Authors: | Rosenthal, Katrin Becker, Martin Rolf, Jascha Siedentop, Regine Hillen, Michael Nett, Markus Lütz, Stephan |
Title: | Catalytic promiscuity of cGAS: a facile enzymatic synthesis of 2′-3′-Linked cyclic dinucleotides |
Language (ISO): | en |
Abstract: | Enzymatic shortcut: Cyclic dinucleotides, which are of great interest to study immunology and immune oncology, can be synthesized in a one-step biotransformation significantly shortening the chemical synthesis route. The enzyme displays a surprisingly large substrate scope. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that catalyzes the synthesis of the cyclic GMP-AMP dinucleotide 2′3′-cGAMP. 2′3′-cGAMP functions as inducer for the production of type I interferons. Derivatives of this important second messenger are highly valuable for pharmaceutical applications. However, the production of these analogues requires complex, multistep syntheses. Herein, human cGAS is shown to react with a series of unnatural nucleotides, thus leading to novel cyclic dinucleotides. Most substrate derivatives with modifications at the nucleobase, ribose, and the α-thio phosphate were accepted. These results demonstrate the catalytic promiscuity of human cGAS and its utility for the biocatalytic synthesis of cyclic dinucleotide derivatives. |
Subject Headings: | biocatalysis catalytic promiscuity cGAS Cyclic dinucleotides Enzymes |
URI: | http://hdl.handle.net/2003/40333 http://dx.doi.org/10.17877/DE290R-22208 |
Issue Date: | 2020-07-07 |
Has relation to: | https://creativecommons.org/licenses/by/4.0/ |
Appears in Collections: | Arbeitsgruppe Bioverfahrenstechnik |
Files in This Item:
File | Description | Size | Format | |
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cbic.202000433.pdf | 765.81 kB | Adobe PDF | View/Open |
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