Abstract
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.
Highlights
Many fungi are recognized as opportunistic pathogens, causing invasive infections and critical illness in humans (Romani, 2011; Köhler et al, 2017)
In order to elucidate the influence of H2S on fungi, the S288C strain of budding yeast S. cerevisiae was employed as the model organism first to examine if H2S could be generated during the catabolization of SPRC by the yeast and to explore if any transcriptomic and phenotypic alterations occurred in the yeast when H2S was served
The analyses conducted in the present study revealed that the sulfur amino acid-related pathways were upregulated upon H2S generation from SPRC catabolism, a metabolic map based on the Saccharomyces Genome Database (SGD) is summarized in Figure 4 for comprehension, as the sulfur amino acid biosynthesis in S. cerevisiae involves numerous enzymes required for de novo biosynthesis of sulfur amino acids as well as for transferring the organic sulfur among the metabolites
Summary
Many fungi are recognized as opportunistic pathogens, causing invasive infections and critical illness in humans (Romani, 2011; Köhler et al, 2017). The canonical donors of exogenous H2S, such as sulfide salts, are reported to cause a spike in the generation of H2S, resulting in an unstable level of H2S concentration (Li et al, 2009; Zhao et al, 2013). S-propargyl-cysteine (SPRC) was developed to replace sulfide salts for a gentle and stable generation of H2S (Wang et al, 2009). In this context, the present study employed SPRC as the donor of H2S and budding yeast Saccharomyces cerevisiae as the model organism to investigate the influence of H2S on the transcriptome and phenotype alterations in the yeast to identify any potential H2S-related factor for inhibition by drugs (Denoth Lippuner et al, 2014; Mulla et al, 2014; Voisset and Blondel, 2014)
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