Mechanistic Studies on the Reactions of Cobalamins with the Nitrogen Oxide Species NONOates and Peroxynitrite

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This Research award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports work by Professor Nicola Brasch at Kent State University to carry out studies on the reactions of vitamin B12 derivatives (cobalamins, Cbls) with NONOates and peroxynitrite. The rates and mechanisms of the reactions between Cbls and NONOates and the related N-substituted hydroxyamines will be determined. Determining the mechanisms of these reactions is important, given the widespread involvement of NONOates in biological systems and the broader impact extending to (H)NO-releasing pharmaceuticals. The overwhelming focus of non-clinical B12 research in the past four decades concerns its role in B12-dependent enzyme reactions, but there is increasing evidence that Cbls may reduce overproduction of reactive oxygen or nitrogen species such as nitric oxide and peroxynitrite. Cbls efficiently scavenge nitric oxide; however it is not yet known whether they react with the much more potent peroxynitrite. Rates and mechanisms of the reactions between Cbls and peroxynitrite will be determined. The ability of Cbls to inhibit peroxynitrite-induced tyrosine nitration is also being explored.An Immersive Classroom featuring a Virtual Reality Environment Wall for 3-D stereoscopic visualization was recently installed in the Department of Chemistry at Kent State University. Teaching modules on B12 coenzymes and vitamin B12 suitable for a senior Inorganic Chemistry class and a graduate class in Bioinorganic Chemistry are in development and will be made available to others via the web. This research will improve our understanding of the chemistry of NONOates, peroxynitrite and vitamin B12, and, in the longer term, will provide fundamental scientific information potentially useful as a broader impact in the development of better therapeutics.