Essigmann lab publishes PNAS paper on the link between tautomerism and mutagenesis
The new manuscript, titled "Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine" has been published this week in the early edition of PNAS. The paper studies the mechanism of mutagenesis of the anti-HIV compound KP1212, a drug candidate designed to combat HIV using lethal mutagenesis. Using single-molecule biosynthetic and genetic tools, the study confirmed that KP1212 is mutagenic in vitro and in vivo, and demostrated that it pairs 90% of the time with G and 10% of the time with A. Using advanced spectroscopic techniques (VT-NMR, 1D and 2D IR), it was found that KP1212 is present in solution as a mixture of five rapidly-interconverting tautomeric forms. Assuming that each tautomer has a distinct base-pairing preferece, a model is proposed where the mutagenic properties of KP1212 can be explained by the ability of the molecule to exist in different tautomeric forms. Additionally, the methods outlined in this study can be generalized to study tautomerism of other nucleobases, and help develop next generation of lethal mutagens.