Biological chemistry of hydrogen sulfide and persulfides

Cuevasanta, Ernesto; Möller, Matías N.; Álvarez, Beatriz

doi:10.1016/j.abb.2016.09.018

Cited by 165 publications

(117 citation statements)

References 212 publications

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“…Because of the complexity of H 2 S metabolism 47 , it is methodologically challenging to determine the specific bioactive H 2 S-derived intermediate mediating the observed vasodilatory responses. Given these technical limitations, we instead measured substrate-dependent H 2 S production as a surrogate for the activity of the H 2 S biosynthetic enzymes CSE and 3-MPST.…”

Section: Discussionmentioning

confidence: 99%

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

et al. 2017

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Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (Na2S) would be attenuated in HTN compared to normotensive (NTN) adults. Fifteen NTN [51±2 yrs; blood pressure (BP) 116±3/76±3 mmHg] and 14 HTN adults (57±2 yrs; BP 140±3/89±2 mmHg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10−6 –10−1 mol∙L−1) and Na2S (10−5–101 mol∙L−1) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (AOAA; 0.5 mmol∙L−1). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all p<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN compared to NTN adults (p=0.012). AOAA attenuated ACh-induced vasodilation in NTN adults (ACh: 1.31±0.13 vs. ACh+AOAA: 1.07±0.09 flux∙mmHg−1; P=0.025) but had no effect on vasodilation in HTN adults (ACh: 1.16±0.10 v. ACh+AOAA: 1.37±0.11 flux∙mmHg−1; p=0.47). Na2S-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.

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Section: Discussionmentioning

confidence: 99%

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

et al. 2017

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“…This relative stability of the protonated form of both thiolates partially explains the low reactivity towards oxidants, given the known correlation between p K a , redox potential and chemical reactivity 32,33 . This does not explain, however, why these less nucleophilic cysteines readily react with persulfides, which are weak electrophiles, to form a tetrasulfide bridge 34,35 .…”

Section: Figurementioning

confidence: 97%

Structural determinants of persulfide-sensing specificity in a dithiol-based transcriptional regulator

Capdevila¹,

Walsh²,

Zhang³

et al. 2020

Preprint

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1Cysteine thiol-based transcriptional regulators orchestrate coordinated regulation of redox homeostasis 2 and other cellular processes by "sensing" or detecting a specific redox-active molecule, which in turn 3 activates the transcription of a specific detoxification pathway. The extent to which these sensors are 4 truly specific in cells for a singular class of reactive small molecule stressors, e.g., reactive oxygen or 5 sulfur species, is largely unknown. Here we report novel structural and mechanistic insights into a thiol-6 based transcriptional repressor SqrR, that reacts exclusively with organic and inorganic oxidized sulfur 7 species, e.g., persulfides, to yield a unique tetrasulfide bridge that allosterically inhibits DNA operator-8 promoter binding. Evaluation of five crystallographic structures of SqrR in various derivatized states, 9 coupled with the results of a mass spectrometry-based kinetic profiling strategy, suggest that persulfide 1 0 selectivity is determined by structural frustration of the disulfide form. This energetic roadblock 1 1 effectively decreases the reactivity toward major oxidants to kinetically favor formation of the 1 2 tetrasulfide product. These findings lead to the identification of an uncharacterized repressor from the 1 3 increasingly antibiotic-resistant bacterial pathogen, Acinetobacter baumannii, as a persulfide sensor, 1 4illustrating the predictive power of this work and potential applications to bacterial infectious disease. 1 5 1 6Regulatory posttranslational modifications on thiol groups of redox-active and allosterically important 1 cysteines are a critical component of signaling and redox regulation in cells 1-3 . The successful 2 adaptation of microorganisms to an ever-changing microenvironment depends, to a considerable degree, 3 on the specificity of the regulation of the expression of needed repair enzymes 4-6 . Understanding the 4 extent to which transcriptional regulation is specific to a particular redox-active small molecule(s) is 5 complicated by cross-talk or interconversion among these species in cells 7,8 and the difficulties 6 associated with identifying a posttranslational modification that is biologically meaningful at cell-7 appropriate concentrations that induce a cellular response 9 . Prominent exceptions to this are a handful 8 of transcriptional regulators that employ a metallated cofactor, such as a mononuclear iron 10,11 , an iron-9 sulfur cluster 12,13 or a heme-based sensing moeity 14 ; here, the local inorganic chemistry alone is 1 0 typically sufficient to explain the specificity of these switches toward their inducer 15 . In fact, it remains 1 1 unclear if and how a non-metallated, dithiol-based transcriptional regulator achieves a similar level of 1 2 specificity toward different cellular oxidants.

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“…Persulfidation (transformation of P‐SH into P‐SSH) of cysteine residues by H 2 S is emerging as an important oxidative posttranslational modification . Persulfidation by H 2 S is not well understood, in part because the nucleophilicity of persulfides makes them more reactive than thiols, and therefore difficult to study –. Because H 2 S cannot directly modify cysteine residues—persulfidation of cysteine is an oxidation reaction and H 2 S is a reducing agent—it remains unclear how cysteine persulfidation by H 2 S occurs.…”

Section: Figurementioning

confidence: 99%

Direct Zinc Finger Protein Persulfidation by H₂S Is Facilitated by Zn²⁺

Lange

Shimberg

et al. 2019

Angewandte Chemie

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Biological chemistry of hydrogen sulfide and persulfides

Cited by 165 publications

References 212 publications

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

Structural determinants of persulfide-sensing specificity in a dithiol-based transcriptional regulator

Direct Zinc Finger Protein Persulfidation by H₂S Is Facilitated by Zn²⁺

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Biological chemistry of hydrogen sulfide and persulfides

Cited by 165 publications

References 212 publications

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

Impaired Hydrogen Sulfide–Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults

Structural determinants of persulfide-sensing specificity in a dithiol-based transcriptional regulator

Direct Zinc Finger Protein Persulfidation by H2S Is Facilitated by Zn2+

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Direct Zinc Finger Protein Persulfidation by H₂S Is Facilitated by Zn²⁺