Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP-Lyase Function.

ABSTRACT: 8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK_a is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Brønsted bases binding the active site of OGG1. Systematic interrogation of compound basici

SUBMITTER: Kehler M 

PROVIDER: S-EPMC12160960 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature