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

越来越多的小的、可自由扩散的气体信号分子，被称为“气体传递器”，被认为在动物、植物和细菌的生物信号传递中起着关键作用。单个气体递质信号通路的广泛重叠导致对人类健康产生影响的累积效应。气体递质一氧化氮（NO）的生物活性直接受到其他小的氧基、氮基和硫基生物活性气体分子的影响。我高度跨学科的研究计划的长期目标是探索NO与其他气体传递物质在铁硫（FeS）团簇金属蛋白中心界面的特定反应性。本研究计划包括三个主要的短期目标（SOs）。在SO1中，我们将探索FeS团簇与NO和O2副产物的反应活性。在生物学中，这些分子是触发和指导由专门的FeS簇蛋白介导的针对亚硝化应激的保护性反应的活性因子。我们将利用合成小分子配体和螺旋状合成蛋白质配体设计并合成一系列仿生模型FeS簇状配合物。然后，我们将使用这些来探索氧化环境对NO反应活性的影响，并开发一种强大的光谱方法来表征关键反应中间体。在SO2中，我们将探索NO和H2S在铁硫团簇界面上的反应性交集。在与NO反应后，从FeS簇中丢失的硫化物的命运被认为是生物小分子过硫化物和H2S的来源。因此，我们有兴趣探索从NO和FeS簇的反应中控制产生生物学相关的硫基信号分子，包括H2S。我们将以SO1开发的方法为基础，适应捕获反应中间体和控制硫的形成。在SO3中，我们将使用FeS簇支架作为产生新型假定气体发射器HSNO的基础。我们寻求开发一种全新的蛋白质系统，专门设计用于促进S-N键的形成，随后在受控条件下释放SNO-单元，并可通过糖基化等蛋白质修饰进行靶向。HSNO已被确定为一种新的气体传递体，了解其产生将促进对其在生物学中的作用的理解。影响：该研究项目将利用尖端的合成和分析方法，提高生物相关反应性小分子的科学知识现状。将提供新的工具来检查这些非常不稳定和难以研究的分子。该专业的学生将受益于高度跨学科的培训，其中合成无机化学，生物无机化学和分析化学将被用于实现新的科学发现。

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.