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
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.