doi: 10.1021/acs.jnatprod.8b00847 handle: http://hdl.handle.net/10449/50910

Mushroom tyrosinase-based enzyme inhibition assays are not suitable for bioactivity-guided fractionation of extracts

Martens, S.;
2019

Abstract

Tyrosinase (Tyr) catalyzes the rate-limiting step of melanogenesis in human skin and is thus the main target for treating pigmentation disorders today. This has led to an increased research interest in Tyr inhibitors during the last decades, with a frequent focus on polyphenols. In the early stages of drug discovery, it is typical to avoid the high costs of human Tyr by using the more economic mushroom tyrosinase (mh-Tyr). Since some polyphenols are accepted as substrates by mh-Tyr, the present study aimed to more generally investigate this enzyme’s specificity toward polyphenols and to discuss its significance in the context of bioactivity-guided fractionation. Mh-Tyr substrates can change the sample color during an inhibition assay, leading to unreliable inhibition constants or to the discontinuation of a bioactivity-guided fractionation campaign. A data set of 56 natural products was investigated and classified into assay interferers (AIs) and noninterferers, using a spectrophotometric and an LC-ESIHRMS assay. Based on these experimental findings, structure–activity relationships defining AIs were deduced and implemented into an in silico tool that will allow for rapid prescreening in the future. We anticipate that these results will aid in the search for new Tyr inhibitors and contribute to the understanding of this enzyme, as well as its optimal use in pharmacological research.
Settore BIO/15 - BIOLOGIA FARMACEUTICA
Mayr, F.; Sturm, S.; Ganzera, M.; Waltenberger, B.; Martens, S.; Schwaiger, S.; Schuster, D.; Stuppner, H. (2019). Mushroom tyrosinase-based enzyme inhibition assays are not suitable for bioactivity-guided fractionation of extracts. JOURNAL OF NATURAL PRODUCTS, 82 (1): 136-147. doi: 10.1021/acs.jnatprod.8b00847 handle: http://hdl.handle.net/10449/50910
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