UC San Diego

Guanine deaminase (GDA) deaminates guanine to xanthine. Despite its significance, the study of human GDA remains limited compared to other metabolic deaminases. As a result, its substrate and inhibitor repertoire are limited, and effective real-time activity, inhibitory, and discovery assays are missing. Herein, we explore two emissive heterocyclic cores, based on thieno[3,4-d]pyrimidine (^thN) and isothiazole[4,3-d]pyrimidine (^tzN), as surrogate GDA substrates. We demonstrate that, unlike the thieno analog, ^thG_N, the isothiazolo guanine surrogate, ^tzG_N, does undergo effective enzymatic deamination by GDA and yields the spectroscopically distinct xanthine analog, ^tzX_N. Further, we showcase the potential of this fluorescent nucleobase surrogate to provide a visible spectral window for a real-time study of GDA and its inhibition.