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.