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

ABSTRACT: Hydrogen sulfide (H₂S) 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 H₂S production from SAAs, the chemical mechanism, and its biological implications remain unclear. Here we present non-enzymatic H₂S production in vitro and in blood via a reaction specific for the SAA cysteine serving as substrate and requires coordinated catalysis by Vitamin B₆, 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, NH₃, and H₂S. This work highlights enzymatic production is inducible and robust in select tissues, whereas iron-catalyzed production contributes underappreciated basal H₂S systemically with pathophysiological implications in hemolytic, iron overload, and hemorrhagic disorders.

SUBMITTER: Yang J

PROVIDER: S-EPMC6529520 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Yang Jie J Minkler Paul P Grove David D Wang Rui R Willard Belinda B Dweik Raed R Hine Christopher C

Communications biology 20190521

Hydrogen sulfide (H2S) 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 H2S production from SAAs, the chemical mechanism, and its biological implications remain unclear. Here we present non-enzymatic H2S production in vitro and in blood via a reaction specific for the SAA cysteine serving as substrate and requires coordinated catalysis ...[more]

PMID: 31123718

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Project description:Pathogenic fungi are recognized as a progressive threat to humans, particularly those with the immunocompromised condition. The growth of fungi is controlled by several factors, one of which is signaling molecules, such as hydrogen sulfide (H2S), which was traditionally regarded as a toxic gas without physiological function. However, recent studies have revealed that H2S is produced enzymatically and endogenously in several species, where it serves as a gaseous signaling molecule performing a variety of critical biological functions. However, the influence of this endogenous H2S on the biological activities occurring within the pathogenic fungi, such as transcriptomic and phenotypic alternations, has not been elucidated so far. Therefore, the present study was aimed to decipher this concern by utilizing S-propargyl-cysteine (SPRC) as a novel and stable donor of H2S and Saccharomyces cerevisiae as a fungal model. The results revealed that the yeast could produce H2S by catabolizing SPRC, which facilitated the growth of the yeast cells. This implies that the additional intracellularly generated H2S is generated primarily from the enhanced sulfur-amino-acid-biosynthesis pathways and serves to increase the growth rate of the yeast, and presumably the growth of the other fungi as well. In addition, by deciphering the implicated pathways and analyzing the in vitro enzymatic activities, cystathionine-γ-lyase (CYS3) was identified as the enzyme responsible for catabolizing SPRC into H2S in the yeast, which suggested that cystathionine-γ-lyase might play a significant role in the regulation of H2S-related transcriptomic and phenotypic alterations occurring in yeast. These findings provide important information regarding the mechanism underlying the influence of the gaseous signaling molecules such as H2S on fungal growth. In addition, the findings provide a better insight to the in vivo metabolism of H2S-related drugs, which would be useful for the future development of anti-fungal drugs.

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

Publications

Non-enzymatic hydrogen sulfide production from cysteine in blood is catalyzed by iron and vitamin B<sub>6</sub>.

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