Rosenthal, KatrinBecker, MartinRolf, JaschaSiedentop, RegineHillen, MichaelNett, MarkusLütz, Stephan2021-07-192021-07-192020-07-07http://hdl.handle.net/2003/40333http://dx.doi.org/10.17877/DE290R-22208Enzymatic 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.enbiocatalysiscatalytic promiscuitycGASCyclic dinucleotidesEnzymes660Text