Myoglobin (Mb) and hemoglobin (Hb) are some of the most studied proteins, and their roles in dioxygen (O2) transport and storage are widely understood. Less understood is their involvement in the overall global nitrogen cycle, their interactions with biologically relevant organic nitrogen oxides (RNOx), and the structural and functional changes that these proteins undergo in the process of RNOx interconversion, which is the focus of this work. The functions of Mb and Hb reside mainly in their heme cofactor, as O2 binds directly to the Fe atom embedded within it. Organic nitrosoalkanes (RNO) are valence isoelectronic with O2, and as a result, RNOs often compete with O2 for binding and may form “inhibitory” Fe(II)-RNO complexes. Organic nitrosoalkanes are made physiologically from the oxidation of amines (RNH2) and hydroxylamines (RNHOH) or by the reduction of nitro (RNO2) containing compounds. Once RNOs are created, they can bind hemoproteins which may lead to harmful outcomes. For instance, binding of RNOs to human Hb may lead to methemoglobinemia which can then cause heme loss and successive Fe accumulation in the spleen. Also alarming is the damage caused to liver cytochrome P450s; upon binding, RNOs inhibit P450s, annulling their function in detoxification of xenobiotics. Despite the adverse health implications, there is little structural information regarding the mode of binding of RNOs to hemoproteins, and the effect of such binding on overall protein structure and function. This research delineates the interactions of Mb and Hb with nitrosoalkanes, to determine the effects of ligand sterics on RNO binding and the resulting stability and coordination of the complexes. We will present high-resolution X-ray crystal structures that illustrate how RNOs, which are naturally occurring metabolites, bind Mb and Hb disturbing the vital roles these proteins have on O2 utilization.

Structural and functional changes induced by alkyl RNO binding to myoglobin & hemoglobin

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.