Biosynthesis, Quantification and Genetic Diseases of the Smallest Signaling Thiol Metabolite: Hydrogen Sulfide

Hydrogen sulfide (H₂S) is a gasotransmitter and the smallest signaling thiol metabolite with important roles in human health. The turnover of H₂S in humans is mainly governed by enzymes of sulfur amino acid metabolism and also by the microbiome. As is the case with other small signaling molecules, disease-promoting effects of H₂S largely depend on its concentration and compartmentalization. Genetic defects that impair the biogenesis and catabolism of H₂S have been described; however, a gap in knowledge remains concerning physiological steady-state concentrations of H₂S and their direct clinical implications. The small size and considerable reactivity of H₂S renders its quantification in biological samples an experimental challenge. A compilation of methods currently employed to quantify H₂S in biological specimens is provided in this review. Substantial discrepancy exists in the concentrations of H₂S determined by different techniques. Available methodologies permit end-point measurement of H₂S concentration, yet no definitive protocol exists for the continuous, real-time measurement of H₂S produced by its enzymatic sources. We present a summary of available animal models, monogenic diseases that impair H₂S metabolism in humans including structure-function relationships of pathogenic mutations, and discuss possible approaches to overcome current limitations of study.