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

无机，生物无机和有机化学计划的这项研究奖支持肯特州立大学的Nicola Brasch教授开展维生素B12衍生物（钴，Cbls）与NONOates和过氧亚硝酸盐反应的研究。Cbls和NONOates和相关的N-取代的羟胺之间的反应的速率和机制将被确定。确定这些反应的机制是重要的，因为NONOates广泛参与生物系统和更广泛的影响延伸到（H）NO释放药物。在过去的四十年中，非临床B12研究的压倒性焦点是其在B12依赖性酶反应中的作用，但越来越多的证据表明，CBLS可以减少活性氧或氮物质（如一氧化氮和过氧亚硝酸盐）的过度产生。 Cbls能有效地分解一氧化氮，但是还不知道它们是否能与更有效的过氧亚硝酸根反应。 将确定CBLS和过氧亚硝酸盐之间的反应速率和机制。Cbls抑制过氧亚硝酸盐诱导的酪氨酸硝化的能力也正在探索中。最近在肯特州立大学的化学系安装了一个沉浸式教室，其特点是虚拟现实环境墙用于3-D立体可视化。 适合高级无机化学班和生物无机化学研究生班的B12辅酶和维生素B12教学模块正在开发中，并将通过网络提供给其他人。这项研究将提高我们对NONOates，过氧亚硝酸盐和维生素B12化学的理解，从长远来看，将提供基础科学信息，可能对开发更好的治疗方法产生更广泛的影响。

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.