Gaseous Signaling by NO and H2S

People working on this project:

Tom Hirsch, Sarah Wynia-Smith

The small gaseous molecules nitric oxide (NO) and hydrogen sulfide (H2S) are used as signaling molecules for a number of important enzymes in human and bacterial systems. This project area focuses on investigating these signaling pathways in health and disease.

Nitric Oxide Synthase

Nitric oxide synthase (NOS) is a homodymeric enzyme that catalyzes formation of nitric oxide (NO), an essential signaling molecule in endothelial and neuronal cells that is also involved in the immune response. NOS yields release of NO and citrulline from L-arginine by shuttling electrons from NADPH via FAD and FMN modules in the reductase domain of one monomer to the heme in the oxygenase domain of the other monomer. Electron transfer in both domains depends on calmodulin (CaM) binding. Recent structural investigations have revealed multiple conformations of CaM-NOS. However, the time scales of interchange among conformational states are not known, nor is it clear how the observed conformational changes correlate with the catalytic cycle of the enzyme.   We seek to determine a detailed model of NOS function that describes sequences and rates of conformational changes and shows how they are related to subunit conformational changes and interdomain interactions.

Hydrogen Sulfide Signaling

H2S is a freely diffusible gas used by the body as a neurotransmitter and to regulate muscular tone in the heart, vasculature, and visceral organs.