Modeling Nitric Oxide Signaling Chemistry at Non-Heme Sites

Georgetown University, Washington DC

Investigators

Abstract

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, which naturally occur in the blood and cells. This study seeks an understanding of the discrete molecular pathways by which these species form and interconvert to gain a deeper understanding of nitric oxide's role as a messaging molecule. Graduate, undergraduate, and high school students engaged in this project will gain broad scientific experience as they probe these reactions using specially designed chemical models that emulate key features common to many classes of proteins that interact with nitric oxide. Outreach to younger students (5th-8th grade) will show in a fun and engaging way how nature uses molecules for biological communication. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Timothy H. Warren from Purdue University to examine molecular mechanisms that underlie nitric oxide (NO) signaling by examining the interconversion of NO, S-nitrosothiols (RSNOs) and nitrite (NO2-) at relevant copper and zinc biological sites employing specially designed synthetic models. Binding of NO at copper-thiolates that emulate type 1 copper sites as well as interaction of RSNOs with zinc-thiolates will be examined to observe reversible S-NO bond formation and cleavage. Especially in the zinc system, these studies will form a foundation to connect the metal-centered reactivity of the gasotransmitter H2S with NO and NO2-. Additionally, binding of NO at thiolate-free copper(I) and copper(II) complexes will be examined to understand factors that control the reactivity of copper-bound NO, including unusual anaerobic oxidizing behavior connected with the formation of N2O. Detailed insights obtained for the interconversion of NO and its redox congeners at copper and zinc sites will be further enhanced through spectroscopic and computational collaboration with domestic and international partners.