Crosstalk of NO, O2, and H2S at the [4Fe4S] interface: exploring the reactivity with biomimetic model complexes

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A growing number of small, freely-diffusible gaseous signaling molecules, termed `gasotransmitters,' are understood to play key roles in biological signaling in animals, plants, and bacteria. The extensive overlap in individual gasotransmitter signaling pathways leads to cumulative effects that have implications for human health. The biological activity of the gasotransmitter nitric oxide (NO) is directly influenced in its activity by other small oxygen-, nitrogen-, and sulfur-based bioactive gas molecules. The long term objective of my highly multidisciplinary research program is to explore the specific reactivity of NO with other gasotransmitter species at the interface of iron-sulfur (FeS) cluster metalloprotein centres. This research progam consists of three main short term objectives (SOs). In SO1, we will seek to explore the reaction of FeS clusters with byproducts of NO and O2 reactivity. In biology, these molecules are active agents in triggering and directing a protective response against nitrosative stress mediated by specialized FeS cluster proteins. We will design and synthesize a series of biomimetic model FeS cluster complexes using synthetic small molecule ligands and coiled coil synthetic protein ligands. We will then use these to explore the effect of an oxidative environment on NO reactivity, and develop a robust spectroscopic methodology to characterize key reaction intermediates. In SO2, we will explore the intersection of NO and H2S reactivity at the interface of iron sulfur clusters. The fate of sulfides lost from FeS clusters following reaction with NO has been implicated as a source of biological small molecule persulfide species and H2S. We are therefore interested in exploring the controlled generation of biologically relevant sulfur-based signalling molecules, including H2S, from the reaction of NO and FeS clusters. We will build on methodologies developed in SO1, adapted towards trapping reaction intermediates and control of sulfur species formation. In SO3, we will use the FeS cluster scaffold as a basis for generating the novel putative gasotransmitter HSNO. We seek to develop a de novo protein system designed specifically to promote the formation of an S-N bond with subsequent release of the SNO- unit under controlled conditions and targetable via protein modification such as glycosylation. HSNO has been identified as a new gasotransmitter and understanding its generation would advance understanding of its role in biology. Impacts: The research program will enhance the current state of scientific knowledge of biologically-relevant reactive small molecules using cutting-edge synthetic and analytical approaches. New tools will be provided to examine these very unstable and difficult to study molecules. Students trained in this program will benefit from a highly multidisciplinary training where synthetic inorganic, bioinorganic and analytical chemistries will be utilized to achieve new scientific findings.