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Catalytic Promiscuity of cGAS: A Facile Enzymatic Synthesis of 2′‐3′‐Linked Cyclic Dinucleotides
Author(s) -
Rosenthal Katrin,
Becker Martin,
Rolf Jascha,
Siedentop Regine,
Hillen Michael,
Nett Markus,
Lütz Stephan
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000433
Subject(s) - chemistry , nucleotide , enzyme , biochemistry , second messenger system , nucleobase , stereochemistry , dna , combinatorial chemistry , gene
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.