Oxidative Demethylation in crystallo

Chuan He group (University of Chicago) and collaborators


In epigenetics, as well as in repair of damaged nucleic acids and in regulation of energy homeostasis and obesity, iron-containing monooxygenases perform a variety of oxidation functions in biology. Chemically, these include oxidative demethylation of methylated histones and nucleic acids. AlkB protein from E. coli, a prototype of such demethylases, oxidatively repairs cytotoxic/mutagenic DNA bases, including 1-methyl adenine, 3-methyl cytosine and 1,N6-etheno adenine. Nine human homologues of AlkB have been identified so far, and some of them are known to be involved in pivotal cellular roles. Using a disulfide cross-linking method, Chuan He and coworkers determined the first crystal structures of AlkB bound to dsDNA containing various damaged bases. By exposing the anaerobically-grown crystals to dioxygen, they were able to initiate oxidation reactions in crystallo and structurally characterized three oxidation intermediates. Such structures provide detailed mechanistic insights into these monooxygenase-mediated oxidation reactions, and also shed light on more biological demethylation processes.

Figure: “Movie” of oxidative demethylation in crystallo.


Citation: Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang C-G, Cui Q, He C. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature. 2010 Nov 11; 468: 330-333. doi:10.1038/nature09497.



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