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
Cyclic dinucleotides
Issue Date: 2020-07-07
Has relation to:
Appears in Collections:Arbeitsgruppe Bioverfahrenstechnik

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