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• W4385366907 abstract "Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with the abasic site base excision repair intermediate. For the 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product assisted catalysis approach, where the excised 8-oxoG acts as a Brønsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Here, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent scaffolds enabling OGG1 to cleave abasic sites opposite any canonical nucleobase by β-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of activators, 6-substituted pyrazolo-[3,4-d]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a de novo OGG1 β- elimination in conditions commonly not tolerated. This allows for the development of activators applicable in distinct pH environments of different cellular compartments." @default.
• W4385366907 created "2023-07-29" @default.
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• W4385366907 date "2023-07-27" @default.
• W4385366907 modified "2023-10-17" @default.
• W4385366907 title "Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1" @default.
• W4385366907 doi "https://doi.org/10.26434/chemrxiv-2023-70gws-v2" @default.
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