Nitric oxide has important and diverse roles in mammalian biology including cytotoxic immune response to pathogeninvasion, vasodilation, and intracellular signaling in the cardiovascular and nervous systems. Metal centers are the primary targets, but reactions with dioxygen and other reactive oxygen species give NOx intermediates that have importantphysiological roles. The ferroheme center in soluble guanylyl cyclase (sGC) is the best characterized target for NO. Nitric oxide has also been reported to inhibit metalloenzymes such as catalase and cytochrome oxidase, and its vasodilator properties are directly implicated in blood pressure regulation. Numerous disease states have been shown to involve the over- or under-production on NO. Dintrosyl iron complexes (DNICs) have also been implied in the storage and transport of NO in mammilian systems; animal cells can generate these paramagnetic DNICs with cysteine residues of proteins and low-molecular weight thiols such as glutathione.
Research in this laboratory is generally involved with fundamental chemical studies of systems chosen as models of biologically relevant targets for NO. Reactions of interest include the formation of metal-NO bonds and the reactivity of coordinated NO as well as the manner in which NO coordination changes the properties of other ligands. We are also studying the reactions of other nitrogen oxides (NOx) with metal centers and the potential biological relevance of such interactions. This research is sponsored by the National Science Foundation.
As alluded to in the photochemistry section, carbon monoxide is also studied in this labortory; it is widely known as an acute toxin. However, it is also produced endogenously by inducible heme oxygenase (HO-1), which catalyzes the breakdown of the heme moiety. HO-1 is highly up-regulated under stress conditions; it is suggested that CO exerts an anti-inflammatory, apoptotic, and anti-proliferative effect in various disease states ranging from hemolytic disease to diabetes.
Finally, in conjunction with other collaborators, we are beginning to explore the physiological activity of small concentrations of carbon disulfide (CS2) with potential biological target molecules.