Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology

Abstract

Hydrogen sulfide (H2S) has emerged as a relevant signaling molecule in physiology, taking its seat as a bona fide gasotransmitter akin to nitric oxide (NO) and carbon monoxide (CO). After being merely regarded as a toxic poisonous molecule, it is now recognized that mammalian cells are equipped with sophisticated enzymatic systems for H2S production and breakdown. The signaling role of H2S is mainly related to its ability to modify different protein targets, particularly by promoting persulfidation of protein cysteine residues and by interacting with metal centers, mostly hemes. H2S has been shown to regulate a myriad of cellular processes with multiple physiological consequences. As such, dysfunctional H2S metabolism is increasingly implicated in different pathologies, from cardiovascular and neurodegenerative diseases to cancer. As a highly diffusible reactive species, the intra- and extracellular levels of H2S have to be kept under tight control and, accordingly, regulation of H2S metabolism occurs at different levels. Interestingly, even though H2S, NO, and CO have similar modes of action and parallel regulatory targets or precisely because of that, there is increasing evidence of a crosstalk between the three gasotransmitters. Herein are reviewed the biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO.

Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis

“…For example, in contrast to •NO and CO, which bind primarily to the binuclear center in the fully reduced (Fe 2+ /Cu 1+ ) state, sulfide does not react with the fully reduced enzyme, but reacts with met (Fe 3+ ) heme. Hence, reactions with sulfide occur in the oxidized or mixed valence states 55,69 . A recent model for sulfide-mediated inhibition of cytochrome c oxidase proposed that both Fe 3+ heme a3 and Cu B (Cu 1+ or Cu 2+ ) can bind H 2 S or SH −69 .…”

“…Crosstalk between H 2 S and •NO alters Mtb infection. Studies in mammalian systems have shown crosstalk between •NO and H 2 S 55,56 . We observed increased iNOS levels in the lungs of Mtbinfected Cbs +/− mice compared to WT at 8 weeks post infection (Fig.…”

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

“…However, cysteine degradation can be pivotal in cancer cell metabolic rewiring not only due to the production of H 2 S but also as an important carbon source, as recently reviewed by Serpa [ 89 ]. H 2 S is itself a powerful antioxidant [ 90 ], displaying a reduction potential very similar to the redox pair glutathione disulfide/glutathione (GSSG/GSH), the predominant scavenger of free radicals in mammals cells [ 91 ]. H 2 S controls oxidative stress in different ways: by stimulating the production of GSH through the activation of the expression of cystine/cysteine transporters, by directly interacting with ROS [ 92 ] and by modulating the persulfidation of different antioxidant response proteins, such as Keap1 [ 93 ] upstream activator of mitochondrial redox signaling p66Shc [ 94 ], and CuZn superoxide dismutase [ 95 , 96 ].…”

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

“…CO and H 2 S, likewise NO have similar activity and regulate parallel molecular pathways, also due to mutual interaction and the cross-talk between these molecules [51,52]. H 2 S and CO were shown to prevent gastric mucosa against NSAIDs-or alendronate-induced damage and to accelerate ulcer healing due to an improvement of gastric microcirculation [15,[53][54][55].…”