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.
Highlights
This study demonstrated the competitive advantage of serine over cysteine as a substrate for its condensation with homocysteine, with a 2–5-fold higher catalytic efficiency of the canonical reaction compared to the H2S-generating reaction
To endothelial NO synthase (eNOS), initial contradictory results indicated either an increase or a decrease in inducible NO synthase (iNOS)-mediated nitric oxide (NO) production in response to sulfide exposure [234]. This controversy was addressed by comparatively investigating the effects of different H2S donors [235], showing that the rate of H2S release by the donors is a key determinant for the downstream effects
The last couple of decades witnessed an accumulation of data showing that (i) H2S is endogenously synthesized and catabolized by specialized enzymes and kept under a tight control through multiple intricate regulatory mechanisms, (ii) the signaling functions attributed to H2S are mainly linked to the interaction with and modification of target proteins, via reaction with metal centers and through cysteine persulfidation that alters protein structure and function, (iii) dysregulation of H2S homeostasis is at the basis of several pathologies, including cardiovascular and neurodegenerative diseases and cancer, and (iv) possible mechanisms underlying a functional crosstalk between the three gasotransmitters have been unveiled
Summary
Hydrogen sulfide is a colorless flammable gas It is a weak acid, existing in aqueous solution in equilibrium with hydrosulfide (HS−) papnhKdyas2i~sou1lol9figdi(ceHalS(−Sp/2HS−2)−v, )aa,lucacetos2,r5dth°iCnegS([23t−o]caopnnKdcae1rne~tf7rear0etino(cnHesi2nSth/sHeorlSeu−itn)io).annAidst negligible. According to this equilibrium, at the physiological pH 7.4, c.a. 70% of hydrogen sulfide is in its. With its electronic configuration [Ne] 3s2 3p4, is a highly redox versatile element, with oxidation states ranging from −2 to +6 (as in sulfate), due to the six valence electrons This versatility certainly accounts for its biological usefulness and is probably related to the major role of sulfur in the emergence and evolution of life on Earth (reviewed in [4]). More details on the formation of persulfides and polysulfides, and their physiological relevance intertwined with that of hydrogen sulfide, are given below
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