Theory uncovers an unusual mechanism of DNA repair of a lesioned adenine by AlkB enzymes

Binju Wang, Dandamudi Usharani, Chunsen Li, Sason Shaik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

DNA-base lesions cause cancer and propagate into the genome. We use in-protein QM/MM calculations to study the repair of etheno-bridged adenine (εA) by the iron(IV)-oxo species of AlkB enzymes. Recent experimental investigations, using mass-spectrometry and in crystallo isolation, suggested that εA was repaired by formation of an epoxide (εA-ep) that further transforms to a glycol (εA-gl), ending finally in adenine and glyoxal. Theory reproduces the experimentally observed barrier for the rate-determining step and its pH dependence. However, as we show, the mass-spectrometrically identified species are side-byproducts unassociated with the repair mechanism. The repair is mediated by a zwitterionic species, of the same molecular mass as the epoxide, which transforms to an intermediate that matches the in crystallo trapped species in structure and mass, but is NOT the assumed εA-gl iron-glycol complex. Verifiable/falsifiable predictions, regarding the key protein residues, follow. The paper underscores the indispensable role of theory by providing atomistic descriptions of this vital mechanism, and guiding further experimental investigations.

Original languageEnglish
Pages (from-to)13895-13901
Number of pages7
JournalJournal of the American Chemical Society
Volume136
Issue number39
DOIs
StatePublished - 9 Sep 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

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