Chemical Zymogens: Specificity and Steroidal Control of Reactivation.

Activating and masking enzymatic activity on demand is of the highest importance in nature. It is achieved by chemical interconversion of enzymes and the corresponding zymogens through, for example, proteolytic processing or reversible phosphorylation, and affords on-demand activation of enzymes, controlled in space and/or time. In stark contrast, examples of chemical zymogens are very few, and in most cases these are based on disulfide chemistry, which is largely indiscriminate as to the nature of the activating thiol. In this work, we address an outstanding challenge of specificity of reactivation of chemical zymogens. We achieve this through engineering affinity between the chemical zymogen and the activator. Additional, higher-level control over zymogen reactivation is installed in a nature-mimicking approach using steroidal hormones. Taken together, the results of this study take a step towards establishing the specificity of reactivation of synthetic, chemical zymogens. We anticipate that the results of this study will contribute significantly to the development of chemical zymogens as tools for diverse use in chemical biology and biotechnology. © 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.

Citation

Mireia Casanovas Montasell, Anna Baumann, Alexander N Zelikin. Chemical Zymogens: Specificity and Steroidal Control of Reactivation. Chembiochem : a European journal of chemical biology. 2023 Aug 01;24(15):e202300304

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PMID: 37071475

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