Sulfinic Acid Research Articles

The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H2S metabolism

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are two rare genetic disorders that are caused by impairment of the mitochondrial enzyme sulfite oxidase. Sulfite oxidase is catalyzing the terminal reaction of cellular cysteine catabolism, the oxidation of sulfite to sulfate. Absence of sulfite oxidase leads to the accumulation of sulfite, which has been identified as a cellular toxin. However, the molecular pathways leading to the production of sulfite are still not completely understood. In order to identify novel treatment options for both disorders, the understanding of cellular cysteine catabolism – and its alterations upon loss of sulfite oxidase – is of utmost importance. Here we applied a new detection method of sulfite in cellular extracts to dissect the contribution of cytosolic and mitochondrial glutamate oxaloacetate transaminase (GOT) in the transformation of cysteine sulfinic acid to sulfite and pyruvate. We found that the cytosolic isoform GOT1 is primarily responsible for the production of sulfite. Moreover, loss of sulfite oxidase activity results in the accumulation of sulfite, H2S and persulfidated cysteine and glutathione, which is consistent with an increase of SQR protein levels. Surprisingly, none of the known H2S-producing pathways were found to be upregulated under conditions of sulfite toxicity suggesting an alternative route of sulfite-induced shift from oxidative to H2S dependent cysteine catabolism.

Recent Progress in Sulfonylation via Radical Reaction with Sodium Sulfinates, Sulfinic Acids, Sulfonyl Chlorides or Sulfonyl Hydrazides

AbstractSodium sulfinates, sulfinic acids, sulfonyl chlorides and sulfonyl hydrazides as readily available and efficient sulfonylation reagents have been extensively explored in recent years. Sulfonyl radical can be generated from these sulfonyl reagents via different methods, then the sulfonyl radical could react with various substrates via different pathways to afford the corresponding products. In this review, we will summarize the progress in sulfonylation via radical reaction using sodium sulfinates, sulfinic acids, sulfonyl chlorides and sulfonyl hydrazides in recent three years. In terms of the different sulfonylation reagents, we classify these sulfonylation reactions into four types: 1. Sulfonylation reaction using sodium sulfinates. 2. Sulfonylation reaction using sulfinic acid. 3. Sulfonylation reaction using sulfonyl chlorides. 4. Sulfonylation reaction using sulfonyl hydrazides.

Water‐Promoted Dehydrative Tsuji–Trost Reaction of Non‐Derivatized Allylic Alcohols with Sulfinic Acids

A mild, green and extra activator‐free synthesis of allylic sulfones from non‐derivatized allylic alcohols and sulfinic acids was developed and only the easily‐available Pd(PPh3)4 was used as the catalyst. This new method could be easily scaled up to gram scale, affording the target allylic sulfones in a nearly quantitative yield with water as the sole by‐product. Mechanism studies both by various NMR techniques and by theoretical calculations suggested two reaction pathways may be involved in the reaction, which are dependent on the reaction media, that is, an eight‐membered ring binding species may be formed in aqueous media between allylic alcohol, sulfinic acid and water, while a six‐membered ring binding species may be formed in common aprotic organic solvent between allylic alcohol and sulfinic acid. Both binding species may be accounted for the efficient activation of allylic alcohols via hydrogen bonding.

Visible‐Light‐Induced Radical Cascade Cyclizations of 1,7‐Enynes with Sulfinic Acids: Direct Access to Sulfonated Chromanes and Sulfonated Tetrahydroquinolines under Metal‐Free Conditions

AbstractVisible‐light‐induced strategy to access sulfonated chromanes and sulfonated 1,2,3,4‐tetrahydroquinolines via a radical cascade cyclization of 1‐(arylethynyl)‐2‐(vinyloxy)benzenes and N‐allyl‐2‐(arylethynyl)anilines with aromatic and aliphatic sulfinic acids has been developed. In the presence of TBHP (7.5 mol%) as an oxidant and Eosin Y (3.0 mol%) as a photocatalyst, the reactions undergo smoothly to afford the corresponding products in good yields at room temperature under metal‐free conditions. This transformation features low loading of TBHP, mild reaction conditions, simple operation, broad functional‐group tolerance, and good yields of products.magnified image

A modular template for the design of thiol-triggered sensors and prodrugs.

A unique reaction between thiols (RSH) and alkyl sulfonylbenzothiazole was discovered. This reaction was specific for thiols and produced a sulfinic acid (RSO2H) as the intermediate, which further triggered an intramolecular cyclization to release a -OH containing payload. This reaction was used to develop thiol-triggered fluorescent sensors and prodrugs. The modular design of this template provides tunability of the release profiles of the payloads.

Peroxiredoxin 3 Has Important Roles on Arsenic Trioxide Induced Apoptosis in Human Acute Promyelocytic Leukemia Cell Line via Hyperoxidation of Mitochondrial Specific Reactive Oxygen Species.

NB4 cell, the human acute promyelocytic leukemia (APL) cell line, was treated with various concentrations of arsenic trioxide (ATO) to induce apoptosis, measured by staining with 7-amino-actinomycin D (7-AAD) by flow cytometry. 2’, 7’-dichlorodihydro-fluorescein-diacetate (DCF-DA) and MitoSOXTM Red mitochondrial superoxide indicator were used to detect intracellular and mitochondrial reactive oxygen species (ROS). The steady-state level of SO2 (Cysteine sulfinic acid, Cys-SO2H) form for peroxiredoxin 3 (PRX3) was measured by a western blot. To evaluate the effect of sulfiredoxin 1 depletion, NB4 cells were transfected with small interfering RNA and analyzed for their influence on ROS, redox enzymes, and apoptosis. The mitochondrial ROS of NB4 cells significantly increased after ATO treatment. NB4 cell apoptosis after ATO treatment increased in a time- dependent manner. Increased SO2 form and dimeric PRX3 were observed as a hyperoxidation reaction in NB4 cells post- ATO treatment, in concordance with mitochondrial ROS accumulation. Sulfiredoxin 1 expression is downregulated by small interfering RNA transfection, which potentiated mitochondrial ROS generation and cell growth arrest in ATO- treated NB4 cells. Our results indicate that ATO-induced ROS generation in APL cell mitochondria is attributable to PRX3 hyperoxidation as well as dimerized PRX3 accumulation, subsequently triggering apoptosis. The downregulation of sulfiredoxin 1 could amplify apoptosis in ATO-treated APL cells.

Mechanistic Insights into Dissolved Organic Sulfur Photomineralization through the Study of Cysteine Sulfinic Acid.

Photochemical reactions convert dissolved organic matter (DOM) into inorganic and low-molecular-weight organic products, contributing to its cycling across environmental compartments. However, knowledge on the formation mechanisms of these products is still scarce. In this work, we investigate the triplet-sensitized photodegradation of cysteine sulfinic acid, a (photo)degradation product of cysteine, to sulfate (SO42-). We use kinetic analysis, targeted experiments, and previous literature from several fields of chemistry to explain the elementary steps that lead to the release of sulfate. Our analysis indicates that triplet sensitizers act as one-electron oxidants on the sulfinate S lone pair. The resulting radical undergoes C-S fragmentation to form SO2, which becomes hydrated to sulfite/bisulfite (S(IV)). S(IV) is further oxidized to SO42- in the presence of triplet sensitizers and oxygen. We point out that the reaction sequence SO2 ⇌ S(IV) → SO42- is valid independently of the chemical structure of the model compound and might represent a sulfate photoproduction mechanism with general validity for DOS. Our mechanistic investigation revealed that amino acids in general might also be photochemical precursors of CO2, ammonia, acetaldehyde, and H2O2 and that reaction byproducts can influence the rate and mechanism of S(IV) (photo)oxidation.

Dietary taurine intake affects growth and taurine synthesis regulation in golden pompano, Trachinotus ovatus (Linnaeus 1758)

Taurine serves an important role in many species, including fish. The purpose of this study was to investigate the effects of varying dietary taurine levels on the growth, antioxidant capacity, and tissue deposition of taurine in golden pompano. In addition, the mechanism of taurine synthesis was studied via enzyme activity and gene expression of the following enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine dioxygenase (CDO), cysteine sulfinic acid decarboxylase (CSAD), and 2-aminoethanethiol dioxygenase (ADO). Taurine concentrations of 1.3, 4.4, 7.4, 10.5 and 12.7 g kg−1 were added to the basic feed, hereafter labelled the T0, T1, T2, T3 and T4 diets, respectively. A control diet was supplemented with 1.3 g kg−1 taurine. Following 8 weeks of treatment, the results showed that the specific growth rate increased with the increase in dietary taurine content; the growth rate peaked at the 10.5 g kg−1 dietary taurine level (P < 0.05). The hepatosomatic index was significantly reduced as dietary taurine levels increased (P < 0.05). Crude protein and crude lipid in the body increased significantly with the intake of exogenous taurine (P < 0.05). The increase in dietary taurine significantly increased the total antioxidant capacity, as well as the superoxide dismutase, catalase, and glutathione peroxidase activities; however, the malondialdehyde concentration correspondingly decreased (P < 0.05). The taurine content in whole fish, liver, heart, eye, kidney, brain, muscle and gill significantly increased with the increase in dietary taurine (P < 0.05). The activity of CSE, CDO, CSAD and ADO decreased with the increase in dietary taurine (P < 0.05). Taurine intake had no significant impact on CBS activity (P > 0.05). The gene expression of CBS, CSE, CDO, CSAD and ADO exhibited a downward trend with an increase of taurine (P < 0.05). These results indicate that taurine plays an important role in the growth of golden pompano. Polynomial regression analysis revealed that the taurine requirements of golden pompano could be satisfied if the taurine content reached at least 10.0 g kg−1. In addition, taurine has a regulating effect on taurine synthesis in golden pompano.

Structures of Arabidopsis thaliana oxygen-sensing plant cysteine oxidases 4 and 5 enable targeted manipulation of their activity

In higher plants, molecular responses to exogenous hypoxia are driven by group VII ethylene response factors (ERF-VIIs). These transcriptional regulators accumulate in the nucleus under hypoxia to activate anaerobic genes but are destabilized in normoxic conditions through the action of oxygen-sensing plant cysteine oxidases (PCOs). The PCOs catalyze the reaction of oxygen with the conserved N-terminal cysteine of ERF-VIIs to form cysteine sulfinic acid, triggering degradation via the Cys/Arg branch of the N-degron pathway. The PCOs are therefore a vital component of the plant oxygen signaling system, connecting environmental stimulus with cellular and physiological response. Rational manipulation of PCO activity could regulate ERF-VII levels and improve flood tolerance, but requires detailed structural information. We report crystal structures of the constitutively expressed PCO4 and PCO5 from Arabidopsis thaliana to 1.24 and 1.91 Å resolution, respectively. The structures reveal that the PCOs comprise a cupin-like scaffold, which supports a central metal cofactor coordinated by three histidines. While this overall structure is consistent with other thiol dioxygenases, closer inspection of the active site indicates that other catalytic features are not conserved, suggesting that the PCOs may use divergent mechanisms to oxidize their substrates. Conservative substitution of two active site residues had dramatic effects on PCO4 function both in vitro and in vivo, through yeast and plant complementation assays. Collectively, our data identify key structural elements that are required for PCO activity and provide a platform for engineering crops with improved hypoxia tolerance.

Oxidant-induced glutathionylation at protein disulfide bonds

Disulfide bonds are a key determinant of protein structure and function, and highly conserved across proteomes. They are particularly abundant in extracellular proteins, including those with critical structural, ligand binding or receptor function. We demonstrate that oxidation of protein disulfides induces polymerization, and results in oxygen incorporation into the former disulfide via thiosulfinate generation. These intermediates, which have half-lives of several hours in vitro, undergo secondary reactions that cleave the disulfide bond, by irreversible hydrolysis to sulfinic and sulfonic acids, or reaction with thiols in a process that yields thiolated proteins (e.g. glutathionylated species in the case of reaction with glutathione). The adducts have been characterized by mass spectrometry (as ions corresponding to the addition of 306 and 712 Da for addition of one and two glutathione molecules, respectively) and immunoblotting. These modifications can be induced by multiple biologically-important oxidants, including HOCl, ONOOH, and H2O2, and on multiple proteins, demonstrating that this is a common disulfide modification pathway. Addition of glutathione to give glutathionylated proteins, can be reversed by reducing systems (e.g. tris(2-carboxyethyl)phosphine), but this does not repair the original disulfide bond. Exposure of human plasma to these modifying agents increases protein glutathionylation, demonstrating potential in vivo relevance. Overall these data provide evidence for a novel and facile route to glutathionylated proteins involving initial oxidation of a disulfide to a thiosulfinate followed by rapid reaction with GSH (‘oxidant-mediated thiol-disulfide exchange’). These data elucidate a novel pathway for protein glutathionylation that may have significant implications for redox biology and cell signaling.

Oxidative Sulfonylation of Multiple Carbon‐Carbon bonds with Sulfonyl Hydrazides, Sulfinic Acids and their Salts

AbstractOxidative coupling methodology is widely applied for the formation of carbon‐carbon and carbon‐heteroatom bonds. This review focuses on methods for oxidative sulfonylation of multiple bonds involving sulfonyl hydrazides, sulfinic acids and their salts as sulfonylation reagents. Under oxidative conditions, they generate sulfonyl radicals, trapped by multiple carbon‐carbon bonds resulting in a variety of SO2‐containing products: mainly, vinyl and alkynyl sulfones, hydroxy‐, keto, and halo‐substituted sulfones, sulfonylated derivatives of carbo‐ and heterocycles. This exhaustive review summarizes 321 references from 1996 to 2020 with the specialization of the studies of the last five years, and is divided into the chapters according to the classes of compounds being sulfonylated.magnified image

Palladium-Catalyzed Regio- and Enantioselective Hydrosulfonylation of 1,3-Dienes with Sulfinic Acids: Scope, Mechanism, and Origin of Selectivity.

Chiral sulfones are important structural motifs in organic synthesis because of their widespread use in pharmaceutical chemistry. In particular, chiral allylic sulfones have drawn particular interest because of their synthetic utility. However, enantioselective synthesis of 1,3-disubstituted unsymmetrical chiral allylic sulfones remains a challenge. In this article, we report a protocol for (R)-DTBM-Segphos/Pd-catalyzed regio- and enantioselective hydrosulfonylation of 1,3-dienes with sulfinic acids, which provides atom- and step-economical access to 1,3-disubstituted chiral allylic sulfones. The reaction occurs under mild conditions and has a broad substrate scope. Combined experimental and computational studies suggest that the reaction is initiated by a ligand-to-ligand hydrogen transfer followed by a C-S bond reductive elimination via a six-membered transition state. Steric repulsion between the olefinic C-H of the substrate and the tert-butyl group of (R)-DTBM-Segphos was found to be a key factor in the enantiocontrol.

Free-amino acid metabolic profiling of visceral adipose tissue from obese subjects.

Interest in adipose tissue pathophysiology and biochemistry have expanded considerably in the past two decades due to the ever increasing and alarming rates of global obesity and its critical outcome defined as metabolic syndrome (MS). This obesity-linked systemic dysfunction generates high risk factors of developing perilous diseases like type 2 diabetes, cardiovascular disease or cancer. Amino acids could play a crucial role in the pathophysiology of the MS onset. Focus of this study was to fully characterize amino acids metabolome modulations in visceral adipose tissues (VAT) from three adult cohorts: (i) obese patients (BMI 43-48) with metabolic syndrome (PO), (ii) obese subjects metabolically well (O), and (iii) non obese individuals (H). 128 metabolites identified as 20 protein amino acids, 85 related compounds and 13 dipeptides were measured by ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) and gas chromatography-/mass spectrometry GC/MS, in visceral fat samples from a total of 53 patients. Our analysis indicates a probable enhanced BCAA (leucine, isoleucine, valine) degradation in both VAT from O and PO subjects, while levels of their oxidation products are increased. Also PO and O VAT samples were characterized by: elevated levels of kynurenine, a catabolic product of tryptophan and precursor of diabetogenic substances, a significant increase of cysteine sulfinic acid levels, a decrease of 1-methylhistidine, and an up regulating trend of 3-methylhistidine levels. We hope this profiling can aid in novel clinical strategies development against the progression from obesity to metabolic syndrome.

Recent Advances of Sulfonylation Reactions in Water.

The sulfonyl groups are general structural moieties present in agrochemicals, pharmaceuticals, and natural products. Recently, many efforts have been focused on developing efficient procedures for preparation of organic sulfones. Water, a proton source, is considered one of the most ideal and promising solvents in organic synthesis for its easy availability, low cost, nontoxic and nonflammable characteristics. From the green and sustainable point of view, more and more reactions are designed proceeding in water. The review focuses on recent advances of sulfonylation reactions proceeding in water. Sulfonylation reactions using sodium sulfinates, sulfonyl hydrazides, sulfinic acids, and sulfonyl chlorides as sulfonating agents were introduced in detail. In this review, sulfonylation reactions proceeding in water developed in recent four yields were presented. Sulfonylation reactions using water as solvent have attracted more and more attention because water is one of the most ideal and promising solvents in organic synthesis for its facile availability, low cost, nontoxic and nonflammable properties. Numerous sulfonating agents such as sodium sulfinates, sulfonyl hydrazides, sulfinic acid, sulfonyl chlorides and disulfides are efficient for sulfonylation reactions which proceed in water.

Isothiourea‐Catalyzed Synthesis of Pyrrole‐ and Indole‐Functionalized Tetrasubstituted Pyridines

AbstractThe generation of pyrrole‐ and indole‐functionalized tetrasubstituted pyridines in a one‐pot process from 2‐(pyrrol‐1‐yl)acetic acid or 2‐(indol‐1‐yl)acetic acid and α,β‐unsaturated N‐sulfonyl‐ketimines is described. The process is proposed to operate via an isothiourea‐catalyzed Michael addition‐lactamization, followed by elimination of sulfinic acid and O‐acylation to provide the final pyridine product.

Redox Pioneer: Professor Sue Goo Rhee.

Dr. Sue Goo Rhee is recognized as a Redox Pioneer because he has published five articles in the field of antioxidants and redox signaling that have been cited >1000 times and 69 of his articles in this field have been cited between 100 and 1000 times. Dr. Rhee is known for his discovery of the first three prototypical members of the phospholipase C family, and for the discovery of the ubiquitously expressed peroxiredoxins. Peroxiredoxin catalyzes the thiol-mediated reduction of H2O2. These enzymes protect cellular molecules from oxidative damage. Importantly, they also regulate cell signaling by modulating the intracellular levels of H2O2 that are induced by signaling agonists. He elucidated the mechanism by which the peroxiredoxins participate in signaling by H2O2: Dr. Rhee demonstrated that growth agonists such as epidermal growth factor induce a transient elevation of intracellular H2O2 that oxidize the catalytically essential cysteine residue of protein tyrosine phosphatases. The oxidation inactivates the phosphatases, allowing enhanced protein tyrosine phosphorylation to mediate cell signaling. In addition, he established that peroxiredoxins are exquisitely regulated through phosphorylation, glutathionylation, and hyperoxidation of their active site cysteine to cysteine sulfinic acid. Dr. Rhee showed that cysteine oxidation to its sulfinic acid derivative is not irreversible as previously thought. The reduction of hyperoxidized peroxiredoxin is catalyzed by sulfiredoxin. His further investigations implicated cyclic hyperoxidation and reduction of peroxiredoxin in the regulation of certain circadian rhythms.

One-pot two-step reaction of selenosulfonate with isocyanides and allyl alcohol under aqueous conditions: Atom-economic synthesis of selenocarbamates and allyl sulfones

In many reactions involving selenosulfonate or thiosulfonate, the sulfone group often leaves in form of benzenesulfinic acid or sodium benzenesulfinate. A one-pot two-step reaction of selenosulfonate with isocyanides and allyl alcohol under aqueous conditions to afford selenocarbamates and allyl sulfone compounds is reported. The sulfinic acid as the first-step side product is converted to the allyl sulfone compound by water promoted reaction with allyl alcohol. Water acts as both an oxygen source of selenocarbamates and as a promoter to drive the second step reaction. The reactions have the advantages of mild conditions, green, environment-friendly, and high atomic economy.

Oxidation of bacillithiol by myeloperoxidase-derived oxidants

Bacillithiol is a major low-molecular-weight thiol in gram-positive firmicutes including the human pathogen Staphylococcus aureus. Bacillithiol is regarded as an important defence mechanism against oxidants produced by the immune system, especially myeloperoxidase-derived hypochlorous acid (HOCl). However, it is unknown how fast BSH reacts with HOCl and what products are formed in the reaction. In the present study, we used sensitive MRM-based LC-MS methods to characterize the reaction of BSH with HOCl in cell-free solutions and in S. aureus. In the cell-free system, BSH formed predominantly the disulfide dimer (BSSB) at low mole ratios of HOCl and the sulfinic and sulfonic acids at higher oxidant concentrations. HOCl also promoted the formation of bacillithiol sulfonamide. In S. aureus, the oxidation pattern was similar except that a small proportion of BSH also formed mixed disulfides with protein thiols.Using competition with methionine, we determined the second-order rate constant for the reaction of HOCl with BSH to be 6 × 107 M-1s-1, which indicated a fast, near diffusion-controlled reaction. Other reactive halogen species, including hypothiocyanous acid (HOSCN), also produced bacillithiol sulfonamide, albeit to a smaller extent than HOCl. The sulfonamide was not produced by hydrogen peroxide, which instead formed BSSB.This study helps our understanding of BSH redox biology and provides tools for gauging the exposure of BSH-producing bacteria to oxidative stress.

Sulfonyl Hydrazides in Organic Synthesis: A Review of Recent Studies

AbstractSulfonyl hydrazides are widely used as organic reagents. Advances in the past decade are summarized in the following categories by key intermediates: (1) [RO2S.]; (2) RO2SSR; (3) [ArS.]; (4) [RO2S−]; (5) RSO2‐[Metal] species; (6) Ar‐[Metal] species; (7) RSX; (8) RS‐DBU; (9) nucleophilic amino group; (10) sulfonyl hydrazides as diazene or sulfinic acid surrogate. Reactions with alkenes, alkynes, aldehydes, alcohols, thiophenol, Grignard reagents, among others, are discussed. We hope this review will promote future research in this area.magnified image

Reciprocal-Activation Strategy for Allylic Sulfination with Unactivated Allylic Alcohols.

A reciprocal-activation strategy for allylic sulfination with unactivated allylic alcohols was developed. In this reaction, the hydrogen bond interaction between allylic alcohols and sulfinic acids allowed for reciprocal activation, which enabled a dehydrative cross-coupling process to occur under mild reaction conditions. This reaction worked in an environmentally friendly manner, yielding water as the only byproduct. A variety of allylic sulfones could be obtained in good to excellent yields with wide functional group tolerance. In gram scale reactions, allylic sulfones could be conveniently isolated in high yield by filtration.