Hydrogen sulfide (H2S)
In human physiology, hydrogen sulfide (H2S), a small gaseous molecule that diffuses across aqueous and hydrophobic milieu, has been shown to team up with NO and CO as the third ‘gasotransmitter’. Several physiological processes are regulated by H2S, including blood flow, cellular stress response, inflammation, immune defense, apoptosis and energy metabolism. Consequently, disturbed H2S metabolism is associated with numerous human pathologies, from cardiovascular and inflammatory disorders, to neurodegeneration and cancer. Interestingly, recent studies also implicate H2S oxidation as an important aspect of bacterial antibiotic resistance and sulfide homeostasis.
As any other reactive signaling molecule, H2S homeostasis requires a fine balance between its synthesis and breakdown. H2S detoxification relies on a mitochondrial pathway involving a sulfide:quinone oxidoreductase (SQR), a persulfide dioxygenase, rhodanese and a sulfite oxidase. The reduction of quinone to quinol by SQR couples H2S oxidation to oxygen respiration by the mitochondrial electron transfer chain. Overexpression of H2S synthesis and breakdown enzymes in colorectal cancer contributes to cancer cell bioenergetics, positioning these enzymes as promising drug targets.
Although numerous studies have focused on the functional analysis of H2S catabolism components, there is a paucity of structural data to support i) the understanding of functional/physiological data, and ii) the discovery and design of modulatory compounds with potential pharmacological interest. Our Team is interested in several of these hydrogen sulfide interconverting enzymes as potential drugs targets for structure-aided drug design.
In cooperation with several Collaborators around the World, these structural studies are carried out in parallel with functional studies focusing on enzymatic mechanisms.
We ultimately aim at screening for synthetic compounds with modulatory activity towards the target proteins. Altogether, the integrated information from the structural and the functional point of view will support the understanding of multiple physiological observations and the discovery and validation of compounds with pharmacologic potential.
