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

Abstract

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.

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

“…CBS and CSE belong to the transsulfuration pathway, which is mainly devoted to (1) the endogenous generation of cysteine, (2) homocysteine detoxification, and (3) H 2 S generation (and concomitant lanthionine production). In red blood cells (and other tissues, such as spleen, heart, lung, muscle, bone marrow) it is likely most often produced nonenzymatically, utilizing cysteine [43]. H 2 S can signal through four mechanisms [44]: (1) reduction and/or direct binding of metalloprotein heme centers; (2) antioxidant action through reactive oxygen species (ROS)/reactive nitrogen species scavenging; (3) post-translational modification of proteins by addition of a thiol (-SH) group onto reactive cysteine residues, so-called persulfidation (or S-sulfhydration), and formation of polysulfides [45,46]; (4) a postulated redox-linked metabolic reprogramming mechanism through sulfide quinone oxidoreductase in mitochondria [47].…”

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

“…CGL and CBS are predominantly cytoplasmic, while 3-MST is principally mitochondrial (Kimura, 2014). In addition to their differences in subcellular localization, CGL, CBS, and 3-MST are differentially expressed and active in tissue-specific manners, with CGL contributing the majority of enzymatic H2S production in the kidney, liver, and endothelium (Kabil et al, 2011b;Longchamp et al, 2018;Yang et al, 2019). Lack of CGL expression and/or activity is attributed to hypertension (Yang et al, 2008), neurodegeneration (Paul et al, 2014), and the inability to properly respond to dietary and endocrine cues (Hine et al, 2015;Ishii et al, 2010;Kabil et al, 2011a;Longchamp et al, 2018;Nakano et al, 2015).…”

Hydrogen Sulfide as a Potential Alternative for the Treatment of Myocardial Fibrosis

“…Nonenzymatically, H 2 S can also be released from preexisting intracellular sulfur stores (sulfane sulfur) through the activities of reducing agents [24,30]. For example, the production of H 2 S from sulfur-containing amino acids (e.g., cysteine) via iron and vitamin B 6 under physiological conditions has been found in red blood cells and tissues [31]. However, the exact biological roles of this nonenzymatic production of H 2 S have not yet been established.…”