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Chemical biology of the H2S and NO crosstalk
Nitric Oxide 47 (2015) S5–S13
Contents lists available at ScienceDirect
Nitric Oxide j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n i o x
Oral presentations (OP) OP1 The biology of H2S: What can we learn from the use of H2S donors? Philip K. Moore Office of Deputy President Research and Technology, National University of Singapore, Singapore 119077 The last decade has witnessed rapid growth in interest in the biological roles of hydrogen sulphide (H2S), synthesised naturally from L-cysteine by either cystathionine γ lyase (CSE) or cystathionine β synthetase (CBS) or from 3-mercaptopyruvate by 3-mercaptopyruvate transferase (3-MST). It is becoming increasingly clear that H2S, like nitric oxide (NO) and carbon monoxide (CO), is a key regulator of cell homoeostasis and that disordered synthesis or activity of this endogenous gas contributes to multiple pathologies. This realisation likely underpins the development and biological assessment of a wide variety of H2S donor compounds in the last few years. Many H2S donors have been identified and the list continues to grow. Some of the better studied compounds include thiones such as 5-(p-hydroxyphenyl)-1,2 dithione3-thione (ADT-OH), S-allylcysteine (SAC) and S-propargylcysteine (SSPRC), arylthioamides, GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithoate) as well as H2S-releasing derivatives of a number of nonsteroid anti-inflammatory compounds such as S-diclofenac and S-naproxen. A plethora of potential applications of such compounds has also been suggested including the treatment of a number of cardiovascular, neurological and inflammatory diseases as well as cancer and for the promotion of healthy ageing. In most cases, H2S acts as a cytoprotective agent and restores normal physiological function. However, whilst H2S donors have often proved to be effective in animal models of disease, numerous issues exist with extrapolating the biology of these donors (i.e. exogenous H2S) to the biology of endogenous H2S and in translating these discoveries to the clinic. For example, for many H2S donors, correlating plasma, or intracellular, H2S concentrations with the dose of donor administered and the biological outcome achieved, has not been attempted. This may be due in part to the rapid disappearance of H2S in biological media and, in part, to a dearth of sufficiently sensitive, specific, real time and high throughput measurement techniques. The discovery and biological testing of a range of novel H2S donors are obviously critical steps in translating the early, promising preclinical profile of H2S to the clinic. More extensive study is now required to better characterise these donors as possible drugs, to compare carefully the spectrum of biological effects of exogenous vis-à-vis endogenous H2S and to determine the relative contribution of H2S and other species such as HS−. Acknowledgment: The author would like to acknowledge financial support in the form of a grant from the Ministry of Education, Singapore (MOE 2012-T2-2-003). http://dx.doi.org/10.1016/j.niox.2015.02.007
OP2 Chemical biology of the H2S and NO crosstalk Milos R. Filipovic Friedrich-Alexander University Erlangen-Nuremberg, Germany The cross-talk of hydrogen sulfide (H2S) with nitric oxide (NO) and its siblings started emerging as a new mechanistic concept which can explain some of the physiological effects assigned to H2S. Studies addressing this topic have identified several new signaling molecules as products of the above-mentioned cross-talk. H2S reacts with peroxynitrite (a strong oxidant produced in the reaction of NO with superoxide), in a reaction that generates thionitrate (HSNO2) isomer, which can decompose and serve as an NO donor. In the reaction with S-nitrosothiols or metal-nitrosyls, H 2 S generates thionitrous acid, HSNO, the smallest S-nitrosothiols, which can serve as a trans-nitrosating agent or as a source of the nitroxyl (HNO). Iron-hem metal centers catalyze the reaction between nitrite and sulfide to generate HSNO and HNO, while sulfur and nitrite react in acetone to generate perthionitrite (SSNO−) salt, a molecule that decomposes in air or in water. Finally, H2S reacts directly with NO to generate HNO. 2 μM combination of NO and H2S produce as much HNO/min as 1 mM Angeli’s salt, the most used commercially available HNO donor. HNO activates the TRPA1 channel to stimulate Ca2+ influx into sensory nerve endings, which in turn causes the release of the strongest known vasodilator, calcitonin gene-related peptide (CGRP). The physiological consequences of all products of the H2S/ NO cross-talk will be discussed in the context of cardiovascular, neurovascular and nociceptive signaling. http://dx.doi.org/10.1016/j.niox.2015.02.008
OP3 Mechanistic chemical perspective of hydrogen sulfide signaling Péter Nagy Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary Hydrogen sulfide is now a widely appreciated master regulator in human physiology. Owing to the increasing number of controversial observations in sulfide biology, mechanistic chemical studies on important signaling pathways are gaining ground. I will attempt to provide an overview on what we believe are the most prominent (or rather most well understood to date) chemical features of sulfide’s biological actions (for a recent review of this topic please consult Ref. 1). The bioavailability of sulfide will be discussed with special attention to the proposed biological buffer system and its potential role in signaling processes [2]. In addition, the underlying molecular mechanisms of the three most
Contents lists available at ScienceDirect
Nitric Oxide j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n i o x
Oral presentations (OP) OP1 The biology of H2S: What can we learn from the use of H2S donors? Philip K. Moore Office of Deputy President Research and Technology, National University of Singapore, Singapore 119077 The last decade has witnessed rapid growth in interest in the biological roles of hydrogen sulphide (H2S), synthesised naturally from L-cysteine by either cystathionine γ lyase (CSE) or cystathionine β synthetase (CBS) or from 3-mercaptopyruvate by 3-mercaptopyruvate transferase (3-MST). It is becoming increasingly clear that H2S, like nitric oxide (NO) and carbon monoxide (CO), is a key regulator of cell homoeostasis and that disordered synthesis or activity of this endogenous gas contributes to multiple pathologies. This realisation likely underpins the development and biological assessment of a wide variety of H2S donor compounds in the last few years. Many H2S donors have been identified and the list continues to grow. Some of the better studied compounds include thiones such as 5-(p-hydroxyphenyl)-1,2 dithione3-thione (ADT-OH), S-allylcysteine (SAC) and S-propargylcysteine (SSPRC), arylthioamides, GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithoate) as well as H2S-releasing derivatives of a number of nonsteroid anti-inflammatory compounds such as S-diclofenac and S-naproxen. A plethora of potential applications of such compounds has also been suggested including the treatment of a number of cardiovascular, neurological and inflammatory diseases as well as cancer and for the promotion of healthy ageing. In most cases, H2S acts as a cytoprotective agent and restores normal physiological function. However, whilst H2S donors have often proved to be effective in animal models of disease, numerous issues exist with extrapolating the biology of these donors (i.e. exogenous H2S) to the biology of endogenous H2S and in translating these discoveries to the clinic. For example, for many H2S donors, correlating plasma, or intracellular, H2S concentrations with the dose of donor administered and the biological outcome achieved, has not been attempted. This may be due in part to the rapid disappearance of H2S in biological media and, in part, to a dearth of sufficiently sensitive, specific, real time and high throughput measurement techniques. The discovery and biological testing of a range of novel H2S donors are obviously critical steps in translating the early, promising preclinical profile of H2S to the clinic. More extensive study is now required to better characterise these donors as possible drugs, to compare carefully the spectrum of biological effects of exogenous vis-à-vis endogenous H2S and to determine the relative contribution of H2S and other species such as HS−. Acknowledgment: The author would like to acknowledge financial support in the form of a grant from the Ministry of Education, Singapore (MOE 2012-T2-2-003). http://dx.doi.org/10.1016/j.niox.2015.02.007
OP2 Chemical biology of the H2S and NO crosstalk Milos R. Filipovic Friedrich-Alexander University Erlangen-Nuremberg, Germany The cross-talk of hydrogen sulfide (H2S) with nitric oxide (NO) and its siblings started emerging as a new mechanistic concept which can explain some of the physiological effects assigned to H2S. Studies addressing this topic have identified several new signaling molecules as products of the above-mentioned cross-talk. H2S reacts with peroxynitrite (a strong oxidant produced in the reaction of NO with superoxide), in a reaction that generates thionitrate (HSNO2) isomer, which can decompose and serve as an NO donor. In the reaction with S-nitrosothiols or metal-nitrosyls, H 2 S generates thionitrous acid, HSNO, the smallest S-nitrosothiols, which can serve as a trans-nitrosating agent or as a source of the nitroxyl (HNO). Iron-hem metal centers catalyze the reaction between nitrite and sulfide to generate HSNO and HNO, while sulfur and nitrite react in acetone to generate perthionitrite (SSNO−) salt, a molecule that decomposes in air or in water. Finally, H2S reacts directly with NO to generate HNO. 2 μM combination of NO and H2S produce as much HNO/min as 1 mM Angeli’s salt, the most used commercially available HNO donor. HNO activates the TRPA1 channel to stimulate Ca2+ influx into sensory nerve endings, which in turn causes the release of the strongest known vasodilator, calcitonin gene-related peptide (CGRP). The physiological consequences of all products of the H2S/ NO cross-talk will be discussed in the context of cardiovascular, neurovascular and nociceptive signaling. http://dx.doi.org/10.1016/j.niox.2015.02.008
OP3 Mechanistic chemical perspective of hydrogen sulfide signaling Péter Nagy Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary Hydrogen sulfide is now a widely appreciated master regulator in human physiology. Owing to the increasing number of controversial observations in sulfide biology, mechanistic chemical studies on important signaling pathways are gaining ground. I will attempt to provide an overview on what we believe are the most prominent (or rather most well understood to date) chemical features of sulfide’s biological actions (for a recent review of this topic please consult Ref. 1). The bioavailability of sulfide will be discussed with special attention to the proposed biological buffer system and its potential role in signaling processes [2]. In addition, the underlying molecular mechanisms of the three most