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Experimental and computational snapshots of C-C bond formation in a C-nucleoside synthase

Li, Wenbo, Girt, Georgina C., Radadiya, Ashish ORCID:, Stewart, James J. P., Richards, Nigel G. J. ORCID: and Naismith, James H. 2023. Experimental and computational snapshots of C-C bond formation in a C-nucleoside synthase. Open Biology 13 (1) , 220287. 10.1098/rsob.220287

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The biosynthetic enzyme, ForT, catalyses the formation of a C-C bond between 4-amino-1H-pyrazoledicarboxylic acid and MgPRPP to produce a C-nucleoside precursor of formycin A. The transformation catalysed by ForT is of chemical interest because it is one of only a few examples in which C-C bond formation takes place via an electrophilic substitution of a small, aromatic heterocycle. In addition, ForT is capable of discriminating between the aminopyrazoledicarboxylic acid and an analogue in which the amine is replaced by a hydroxyl group; a remarkable feat given the steric and electronic similarities of the two molecules. Here we report biophysical measurements, structural biology and quantum chemical calculations that provide a detailed molecular picture of ForT-catalysed C-C bond formation and the conformational changes that are coupled to catalysis. Our findings set the scene for employing engineered ForT variants in the biocatalytic production of novel, anti-viral C-nucleoside and C-nucleotide analogues.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: The Royal Society
Date of First Compliant Deposit: 12 January 2023
Date of Acceptance: 30 November 2022
Last Modified: 14 Jun 2023 18:22

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