Non-enzymatic hydrogen sulfide production from cysteine in blood is catalyzed by iron and vitamin B6

This is the authors' abstract. We don't add key points for this paper.

Hydrogen sulfide (H 2 S) plays important roles in metabolism and health. Its enzymatic generation from sulfur-containing amino acids (SAAs) is well characterized. However, the existence of non-enzymatic H 2 S production from SAAs, the chemical mechanism, and its biological implications remain unclear. Here we present non-enzymatic H 2 S production in vitro and in blood via a reaction specific for the SAA cysteine serving as substrate and requires coordinated catalysis by Vitamin B 6 , pyridoxal(phosphate), and iron under physiological conditions. An initial cysteine-aldimine is formed by nucleophilic attack of the cysteine amino group to the pyridoxal(phosphate) aldehyde group. Free or heme-bound iron drives the formation of a cysteine-quinonoid, thiol group elimination, and hydrolysis of the desulfurated aldimine back to pyridoxal(phosphate). The reaction ultimately produces pyruvate, NH 3 , and H 2 S. This work highlights enzymatic production is inducible and robust in select tissues, whereas iron-catalyzed production contributes underappreciated basal H 2 S systemically with pathophysiological implications in hemolytic, iron overload, and hemorrhagic disorders.