This award in the Chemistry of Life Processes (CLP) program supports work by Professor Timothy H. Warren at Georgetown University to carry out fundamental studies on the generation and interconversion of nitric oxide (NO) and its biochemical relatives S-nitrosothiols (RSNO) and nitroxyl (HNO) at copper ions. Despite the established importance of NO and RSNOs in biochemical signaling pathways leading to physiological responses such as vasodilation along with a rapidly growing interest in HNO, enzymatic pathways for the generation and interconversion of these molecules connected to the biology of nitric oxide are not clearly delineated. A synthetic modeling approach will allow for the detailed examination of transformations among these various NO-derivatives promoted by copper ions in nitrogen-rich coordination environments related to those found in biology. Variation of the copper site along with mechanistic and spectroscopic study will reveal specific factors that promote or inhibit these processes. The straightforward synthesis of copper complexes explored in this work will allow students with very limited synthetic experience, or none at all, such as first year undergraduate (or even high school) students, to contribute to the project.
This study will lay a firm foundation upon which to assess the role of copper ions in the biological formation and interconversion of NO, RSNOs, and HNO from naturally occurring precursors such as hydroxylamine (H2NOH) and N-hydroxyguanidines. The heme-free approach will illuminate roles that metal ions other than iron play in the biological processing of nitric oxide and its molecular relatives which are involved in a myriad of physiological events.
Nitric oxide is a gas generated in biological systems that serves as a molecular messenger to assist in blood pressure regulation, enhance blood flow, participate in heart and lung health, and help nerves communicate. Long lasting effects connected to nitric oxide have been attributed to molecular derivatives of nitric oxide such as S-nitrosothiols and nitrite which naturally occur in the blood and cells. This study has reveals new, discrete molecular pathways by which these species form and interconvert to gain a deeper understanding of nitric oxide’s role as a messaging molecule. This NSF supported work greatly benefited from ongoing collaborations with several US and international scientists from Germany and Turkey. Many (9) students from elsewhere in the US or abroad (Switzerland, Germany, China) have had the opportunity to spend 2-3 month stays in the PI's laboratory at Georgetown. The PI has further broadened his outreach activities to connect with high-risk middle school students from low income families in under-resourced communities through the organization Higher Achievement. Founded in Washington, DC in 1975, it hosts a rigorous after-school (3-8 pm; 3 days/week) and summer academic program (40 h/week; 6 weeks) to great success – 93% of the graduates go on to college. On July 31, 2012, the PI gave a Chemistry "Demo" lecture at Georgetown to ca. 90 fifth and sixth graders, sharing the fun and excitement of chemistry in the context of current events. The event was capped by visits by smaller groups to the PI’s laboratory with liquid nitrogen ice cream for dessert. A similar event was hosted by the PI at Georgetown on August 6, 2013.
