Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2020 / Article
Special Issue

Biochemistry and Biology of Endogenous and Exogenous Sulfur Compounds in the Modulation of Reactive Oxygen Species Metabolism

View this Special Issue

Review Article | Open Access

Volume 2020 |Article ID 8294158 | https://doi.org/10.1155/2020/8294158

Antonio Francioso, Alessia Baseggio Conrado, Luciana Mosca, Mario Fontana, "Chemistry and Biochemistry of Sulfur Natural Compounds: Key Intermediates of Metabolism and Redox Biology", Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 8294158, 27 pages, 2020. https://doi.org/10.1155/2020/8294158

Chemistry and Biochemistry of Sulfur Natural Compounds: Key Intermediates of Metabolism and Redox Biology

Academic Editor: Giuseppe Cirillo
Received10 Apr 2020
Revised28 Jun 2020
Accepted29 Jul 2020
Published30 Sep 2020

Abstract

Sulfur contributes significantly to nature chemical diversity and thanks to its particular features allows fundamental biological reactions that no other element allows. Sulfur natural compounds are utilized by all living beings and depending on the function are distributed in the different kingdoms. It is no coincidence that marine organisms are one of the most important sources of sulfur natural products since most of the inorganic sulfur is metabolized in ocean environments where this element is abundant. Terrestrial organisms such as plants and microorganisms are also able to incorporate sulfur in organic molecules to produce primary metabolites (e.g., methionine, cysteine) and more complex unique chemical structures with diverse biological roles. Animals are not able to fix inorganic sulfur into biomolecules and are completely dependent on preformed organic sulfurous compounds to satisfy their sulfur needs. However, some higher species such as humans are able to build new sulfur-containing chemical entities starting especially from plants’ organosulfur precursors. Sulfur metabolism in humans is very complicated and plays a central role in redox biochemistry. The chemical properties, the large number of oxidation states, and the versatile reactivity of the oxygen family chalcogens make sulfur ideal for redox biological reactions and electron transfer processes. This review will explore sulfur metabolism related to redox biochemistry and will describe the various classes of sulfur-containing compounds spread all over the natural kingdoms. We will describe the chemistry and the biochemistry of well-known metabolites and also of the unknown and poorly studied sulfur natural products which are still in search for a biological role.

1. Introduction

In living organisms, sulfur is one of the most fundamental elements and the seventh most abundant mineral in the human body. Sulfur belongs to chalcogens, elements of the 16 group of the periodic table, which display the awesome characteristic of having a variety of redox states and redox potentials allowing them to form interchalcogen bonds and atom exchange reactions, giving rise to a vast number of sulfur species that take part in biological processes. Noteworthy, the bulk of biomolecules consists only of carbon, hydrogen, nitrogen, and oxygen atoms, and the presence of sulfur accounts for the distinctive properties of sulfur compounds. Actually, sulfur and oxygen belong to the same group in the periodic table; however, Met and Cys analogues with the sulfur atom replaced by oxygen do not serve the same function. Sulfur has unique characteristics that differentiate it from oxygen. The increased atomic size confers to sulfur a lower electronegativity than oxygen. The thioether (R2S) moiety of Met is more reactive than the analogue ether (R2O). Thioethers can form sulfonium ions (R3S+) by donating electrons to other organic species thanks to their ability to sink electrons and stabilize a negative charge on a neighboring carbon [1]. These compounds undergo sequential oxidation to sulfoxides (R2SO) and sulfones (R2SO2), conferring to these derivatives novel unexpected roles. In cell metabolism, a sulfonium compound such as S-adenosylmethionine (SAM) mediates most biochemical methylation reactions. It is doubtful whether other amino acid derivatives or other “-onium” compounds could play this role: quaternary ammonium compounds are unable to effectively methylate acceptor compounds, and oxonium compounds, such as a hypothetical oxygen analogue of SAM, would produce such a powerful methylating agent that it would methylate cellular nucleophiles without the need for an enzyme [2, 3]. The sulfur compounds contained in food are amino acids or vitamins including methionine (Met), cysteine (Cys), homocysteine (HCy), cystine (Cys-Cys), taurine (Tau), lipoic acid, thiamine, and biotin as well as the glucosinolates and allylic sulfur compounds that are contained in cabbage and cauliflower (cruciferous vegetables). The amount of sulfur compounds in food greatly varies depending on the type of food: 8% for egg white, 5% for beef as well as for chicken and fish, and 4% for dairy products and plant proteins [4]. The recommended dietary allowance (RDA) for sulfur has been estimated to be 13-14 mg/kg of body weight per day. Considering 70 kg weight for a person, not affected by sex or age, this means 1.1 g of sulfur per day [59]. Among the sulfur compounds ingested with food, Met and Cys represent the largest part and are extensively metabolized by the organisms [3]. The Met/Cys ratio in food is 3/1 for dairy products, fish, and meat and 4/3 for eggs and plant products such as soybeans [10, 11]. Met is an essential amino acid assumed by diet and cannot be synthesized contrary to nonessential Cys. Numerous key metabolic intermediates such as HCy, Cys-Cys, and Tau are generated by these sulfur amino acids [4, 12]. Throughout the transsulfuration pathway, Met can be converted to Cys with a yield depending on cell needs. Interestingly, both these two sulfur amino acids cannot be stored as such in the body but cysteine can be stocked as glutathione (GSH) and sulfur excess is promptly excreted in the urine after its oxidation to sulfate or reabsorbed if required [13].

In this review, we will explore the fundamental aspects of sulfur metabolism and redox biochemistry and the large pool of naturally occurring sulfur-containing compounds. We will focus on the chemistry and the biochemistry of exogenous and endogenous sulfur metabolites. We will underline the importance of well-known and widely studied molecules, and we will also focus on unknown and poorly studied sulfur natural products whose biological role is still a mystery and needs to be investigated [14, 15].

2. How Sulfur Comes to “Life”

Sulfur, as well as nitrogen, needs to be fixed in organic molecules with a process part of the so-called biogeochemical “sulfur cycle.” Before being incorporated into the essential organic molecules, sulfur needs to be fixed with carbon in an organic skeleton. A significant part of sulfur fixation starts in the oceans that represent a major reservoir of sulfur on Earth, with large quantities in the form of dissolved sulfate and sedimentary minerals. Inorganic sulfur, mostly SO42- coming from gypsum and from pyrite oxidation, is fixed by algae in the ocean upper water column to dimethylsulfoniopropionate (DMSP) [16]. DMSP produced by algae is utilized by a diverse assemblage of microbes, leading to the production of methanethiol (MeSH) and dimethylsulfide (DMS) [17, 18] (Figure 1). These compounds are highly volatile and represent a significant amount of sulfur transfer from the oceans to the atmosphere and ultimately to land. On the other hand, volcanic emissions are the main natural sources of on-land sulfur release to the atmosphere in which furthermore is oxidized via photochemical processes to various sulfur oxidation state species [19]. SO42-, MeSH, and DMS are the most important precursors of sulfur organic compounds synthetized by plants and microorganisms [20] (Figure 1).

Cys is the precursor (thiol-reduced sulfur donor) of most organic sulfur-containing molecules in the plant metabolome. Sulfur fixation is strictly related to Cys biosynthesis in which through different enzymatic steps, oxidized sulfate, alkane sulfates, or thiosulfate are reduced to sulfide and subsequently incorporated to Cys upon Ser activation (O-acetylserine) [21]. Plants are also able to produce a large variety of sulfur-containing products with interesting chemical, biochemical, and pharmacological features [2225].

One of the principal ways to introduce inorganic sulfur in metabolism is via SO42- incorporation in adenosine phosphosulfate (APS). APS is the crucial transporter of inorganic sulfur and serves as a central metabolic route for Cys biosynthesis (Figure 2) [26].

Among plant volatile organic compounds, the class of volatile sulfur compounds (VSCs) represents an important tool for plant physiology. Vegetables are one of the sources in diet for the uptake of Met and Cys, and plants possess specific metabolic pathways for the production of diverse sulfur-containing organic compounds with different important roles (defense, signaling, and communication) [2729].

In mammals, sulfur occurs mainly in proteins as Cys and Met but also in coenzymes such as Coenzyme A (CoA), biotin, lipoic acid, and thiamine (Figure 3).

It is also common in the form of iron-sulfur clusters in metalloproteins and in bridging ligands as in cytochromes. Animals are completely dependent on preformed organic sulfur compounds to satisfy their sulfur needs [3]. Primary plant metabolism produces Met that is the essential source of sulfur for mammals and higher species such as humans. However, some higher species such as humans are able to build new sulfur-containing chemical entities starting from plants’ sulfur precursors. Sulfur metabolism in humans is very complicated and plays a central role in redox biochemistry. The large number of oxidation states that this element can display makes it ideal for redox biological reaction and electron transfers (e.g., Fe-S clusters in mitochondrial proteins). Also, the biosynthesis of particular sulfur metabolites is a unique feature in some species from the animal kingdom and seems to occur via diverse biochemical pathways evolutionally far from plant sulfur metabolism [30].

The sulfur cycle, like the nitrogen cycle, is extremely important and promoted by specific prokaryotes. Most of the organic sulfur coming from this cycle is generated in the oceanic environment by microorganisms that can convert and incorporate inorganic sulfur in organic molecules necessary to satisfy the sulfur needs of all the other living beings. The metabolism of organic sulfur is at the same time a key component of the global sulfur cycle. Phototrophic and diazotrophic marine organisms such as particular marine cyanobacteria and red algae are able to use sulfur compounds as electron acceptors or donors in sulfate/sulfur reduction and oxidation [31].

3. Naturally Occurring Organosulfur Compounds in Terrestrial Plants and Marine Organisms

3.1. Natural Products from the Marine World

Marine organisms are a relatively recent successful source of novel natural bioactive compounds due also to the presence of diverse still not explored habitats and ecosystems. Several papers in the last decades reported the pharmacological activities of different compounds such as ziconotide for the management of severe chronic pain and eribulin mesylate, an antimetastatic breast cancer, both successful derivatives of compounds coming from the “marine world” [32].

3.1.1. Sulfurous Amines and Amino Acids

Marine microorganisms and algae are able to produce a wide range of sulfur-containing natural products, also because of the abundance of this element in the marine environment. Most of the biosynthetic routes and the biological significance of these compounds are still unknown [33]. The most ubiquitous group is that of sulfur amines and amino acids. These compounds have been found in a variety of marine organisms including algae, gorgonians, clams, and fishes, and they include Met, Cys, methionine sulfone, methionine N-methyl sulfoxide, and several aliphatic sulfonated amines (Figure 4). Studies performed on deep sea animals have detected also a high level of hypotaurine (Htau) as well as thiotaurine (Ttau) (Figure 4) [34].

These latter two sulfur amino acids seem to act as osmolytes, to balance internal osmotic pressure with that of the ocean. Ttau, in particular, seems to transport and/or to detoxify sulfide and is probably produced by the interaction of the sulfinic group of Htau with H2S [3436]. The spontaneous oxidation of sulfide can produce different reactive oxygen and sulfur radical species. The presence of Ttau in these organisms is related to their need to decrease the level of sulfide; consequently, Ttau formation can be included in the mechanisms developed to counteract the presence of oxygen and sulfur radicals in the deep sea organisms. Moreover, Ttau has been proposed as a marker in animals with a sulfide-based symbiosis. This organic thiosulfate has the ability to release hydrogen sulfide (H2S) in a thiol-dependent reaction [37]. In particular, a thiosulfate reductase activity occurring in various cells uses electrons of thiols, such as GSH, to reduce sulfane sulfur of thiosulfonates, such as Ttau to H2S [38]. The H2S gasotransmitter is one of the most important sulfur inorganic compounds whose role is crucial in oxidative stress and inflammation processes. H2S has important signaling properties but also plays a crucial role in cellular redox homeostasis by modulating GSH concentration and Nrf2 factor transcription [39, 40].

3.1.2. Histidine and Aromatic Derivatives

Other groups of marine sulfur products are represented by the histidine derivatives and the aromatic amine derivatives. The first one includes ovothiols from echinoderm egg species such as 1-methyl-5-mercapto-L-histidine and their disulfide derivatives (Figure 5) [41], and the second includes one of the precursors of melanin produced by tyrosinase enzymes, such as 2,5-S,S-dicysteinyldopa that is part of the red-violet marine pigment, adenochrome, extracted from the branchial heart of the common octopus, Octopus vulgaris (Figure 5) [42]. One of the marine natural products belonging to this class of compounds that was recently found to be very promising for its biological activities is ergothioneine (Figure 5), a sulfur histidine compound derived from 2-mercapto-L-histidine by quaternization of the α-amino group and characterized by the presence of the sulfur thione tautomeric form [4346]. Certain mushrooms (in the Basidiomycetes class), fungi such as Aspergillus oryzae, Streptomyces species, and cyanobacteria are the only organisms capable of producing this compound that demonstrates to possess a high pharmacological potential mainly due to its thione moiety that confers to the compound high stability and activity against ROS [47, 48].

3.1.3. Indolic Compounds and Thiazolic Peptides

Besides, indole compounds derived from tryptophan metabolism were found in marine species (Figure 6). Among this group, the occurrence of simple brominated methylthioindoles has been reported from a Taiwanese collection of the red alga Laurencia brongniarti (2,4,6-tribromo-3-methylthioindole and derivatives). Simple brominated methylthioindoles are encountered in the molluscan families Muricidae and Thaisidae as the precursors of the pigment Tyrian purple, used since ancient times as a valuable coloring matter. Another important indole (or guanidine) alkaloid is dendrodoine, the first identified naturally occurring 1,2,4-thiadiazole ring system extracted from a tunicate Dendrodoa grossularia with cytotoxic properties [49, 50]. The thiazoles and thiazolidinones group includes also dysidenin and isodysidenin pseudopeptides isolated from a collection of the marine sponge Dysidea herbacea. Furthermore, the tunicate Lissoclinum patella collected from Palau, Western Caroline Islands, gave the first two examples of thiazole-containing macrocyclic peptides, ulicyclamide and ulithiacyclamide [51].

3.2. Terrestrial Products

Terrestrial organisms such as plants and fungi are also able to produce an interesting pool of sulfur organic compounds.

3.2.1. Alkyl and Allyl-S-Oxides

Forms of sulfur compounds relevant to human nutrition are present in foods such as garlic, onion, and broccoli. Yet, the ingestion of these forms of sulfur compounds is very important for human health since it provides many antioxidants and immunomodulating substances that are useful to maintain an adequate physiological function of most body organs [52]. Garlic (Allium sativum) is the perfect example of bioactive sulfur compound (antioxidant and antibacterial molecules) intake with the diet. Allium species have a characteristic flavor that is due to the production of particular compounds when fresh garlic is crushed. When garlic is chopped, the precursors allin, isoallin, and other S-alk(en)yl-L-cysteine-S-oxides are converted via an enzymatic process mediated by allinase enzyme into the respective thiosulfinates such as allicin, isoallicin, and allysulfinates, which are also responsible for the aroma of fresh garlic and its antiseptic activity (Figure 7). Also, in onions, a series of VSCs is formed by cleavage of S-alk(en)yl cysteine sulfoxides catalyzed by allinase and lachrymatory factor synthase [53].

3.2.2. Glucosinolates and Isothiocyanates

Glucosinolates are another important class of organosulfur plant secondary metabolites and are present mostly in species of the Brassicacee family, such as cabbage, broccoli, and horseradish, and are derived from glucose and thiohydroxamic acids starting from different amino acids [54]. Nonaromatic glucosinolates are derived mainly from Met and aliphatic amino acids, while aromatic glucosinolates, such as glucobrassicin, are derived from tryptophan as an amino acid donor. As for garlic S-alk(en)yl-L-cysteine-S-oxides, also glucosinolates represent inactive precursors that release the biologically active sulfur species when the plant material is cut, chewed, or crushed. When the enzyme myrosinase enters in contact with the glucosinolates, substrates cleave off the glucose moiety and release isothiocyanates (commonly known as mustard oil), which are responsible for pungency and defense mechanism (Figure 8) [55].

When the plant is attacked or damaged, the organism is already prepared with this two-component system (enzyme-precursor) and immediately starts the enzymatic hydrolysis of glucosinolates and the subsequent formation of the bioactive isothiocyanates [56]. Allyl isothiocyanates (Figure 9) from radish, horseradish, and wasabi are well-recognized VSCs for strong repellent activity against various arthropods, nematodes, and microorganisms and possess a good chemopreventive activity [57]. An important part of the beneficial effect of the Mediterranean diet is related to isothiocyanate intake such as sulforaphane (Figure 9). Sulforaphane, an isothiocyanate compound that occurs in high concentration as its precursor glucoraphanin, is abundant in broccoli, Brussels sprouts, and cabbages and many biological effects such as anti-inflammatory, antidiabetic, anticancer, and neuroprotective effects were recently ascribed to this compound [58].

3.2.3. Polysulfides and Phytochelatins

Other two important classes of nonaromatic sulfur derivatives are cyclic methylene-sulfur compounds (polysulfides) and phytochelatin polymers. The most famous molecule belonging to cyclic polysulfides is lenthionine. Lenthionine (Figure 10) and 1,2,4,6-tetrathiepane were earlier isolated from an extract of the edible “shiitake” mushroom (Lentinus edodes) and are partly responsible for its flavor. Lenthionine biosynthesis was not completely elucidated, but it seems also in this case as for garlic thiosulfinates that catalytic cleavage of C-S lyase enzyme is the crucial step for the formation of the final product [59, 60]. Phytochelatins (Figure 10) are a class of sulfur derivatives which are polymeric peptides. They are synthetized by plants, fungi, and cyanobacteria when the cellular environment is rich in metal ions. Structurally, they are polymers of GSH and their principal role is the environmental detoxification exerted by their strong activity as chelating agents [61].

4. Biochemical Aspects of Endogenous Sulfurous Metabolites

The metabolism of sulfur-containing amino acids consists of a variety of reactions and pathways with several intermediates and products whose biochemical significance still needs to be fully elucidated [6266]. Crucial functions for cell survival are served by some of these metabolites. Met and Cys are the two main sulfur amino acids. They are incorporated into proteins and have important catalytic roles in the active sites of many enzymes [67, 68]. Dietary proteins normally supply Met and Cys. In addition to the intake of dietary protein, turnover of body proteins releases free Met and Cys into the body pools [69, 70].

Met serves as the source of sulfur for Cys biosynthesis in a one-way transsulfuration pathway that links metabolically Met and Cys. In mammals, Met is an essential amino acid as it cannot be synthesized in amounts sufficient to maintain the normal growth, whereas Cys is considered a semiessential amino acid because it can be produced from Met sulfur and serine via transsulfuration. Cys and Met oxidation and catabolism yield a considerable amount of energy. This was originally believed to be wasted, as the oxidation of this sulfur to sulfate (−2 → +6) was not thought to be coupled to ATP synthesis [71]. However, recent findings suggest that H2S derived from Cys and Met metabolism can stimulate oxidative phosphorylation via sulfide:quinone oxidoreductase (SQR) and sulfite oxidase [7276]. Beyond this energetic potential of Cys and Met, these sulfur amino acids exert crucial functions through their well-known metabolites, such as SAM, Tau, and GSH.

4.1. Transmethylation/Transsulfuration Pathway

In mammalian cells, the transmethylation/ transsulfuration pathway is central for sulfur amino acid metabolism and the regulation of redox balance. The pathway involves the transfer of sulfur from HCy to Cys via cystathionine and is the only route for biosynthesis of Cys. This pathway is intimately linked to the transmethylation pathway via HCy, which can be remethylated to generate Met or be irreversibly converted to Cys (Figure 11).

Met metabolism begins with the activation of Met to SAM by Met adenosyltransferase (MAT). The reaction requires ATP and the sequential cleavage of all its high-energy phosphate groups. SAM as a methyl group donor generates S-adenosylhomocysteine (SAHCy) by cellular methyltransferases. SAHCy is hydrolyzed to yield HCy and adenosine by SAHCy hydrolase (SAH). This sequential reaction route is present in all cell types and is referred to as the transmethylation pathway. HCy is methylated back to Met by the Met synthase (MS) and, only in the liver and the kidney of some species, by betaine:homocysteine methyltransferase (BHMT) [77]. The HCy remethylation is catalyzed by both MS and BHMT, and the combination of transmethylation and remethylation comprises the Met cycle.

The transsulfuration pathway diverts HCy from the Met cycle, converting HCy to Cys by the sequential action of two pyridoxal 5-phosphate- (PLP-) dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). HCy, which is derived from dietary Met, is converted to cystathionine by CBS, which is acted on by CSE to generate Cys. The transmethylation and remethylation pathway occurs in all cells, whereas the transsulfuration pathway is restricted to certain tissues. An exogenous source of Cys is required in conditions where transsulfuration reactions do not occur at a sufficient rate [7880]. These tissues accumulate HCy (or cystathionine) which must be exported to other tissues for further metabolism/removal. The transsulfuration pathway occurs in tissues that contain both CBS and CSE [81]. CBS activity is widely present in mammalian organs including the liver, adipose tissue, kidney, and brain [82]. Conversely, it is widely assumed that a high level of CSE is present in the liver, kidney, and pancreas, whereas CSE activity is absent in the brain [83], However, recent studies have demonstrated that also CSE is both present and active in the brain [84, 85]. Both CSE and CBS occupy a central role in the cell redox regulation. It has been reported that approximately half of the intracellular GSH pool in the human liver is derived from Cys generated from HCy via the transsulfuration pathway [86]. In the mouse brain, the activity of the pathway is lower as compared to that in the liver, but the flux can be regulated by oxidative stress [84, 85]. It has been observed that CSE undergoes inactivation under oxidative stress condition in mice [65]. In this regard, an intact transsulfuration pathway plays a key role in maintaining GSH homeostasis and affords an effective neuroprotection.

4.2. S-Adenosylmethionine

SAM is a high-energy sulfonium compound which acts primarily as a methyl donor in reactions catalyzed by a vast array of methyltransferases. Given its high energy, the molecule is not so stable in vitro and can be degraded rapidly even at room temperature, giving rise to SAHCy, homoserine (HSer), 5-methylthioadenosine (MTA), and S-5-adenosyl-(5)-3-methylpropylamine (dSAM) (Figure 12) [8790].

These SAM-dependent methylations are essential for biosynthesis of various biomolecules including creatine, epinephrine, melatonin, carnitine, and choline. An alternative fate of SAM is decarboxylation to form dSAM, which is the donor of aminopropyl groups for synthesis of spermidine and spermine [63, 91]. As a result of polyamine synthesis, MTA forms from dSAM. Alternatively, SAM provides amino groups in biotin synthesis and 5-deoxyadenosyl radicals and also sulfur atoms in the synthesis of biotin and lipoic acid [9297].

SAM is also a potent allosteric regulator of the transmethylation/transsulfuration pathways. SAM promotes Met catabolism through the transsulfuration pathway and inhibits the remethylation of HCy to Met [98101]. As a result, SAM increases the activity of CBS which is the primary enzyme in transsulfuration and contributes to the synthesis of Cys, thereby increasing the GSH level. The attenuation of oxidative stress by SAM administration has been evidenced by several studies. For example, Li et al. [102] showed that cells can be protected from oxidative stress induced by 𝛽-amyloid peptide after SAM administration; indeed, SAM actually increases endogenous antioxidant defense by restoring the normal GSH/GSSG ratio and inducing antioxidant enzyme activities.

4.3. Nontranssulfuration Pathway

The SAM-independent catabolic pathway of Met also occurs, involving an initial transamination reaction [62]. The transamination of Met forms α-keto-γ-methiolbutyrate, the α-keto acid analogue of Met, which may be further catabolized via oxidative decarboxylation to 3-methylthiopropionate, MeSH, and additional catabolites [103, 104]. This is considered a minor pathway under normal circumstances, but it becomes more significant at high Met concentrations. Because it produces powerful toxins such as MeSH, it has been considered to be responsible for Met toxicity [105]. Indeed, Met has been regarded as a toxic amino acid, whether large amounts are taken up from the diet or it accumulates from metabolic dysfunction of the transsulfuration pathway. Excessive dietary Met causes acute liver injury and erythrocyte membrane damage through mechanisms that are not still fully elucidated [104107]. The toxic effect has been observed especially in rodent tissues where Met transamination occurs and appears to play a crucial role in Met toxicity [106]. In humans, the physiological and toxicological significance of the Met transamination pathway remains unclear [108, 109]. Interestingly, not only Met but also other thioether metabolites undergo transamination generating a class of sulfur-containing heterocyclic compounds called ketimines (described below) [110, 111].

4.4. Cysteine Metabolism

Cys, whether formed from Met and serine via transsulfuration or supplied preformed in the diet, serves as a precursor for synthesis of proteins and several other essential molecules. These metabolites include GSH, CoA, and Tau. These fates of Cys, except GSH, involve loss of the Cys moiety as such. Cys is a substrate for CoA synthesis in that it is used to form the cysteamine (decarboxylated Cys) moiety of the CoA molecule and, hence, contributes to the reactive sulfhydryl group. Cys is also the precursor of the gaseous signaling molecule H2S [112114].

Cys is metabolized via two distinct routes. The first one, called the cysteine sulfinate- (CSA-) dependent (aerobic) pathway, is a series of oxidative steps leading to Htau. The second one, a transsulfuration (anaerobic) pathway, is a source of sulfane sulfur-containing compounds as well as H2S [115]. The enzymes involved in the H2S production include pyridoxal 5-phosphate- (PLP-) dependent CSE and CBS as well as cysteine aminotransferase (CAT) in conjunction with PLP-independent mercaptopyruvate sulfurtransferase (MST) (Figure 13) [112, 116, 117].

Cys is readily oxidized to Cys-Cys and exists in oxidized form in plasma and in the extracellular milieu, thus representing the major transport form of non-protein-bound Cys [118]. Across membranes, Cys and Cys-Cys are transported by different membrane carriers. In the CNS, glial cells mainly import Cys-Cys via the cystine-glutamate antiporter providing the major route for GSH synthesis in the brain [119]. Cys-Cys undergoes β-elimination reaction by transsulfuration enzymes, CBS and CSE, yielding thiocysteine, the persulfide analogue of Cys (RSSH) [120123].

4.5. Glutathione

The GSH tripeptide is derived from Cys, glutamate, and glycine present in all mammalian cells at mM concentration level (1-10 mM) with the highest amount in the liver. GSH has an unusual γ-glutamyl bond linking glutamate and Cys This unconventional peptide bond through the γ-carboxyl group of glutamate rather than the α-carboxyl group confers stability to hydrolysis by cellular peptidases, requiring a specific enzyme for GSH degradation. The first step in the GSH synthesis is catalyzed by the enzyme glutamate-cysteine ligase (GCL) which forms γ-glutamylcysteine in an ATP-dependent reaction [124]. This conjugation reaction between glutamate and Cys is considered the rate-limiting step in GSH synthesis, whereas Cys the limiting substrate [125]. The addition of Gly to γ-glutamylcysteine is catalyzed by the ATP-dependent enzyme glutathione synthase (GS) which results in the formation of the mature GSH tripeptide [126, 127]. The enzyme that accounts for the hydrolysis of the γ-glutamyl bond is γ-glutamyltranspeptidase (γGT), which localizes on the luminal surfaces of cells lining the glands and ducts of various organs particularly the kidney, pancreas, and liver [128] (Figure 14).

As consequence, GSH is resistant to intracellular degradation and is mainly metabolized extracellularly by cells that express γGT. However, recently, cytosolic breakdown pathways for GSH have been described [129]. GSH breakdown by γGT produces glutamate and cysteinylglycine which can be taken up by cells where the released amino acids are reused for the synthesis of GSH (so-called the γ-glutamyl cycle) [130]. In addition to the several vital functions of GSH, GSH serves as a reservoir of Cys and as a means for transporting Cys to extrahepatic tissues. An association between Cys and GSH metabolism disruption and aberrant redox homeostasis and neurodegeneration has been frequently observed [131, 132].

4.6. Coenzyme A, Pantetheine, and Cysteamine

CoA (Figure 15) is synthesized starting from pantothenate and cysteine in five reaction steps (Figure 16). 4-Phosphopantetheine (cysteamine-pantothenate conjugate) is the moiety bearing the reactive thiol for the formation of the high-energy thioester bond in acetyl CoA [133].

CoA breakdown generates pantetheine which is hydrolyzed by the vanin family of pantetheinase enzymes to pantothenate and the aminothiol, cysteamine [134, 135]. Cysteamine is the decarboxylated derivative of Cys. However, in mammals, cysteamine is not formed from Cys directly by decarboxylation. Rather, it is produced mainly by the pantetheinase activity during CoA breakdown (Figure 16). An alternative route to cysteamine from lanthionine has been described, where lanthionine undergoes first decarboxylation to S-2-aminoethyl-L-cysteine (also called thialysine); subsequently, this latter compound is converted to cysteamine by a β-elimination reaction [136]. In humans, cysteamine undergoes different metabolic degradations such as conversion to volatile sulfur compounds, i.e., methanthiol and dimethylsulfide, which have been detected in cystinosis patients treated with this aminothiol [137, 138]. Cysteamine is highly reactive, and it readily oxidizes in solution to form the disulfide cystamine. Cysteamine readily forms mixed disulfides with susceptible Cys thiol groups in a process called cysteaminylation which is key for many reported biological activities [139]. At low concentrations, cysteamine can form a mixed disulfide with Cys, promoting Cys transport into cells. Recently, the complex role of cysteamine and cystamine as oxidative stress sensors has been illustrated by experiments using vanin 1-deficient mice [140, 141]. Interestingly, cysteamine has been used to treat cystinosis and neurodegenerative disorders [142, 143]. A recent review recapitulates the use of cysteamine as a mutation-tailored drug. This aminothiol has been proposed to repair Arg to Cys missense mutations in genetic disorders. Upon binding of cysteamine to the Cys residue by a disulfide bond, a mimic structure resembling the original arginine residue is created on the mutated protein [144].

4.7. Taurine

In the mammalian pathway leading from Cys to Tau, Htau is the main metabolic precursor of Tau. Htau is synthesized by the CSA-dependent (aerobic) pathway of Cys metabolism (Figure 13). The production of Htau is dependent upon the sequential action of cysteine dioxygenase (CDO) that adds molecular oxygen to the thiol group of Cys to form CSA and of cysteine sulfinate decarboxylase (CSAD) that finally generates Htau [115]. In a minor pathway, CSA can also undergo oxidation to produce cysteic acid (CA) and, through subsequent decarboxylation, forms Tau [115, 145]. Another pathway involves the production of Htau from cysteamine via the action of cysteamine dioxygenase (2-aminoethanethiol dioxygenase, ADO) (Figure 17) [146].

CDO and ADO are the only two mammalian thiol oxygenases capable of specifically oxidizing free sulfhydryl groups [147]. The activities for these two proteins were first reported in mammalian tissues almost 60 years ago [148, 149].

The importance of the cysteamine/Htau/Tau pathway has been largely regarded as minor relative to the Cys/CSA/Htau/Tau pathway. Indeed, it is the reaction catalyzed by CDO that has been implicated as the major rate-determining step in the synthesis of Htau and Tau [150]. Interestingly, the brain is capable of synthesizing Tau and yet expresses relatively little CDO [151], and it is, thus, possible that the ADO-mediated pathway is largely responsible for Htau/Tau synthesis in the brain [146].

Noteworthy, the oxidation of the sulfinic group of both Htau and CSA with production of the respective sulfonate (RSO3), Tau and CA, is a crucial point for the generation of Tau in mammalian tissues [145, 152]. However, no specific enzymatic activity has been detected for this oxidation. Conversely, there is strong evidence that in vivo formation of Tau and CA is the result of sulfinate (RSO2) interaction with a variety of biologically relevant oxidizing agents [153156]. The relevance of both CO3⋅– and NO2 in the oxidation of Htau has been recently evidenced by the peroxidase activity of Cu-Zn superoxide dismutase and horseradish peroxidase [157159]. Recently, it has been shown that a wide substrate range enzyme such as flavin monooxygenase 1 (FMO1) is able to catalyze the oxidation of Htau to Tau [160].

Tau is the most abundant free amino acid in animal tissues and is present especially in excitable tissues such as the brain, retina, muscle, and heart, whereas circulating levels are, in comparison, much lower [2, 161163]. The Tau content differs between species such that taurine levels have been reported lower in primates than in rodents. The amounts range from 2 μmol/g wet weight in the human brain to 40 μmol/g in the mouse heart, with even higher concentrations in the eye retina and in the developing brain of mice [164, 165]. In the muscle, retina, and neurons, the Na+-dependent transport through the Tau transport accumulates Tau at high levels [166]. Tau is capable of regulating osmolarity through exchange with the extracellular space without altering membrane potential. This role of Tau as a critical regulator of osmolarity is particularly important in maintaining neuronal function [167]. Both Tau and Htau exhibit neurotransmitter activity reminiscent of γ-aminobutyric acid (GABA) and β-alanine. According to this chemical structure similarity, Tau can mimic some effects provoked by GABA release [168]. In the CNS, where Tau is highly concentrated, this β-amino acid exhibits neuromodulator and neuroprotector activity, also preserving the homeostasis of retinal functions [169]. Tau plays a role also in bile salt formation.

Similarly, Htau is a unique amino sulfinate with a powerful antioxidant capacity [170172]. Htau achieves a millimolar concentration in tissues and biological fluids typically subjected to high oxidative stress, such as the regenerating liver, human neutrophils, and human semen [173175]. Noteworthy, Htau is capable of protecting SOD by the H2O2-mediated inactivation, thus reinforcing the cell defense against oxidative damage [176]. However, the one-electron oxidative reaction between Htau and various biologically relevant oxidants is accompanied by generation of reactive intermediates, such as sulfonyl radicals, which could promote oxidative chain reactions [156, 157].

4.8. Sulfane Sulfur: Persulfides and Thiosulfonates

Low-molecular weight RSSH such as thiocysteine and glutathione persulfides (GSSH) are present at μM concentration inside the cells. Due to highly reducing and nucleophilic properties, RSSH can act as scavenging oxidants and intracellular electrophiles. RSSH are considered the major source of sulfane sulfur in biological systems. One proposed mechanism for sulfane sulfur biological effect is the modification of protein Cys residues by persulfidation [113, 177, 178]. Noteworthy, biological effects attributed to H2S as a signaling molecule may also be partially caused by sulfane sulfur, such as Cys-based persulfides as the actual signaling species [179181]. H2S, indeed, can react with oxidized thiols, such as sulfenates (RSOH), in biological systems to give persulfides [182]. Thiocysteine can be directly generated by transsulfuration enzymes CBS and CSE from Cys-Cys, whereas GSSH is produced in the mitochondrial sulfide oxidation by SQR [40, 120, 183185]. Recently, the in vivo formation of thiocysteine by the transsulfuration pathway has been questioned [186]. Sulfane sulfur species such as thiocysteine, GSSH, and protein-Cys persulfides are also generated by MST [187, 188]. Furthermore, a recent report revealed that a mitochondrial enzyme, cysteinyl-tRNA synthetase (CARS2), plays a major role in converting Cys into Cys per/polysulfide species [189].

The sulfane sulfur of thiocysteine can be transferred by sulfurtransferases to various acceptors, including sulfite and Htau [120, 190]. The transfer of sulfur to Htau produces Ttau, a component of the Tau family characterized by the presence of a sulfane sulfur in the thiosulfonate group (−S2O2). The biological occurrence of Ttau in mammals as a metabolic product of Cys-Cys in vivo was reported initially by Cavallini and coworkers [191] by demonstrating that rats fed with a diet supplemented in Cys-Cys excreted a newly unknown compound identified as the thiosulfonate analogue of Tau, Ttau. Furthermore, Ttau is formed by a sulfurtransferase catalyzing sulfur transfer from mercaptopyruvate to Htau [192, 193]. Structurally, Ttau carries a hypotaurine moiety and a sulfane sulfur moiety generated, respectively, by aerobic and anaerobic metabolism of cysteine. Consequently, Ttau can represent a linking intermediate of the cysteine metabolic paths (Figure 18).

Interestingly, Ttau is capable of releasing H2S in a thiol-dependent reaction. In particular, thiols, such as GSH, and other reducing agents reduce sulfane sulfur of thiosulfonates to H2S [38, 117, 193]. Accordingly, in human neutrophils, GSH acts as a catalyst in the generation of H2S and Htau from Ttau [194].

Overall, Ttau formed as a result of the reaction between Htau and RSSH may be converted back to H2S and Htau (Figure 18). It is likely that Ttau, due to its peculiar biochemical properties, takes part in the modulation and control of H2S signal as suggested by the effect of Ttau on human neutrophil functional responses [37, 195197].

4.9. Lanthionines, Cyclic Ketimine, and Imino Acid Derivatives: Sulfur-Containing Metabolites Still in Search for a Role

Lanthionines are a class of sulfur organic compounds that are extremely interesting but still remain a mystery. From a chemical point of view, lanthionines are thioethers derived from the condensation of aminothiols or amino acids. Cystathionine probably represents one of the most important biological thioethers for humans. This molecule is essential for the transsulfuration pathway in which HCy is converted to Cys in relation to the folate cycle and SAM-mediated methylation pathway [15]. The four most important thioethers involved in this metabolism and other mammalian metabolic disorders are lanthionine, cystathionine, S-2-aminoethyl-L-cysteine (thialysine), and homolanthionine (Figure 19).

The biosynthesis of these compounds in mammals is mediated by the transsulfuration enzymes, CBS and CSE, starting from Cys, cysteamine, and HCy to produce lanthionine, thialysine, and cystathionine, respectively. CBS enzyme can use serine or Cys as the substrate and releases H2O or H2S (Figure 20).

The catabolism of cystathionine involves CSE releasing Cys and α-ketobutyric acid in a reaction that catalyzes a PLP-mediated α-γ elimination. The role of linear thioethers such as lanthionine and thialysine is still unknown from a metabolic point of view, also because they are poor substrates of CSE enzyme and then they should be addressed to different metabolic routes. Some of them such as thialysine can be used as substrates for decarboxylases giving rise to different thioether polyamines (e.g., thiacadaverine). In most of the cases, the fate and significance of lanthionine compounds is unclear and difficult to understand. In this contest, it is important to underline the fundamental contribution of professor Cavallini and coworkers in the study and discovery of some sulfur-containing cyclic ketimines as products of the linear thioethers discussed above [14]. Lanthionine, cystathionine, and thialysine can undergo an oxidative deamination to produce the respective α-keto acids that subsequently cyclize to give rise to their sulfur-containing cyclic ketimine, lanthionine ketimine (LK), cystathionine ketimine (CK), and thialysine ketimine (TK) [110, 198, 199] (Figure 21).

LK, CK, and TK can also be obtained via a chemical reaction in aqueous solutions of Cys, HCy, and cysteamine with bromopyruvic acid [200, 201]. In the case of CK, a seven-membered asymmetric ring, the ketimine could also exist in the isomeric form with the double bond located in the longer carbon chain moiety of the ring. This isomer has been prepared by reacting β-chloro-L-alanine with 2-oxo-4-thiobutyrate obtained enzymatically. One common feature of this class of compounds is their reducing power. Reduced saturated cycles can be obtained by the reduction of the imine bond (C=N) with NaBH4 [202]. TK yields 1,4-thiomorpholine-3-carboxylic acid (TMA), LK gives 1,4-thiomorpholine-3,5-dicarboxylic acid (TMDA), and CK produces 1,4-hexahydrothiazepine-3,5-dicarboxylic acid (cyclothionine) [203]. The reduced products are much more stable than the parent ketimines and can be produced also biochemically by a NADP(H) reductase enzyme [204] (Figure 22).

All of these cyclic derivatives (LK, CK, TK, and their reduced products TMDA, cyclothionine, and TMA) were detected in human urines and mammalian brains [205208]. LK and CK were also directly detected for the first time in the human brain in 1991 by Fontana and coworkers [209]. The very unusual and particular issue is that lanthionine differently from the other linear precursors was never found in human urines and brain tissues [208].

Lanthionines and sulfur cyclic ketimines are a very interesting class of compounds that may play an important physiological role. In degenerative processes, thiol redox biochemistry is crucial and in some neuronal disorders such as Alzheimer’s disease may represent an important diagnostic marker [131]. The metabolism of organic sulfur in many organisms is still not completely understood, and there are many evidences of an emerging role of some of sulfurous ketimines in inflammation and neuronal associated disorders [15]. The brain contains a functional transsulfuration pathway able to generate H2S and several unusual amino acids, such as LK and other sulfur-containing cyclic ketimines and imino acids (Figure 20), whose biological role and significance are still unknown [14, 15, 210]. Among these compounds, LK demonstrated potent antioxidant, neuroprotective, and neurotrophic actions [211], properties that have made this compound a candidate for studies that focus on neurodegenerative diseases and processes including ischemia, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s and Batten’s diseases [15, 210, 212214].

The group of natural heterocyclic sulfur compounds includes not only the six-membered ring cyclic ketimines such as CK, LK, and TK but also the class of five-membered ring heterocycles like terrestrial and marine thiazolidine and thiazoline derivatives such as thioproline, ovothiols, and thiazoline carboxylic acids (e.g., 2-amino-2-thiazoline-4-carboxylic acid (ATCA)) [41, 215218] (Figure 23).

All of these compounds demonstrated to possess different and in some cases convergent biological activities such as oxygen and nitrogen-free radical scavenging capacity, detoxification of cyanide, and antioxidant activity [41, 217, 219222].

4.10. Substrate Flexibility in the Enzymology of Sulfur-Containing Compounds

Many of the enzymes responsible of the metabolic pathways involving sulfur-containing compounds show a relaxed substrate specificity, and at the same time, many reactions involving sulfur-containing molecules are carried out by enzymes also used for different purposes.

This fact came to the attention of Cavallini and colleagues more than sixty years ago, when cystamine and lanthionamine, the R2S analogue of cystamine, were assayed as substrates of diamine oxidase [223, 224]. The interest of this finding was increased by the observation that the rate of the oxidation was in the range of that of traditional substrates and the product of the reaction was a cyclic cystaldimine (1,2-dehydrodithiomorpholine), which was then cleaved giving rise to a variety of products such as thiocysteamine, Htau, Ttau, and Tau.

CSA and CA, but also their homologues, homocysteine sulfinic acid (HCSA) and homocysteic acid (HCA), are also known to take profit from a number of enzymes used for other purposes. In this case, the sulfinic and sulfonic groups can mimic the carboxyl group of the carbon analogues aspartate and glutamate. All these sulfur compounds can substitute glutamate and aspartate in the common amino acid transamination and decarboxylation reaction. The decarboxylation reaction converts the sulfinates, CSA/HCSA, and the sulfonates, CA/HCA, in Htau/homoHtau and Tau/homoTau, respectively [225]. In addition to enzyme reactions, these metabolic derivatives interact with molecular targets such as neurotransmitter receptors, channels, or transporters. Due to structure similarity, HCSA/HCA and their decarboxylated derivatives, homoHtau/homoTau, can represent natural mimetics as neuroactive agents for glutamate and GABA, respectively (Figure 24) [226, 227].

Interestingly, the HCy derivatives can attain a major biological relevance during hyperhomocysteinemia [228]. Mild hyperhomocysteinemia is a common clinical condition associated with an increased risk for cardiovascular and neurodegenerative diseases [229, 230]. Noteworthy, in Down syndrome, or trisomy 21, the overexpression of CBS removes homocysteine from the transmethylation pathway leading to decreased plasma levels of homocysteine and a low incidence of atherosclerosis in these subjects [231, 232]. Consequently, cystathionine, cysteine, and H2S levels are increased, consistent with an increased CBS activity [233, 234].

In mammals, the relaxed substrate specificity makes the two transsulfuration enzymes, CBS and CSE, chiefly responsible for H2S biogenesis [122, 235]. These human enzymes afford H2S generation by a multiplicity of routes involving Cys and/or HCy as substrates. In addition to H2S, a variety of products is generated in these reactions, including lanthionine and homolanthionine [122]. These thioethers have been proposed as markers of H2S production in homocystinurias [236]. CBS is also involved in the formation of thialysine by replacing HCy with cysteamine [237]. Thialysine has been actually detected in brain tissues following gavage feeding of cysteamine in rats [238] and in urine of normal human adults, suggesting thialysine may even be a natural occurring metabolite [208].

According to this substrate flexibility in the enzymology of sulfur amino acid, a vast array of sulfur compounds occurs and can be detected in living organisms, whose biological and metabolic role is worth to be explored.

5. Sulfur-Containing Compounds and Redox Biochemistry

The electronic configuration of sulfur allows it to occur in numerous oxidation states, both negative and positive, ranging from -2 to +6 and possibly including fractional oxidation states [239]. Apart from the well-known ROS and RNS, the existence of reactive sulfur species (RSS) is well documented [240242]. RSS include species such as sulfur-centered radicals (RS), disulfides (RSSR), disulfide-S-oxides, and sulfenic acids (RSOH) and can easily be formed in vitro from thiols by reaction with oxidizing agents such as hydrogen peroxide, singlet oxygen, peroxynitrite, and superoxide. However, the redox potential of RSS is considerably less positive than that of ROS; their biochemical importance is not to be underevaluated. For instance, the thiyl radical is an oxidative stressor whereas the disulfide can be a mild oxidative stressor [239]. All of these RSS could in principle oxidize and subsequently inhibit redox-sensitive proteins. Furthermore, thiols could store nitric oxide via the formation of nitrosothiols, which could release nitroxyl ions [243] or nitric oxide in physiological conditions or in the presence of transition metal chelators [244246].

The best-known RSS is thiyl radical (RS), which is formed by the one-electron oxidation of Cys and is unstable in physiological conditions. If not adequately quenched by ascorbate or GSH, the thiyl radical undergoes a rather efficient intramolecular hydrogen transfer processes, and in oxidative stress conditions, the extent of irreversible protein thiyl radical-dependent protein modification increases [247]. Thiyl radical can be formed in physiological conditions via three major routes: hydrogen donation, enzymatic oxidation, and reaction with ROS. Particularly, formation of this radical has been documented for the reaction of hydrogen peroxide either with hemin or with heme proteins, such as hemoglobin [248, 249]. Many other sulfur-centered radicals could be theoretically formed, but those species are extremely unstable and can only be studied by EPR at very low temperatures; hence, their pathophysiological role, if ever, is still unclear [250]. Sulfinyl and sulfonyl radicals have also been observed as free radical metabolites of Cys oxidation, which are formed during the interaction of thiols with ROS. These species can be further oxidized to highly reactive radical species, which could lead to dimerization or oxidation [239].

Due to its high reactivity, the reduced thiol group of cysteinyl side chains in proteins plays a major role in many biological processes, and its redox state is of paramount importance in maintaining physiological functions such as catalysis, metal binding, and signal transduction. Hence, the redox regulation of the intracellular environment is a critical factor in cellular homeostasis. Particularly, the regulation of thiol redox balance is fundamental for the maintenance of many different cellular processes such as signal transduction, cell proliferation, and protein integrity and function.

The cellular thiol groups are protected by the “thiol redox buffering system,” whose key components are GSH, either reduced (GSH) or oxidized (GSSG), and the families of enzymes glutaredoxins, thioredoxins, and peroxiredoxins. GSH is the major intracellular thiol antioxidant. Apart from the antioxidant activity, GSH has also a role in the detoxification of xenobiotics and heavy metals [251]. Its concentration is in the mM range, up to 10 mM in certain cells making this compound the most concentrated antioxidant in the cells [251]. However, rather than the absolute concentration of GSH, a better index of redox state is represented by the ratio which also reflects changes in redox signaling and control of cell functions [131]. During acute oxidative stress, GSH concentration decreases and the associated increase in GSSG concentration results in an increased turnover of the GSH/GSSG cycle, but GSSG is also actively extruded from the cell; thus, the intracellular turnover of GSH is affected [251]. Under normal conditions, the ratio of GSH/GSSG is around 50 : 1 to 100 : 1, whereas in oxidative stress condition, it can drop to 10 : 1 and even to 1 : 1 [252].

Some disulfides may be strongly oxidizing and cause oxidative damage to cell components. For instance, under conditions of oxidative stress, GSSG could reach toxic concentration in the cells and oxidize proteins like metallothioneins [253]. GSSG is formed from GSH when enzymes like glutathione peroxidase (GSHPx) use GSH as a reducing species to detoxify peroxides or other ROS to prevent oxidative damage. GSH is then regenerated by the aid of NADPH in the presence of glutathione reductase (GR).

Reversible reduction of disulfide bonds can be mediated by a variety of thiol redox enzymes such as the thioredoxins (TRXs) and the glutaredoxins (GRXs). The TRX and GRX systems control cellular redox potential, keeping a reduced intracellular environment, by utilizing reducing equivalents from NADPH. These proteins are expressed in all organisms, tissues, cell types, and organelles, and some of them can shuttle between cellular compartments and the extracellular space [254].

TRXs were first identified as hydrogen donors for ribonucleotide reductase, the essential enzyme providing deoxyribonucleotides for DNA replication. The paramount importance of TRXs in the cell is witnessed by the evidence that TRX knockout is embryonically lethal [254]. There are two main forms of TRXs, TRX-1 which is present in the cytosol and TRX-2 localized in the mitochondria. TRXs are induced by oxidative stress and act as antioxidants by catalyzing the reversible reduction of disulfides utilizing both cysteinyl residues present in the active site, whose motif is Cys-Gly-Pro-Cys. Oxidized TRX is then reduced via TrxR (TRX reductase) using electrons from NADPH. As for TRXs, there are two main forms of TrxRs, one in the cytosol (TrxR-1) and one in the mitochondria (TrxR-2). Due to the easily accessible C-terminal catalytic center, TrxRs can reduce a broad range of substrates including hydrogen peroxide, selenite, lipoic acid, ascorbate, and ubiquinone, and TrxR-2 was demonstrated to act on cytochrome c [255], but the main substrates remain TRXs. In response to oxidative stress, TRXs can be secreted by the cells and exert an anti-inflammatory action by inhibiting neutrophil extravasation into the inflammatory sites, opening to the possibility of using these proteins as therapeutic tools [256, 257].

GRXs are a group of thiol redox enzymes whose active site contains the sequence motif CXXC, same as in TRXs and protein disulfide isomerases. In the GRX system, electrons flow from NADPH to GSH via GR and are then transferred to one of the three up-to-date identified GRXs. Akin TRXs, GRXs are able to reduce protein disulfides but are also able to act on mixed disulfides for which TRXs display low or no activity [258]. GRXs can act via a dithiol or monothiol mechanism, respectively, on protein disulfides or mixed disulfides, particularly on glutathionylated proteins [258]. Protein glutathionylation does not only occur in oxidative stress conditions but rather seems to be a fundamental regulatory mechanism by reversible modification of protein thiols. Hence, deglutathionylation by GRXs could represent a more general mechanism of protein activity control by GRXs than the simple regeneration of protein thiols.

6. Conclusions

Biomolecules consist principally of carbon, hydrogen, and the heteroatoms oxygen and nitrogen. As sulfur and oxygen belong to the same group in the periodic table, the group of chalcogens, the question that arises is as follows: “why analogue compounds with the sulfur atom replaced by oxygen do not serve the same function?”.

Sulfur actually has unique characteristics that differentiate it from oxygen, such as increased atomic size that confers to sulfur a lower electronegativity. This leads to bond formation that is less ionic and weaker than bonds between carbon and sulfur. There are also important differences in primary organosulfur metabolites with respect to oxygenated analogues, such as polarity and reactivity. In particular, thiols and thioether moieties (R2S) can be oxidized to sulfoxides (R2SO) and sulfones (R2SO2) and can form stable sulfonium cations (i.e., SAM) that allow unique carbon alkyl-transfer reactions in biology (e.g., substrates methylation). It is doubtful whether other compounds or other “-onium” compounds could adequately serve this role: quaternary ammonium compounds are too thermodynamically stable to effectively methylate most acceptors, and oxonium compounds are too strong alkylating agents for most of the biological environments with subsequent toxic effects.

Sulfur metabolites are utilized by all living beings and depending on the function are distributed in the different kingdoms from marine organisms to terrestrial plants and animals. Mammals, such as humans, are not able to fix inorganic sulfur in biomolecules and are completely dependent on preformed organic sulfurous compounds to satisfy their sulfur needs. However, some higher species such as humans are able to build new sulfur-containing chemical entities starting especially from plants’ organosulfur precursors. Sulfur metabolism in humans is very complicated and plays a central role in redox biochemistry. In this review, we explored sulfur metabolism in relation to redox biochemistry and the large pool of naturally occurring sulfur-containing compounds in the marine and terrestrial “world.” We focused on the chemistry and the biochemistry of exogenous and endogenous sulfur metabolites underling the importance of well-known and studied molecules and also of the unknown and poorly studied sulfur natural products whose biological role is still a mystery and needs to be investigated.

It is worth investigating the role of these and other still unknown natural sulfur compounds also in view of the extremely promising beneficial activity that the molecules could exert in different pathophysiological conditions.

The biosynthesis of particular sulfur metabolites is a unique feature in some species from the animal kingdom and seems to occur via diverse biochemical pathways evolutionally far from microorganisms and plants’ sulfur metabolism. It is also important to underline the somehow paradoxical situation beyond sulfur biochemistry, probably the oldest redox metabolic form of “life” on Earth and at the same time a continuously newly uncovered field with still more and more opened scientific questions.

Acronyms

ADO:Cysteamine dioxygenase
APS:Adenosine phosphosulfate
ATCA:2-Amino-2-thiazoline-4-carboxylic acid
BHMT:Betaine:homocysteine methyltransferase
CA:Cysteic acid
CARS2:Cysteinyl-tRNA synthetase
CAT:Cysteine aminotransferase
CBS:Cystathionine β-synthase
CDO:Cysteine dioxygenase
CoA:Coenzyme A
CSA:Cysteine sulfinate
CSAD:Cysteine sulfinate decarboxylase
CSE:Cystathionine γ-lyase
Cys:Cysteine
Cys-Cys:Cystine
DMS:Dimethylsulfide
DMSP:Dimethylsulfoniopropionate
dSAM:S-5-Adenosyl-(5)-3-methylpropylamine
GABA:γ-Aminobutyric acid
GR:Glutathione reductase
GRXs :Glutaredoxins
GSH:Glutathione
GSHPx:Glutathione peroxidase
GSSH:Glutathione persulfides
H2S:Hydrogen sulfide
HCA:Homocysteic acid
HCSA :Homocysteine sulfinic acid
HCy:Homocysteine
Htau:Hypotaurine
MAT:Met adenosyltransferase
MeSH :Methanethiol
Met:Methionine
MS:Met synthase
MST:Mercaptopyruvate sulfurtransferase
MTA:5-Methylthioadenosine
R2O:Ether
R2S:Thioether
R2SO :Sulfoxides
R2SO2:Sulfones
R3S+:Sulfonium ion
RDA:Recommended dietary allowance
RNS :Reactive nitrogen species
ROS:Reactive oxygen species
RS:Sulfur-centered radicals
RSO2:Sulfinate
RSO3:Sulfonate
RSOH:Sulfenic acids
RSS:Reactive sulfur species
RSSR:Disulfides
−S2O2:Thiosulfonate group
SAH:S-Adenosylhomocysteine hydrolase
SAHCy:S-Adenosylhomocysteine
SAM:S-Adenosylmethionine
SQR:Sulfide:quinone oxidoreductase
Tau:Taurine
TMA:1,4-Thiomorpholine-3-carboxylic acid
TMDA:1,4-Thiomorpholine-3,5-dicarboxylic acid
TRXs:Thioredoxins
Ttau:Thiotaurine
VSCs:Volatile sulfur compounds
γGT:γ-Glutamyltranspeptidase.

Conflicts of Interest

The authors declare no conflict of interest.

Authors’ Contributions

Antonio Francioso and Alessia Baseggio Conrado equally contributed to this work and co-first authors.

Acknowledgments

This work was supported by funds from MIUR Ateneo 2018 and 2019.

References

  1. N. P. Ward and G. M. DeNicola, “Sulfur metabolism and its contribution to malignancy,” Cellular Nutrient Utilization and Cancer, vol. 347, pp. 39–103, 2019. View at: Publisher Site | Google Scholar
  2. J. T. Brosnan and M. E. Brosnan, “The sulfur-containing amino acids: an overview,” The Journal of Nutrition, vol. 136, no. 6, pp. 1636S–1640S, 2006. View at: Publisher Site | Google Scholar
  3. O. W. Griffith, “Mammalian sulfur amino acid metabolism: an overview,” Methods Enzymology, vol. 143, pp. 366–376, 1987. View at: Publisher Site | Google Scholar
  4. M. E. Nimni, B. Han, and F. Cordoba, “Are we getting enough sulfur in our diet?” Nutrition & Metabolism, vol. 4, no. 1, p. 24, 2007. View at: Publisher Site | Google Scholar
  5. W. ROSE, M. COON, H. LOCKHART, and G. LAMBERT, “The amino acid requirements of man. 11. The threonine and methionine requirements,” Journal of Biological Chemistry, vol. 215, no. 1, pp. 101–110, 1955. View at: Google Scholar
  6. W. Rose and R. Wixom, “The amino acid requirements of man. 13. The sparing effect of cystine on the methionine requirement,” Journal of Biological Chemistry, vol. 216, no. 2, pp. 753–773, 1955. View at: Google Scholar
  7. M. I. Irwin and D. M. Hegsted, “A conspectus of research on amino acid requirements of man,” The Journal of Nutrition, vol. 101, no. 4, pp. 539–566, 1971. View at: Publisher Site | Google Scholar
  8. W. W. Campbell, M. C. Crim, G. E. Dallal, V. R. Young, and W. J. Evans, “Increased protein requirements in elderly people: new data and retrospective reassessments,” The American Journal of Clinical Nutrition, vol. 60, no. 4, pp. 501–509, 1994. View at: Publisher Site | Google Scholar
  9. K. WRETLIND and W. ROSE, “Methionine requirement for growth and utilization of its optical isomers,” Journal of Biological Chemistry, vol. 187, no. 2, pp. 697–703, 1950. View at: Google Scholar
  10. J. O. Anderson, R. E. Warnick, and R. K. Dalai, “Replacing dietary methionine and cystine in chick diets with sulfate or other sulfur compounds,” Poultry Science, vol. 54, no. 4, pp. 1122–1128, 1975. View at: Publisher Site | Google Scholar
  11. J. B. Schutte and M. Pack, “Effects of dietary sulphur-containing amino acids on performance and breast meat deposition of broiler chicks during the growing and finishing phases,” British Poultry Science, vol. 36, no. 5, pp. 747–762, 1995. View at: Publisher Site | Google Scholar
  12. M. C. H. Gruhlke and A. J. Slusarenko, “The biology of reactive sulfur species (RSS),” Plant Physiology and Biochemistry, vol. 59, pp. 98–107, 2012. View at: Publisher Site | Google Scholar
  13. N. Tateishi, T. Higashi, A. Naruse, K. Hikita, and Y. Sakamoto, “Relative contributions of sulfur atoms of dietary cysteine and methionine to rat liver glutathione and proteins,” The Journal of Biochemistry, vol. 90, no. 6, pp. 1603–1610, 1981. View at: Publisher Site | Google Scholar
  14. D. Cavallini, G. Ricci, S. Dupre et al., “Sulfur-containing cyclic ketimines and imino acids. A novel family of endogenous products in the search for a role,” European Journal of Biochemistry, vol. 202, no. 2, pp. 217–223, 1991. View at: Publisher Site | Google Scholar
  15. K. Hensley and T. T. Denton, “Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement,” Free Radical Biology and Medicine, vol. 78, pp. 123–134, 2015. View at: Publisher Site | Google Scholar
  16. D. C. Yoch, “Dimethylsulfoniopropionate: its sources, role in the marine food web, and biological degradation to dimethylsulfide,” Applied and Environmental Microbiology, vol. 68, no. 12, pp. 5804–5815, 2002. View at: Publisher Site | Google Scholar
  17. R. P. Kiene, “Production of methanethiol from dimethylsulfoniopropionate in marine surface waters,” Marine Chemistry, vol. 54, no. 1–2, pp. 69–83, 1996. View at: Publisher Site | Google Scholar
  18. U. Alcolombri, S. Ben-Dor, E. Feldmesser, Y. Levin, D. S. Tawfik, and A. Vardi, “Identification of the algal dimethyl sulfide-releasing enzyme: A missing link in the marine sulfur cycle,” Science, vol. 348, no. 6242, pp. 1466–1469, 2015. View at: Publisher Site | Google Scholar
  19. A. O. Meinrat, “Ocean-atmosphere interactions in the global biogeochemical sulfur cycle,” Marine Chemistry, vol. 30, pp. 1–29, 1990. View at: Publisher Site | Google Scholar
  20. R. P. Kiene, L. J. Linn, J. González, M. A. Moran, and J. A. Bruton, “Dimethylsulfoniopropionate and methanethiol are important precursors of methionine and protein-sulfur in marine bacterioplankton,” Applied and environmental microbiology, vol. 65, no. 10, pp. 4549–4558, 1999. View at: Publisher Site | Google Scholar
  21. N. M. Kredich, “Biosynthesis of cysteine,” EcoSal Plus, vol. 3, no. 1, 2008. View at: Publisher Site | Google Scholar
  22. D. Cavallini, G. E. Gaull, and V. Zappia, Eds., Natural sulfur compounds: novel biochemical and structural aspects, Plenum Press, New York, 1980.
  23. M. Iranshahi, “A review of volatile sulfur-containing compounds from terrestrial plants: biosynthesis, distribution and analytical methods,” Journal of Essential Oil Research, vol. 24, no. 4, pp. 393–434, 2012. View at: Publisher Site | Google Scholar
  24. L. W. Wattenberg, V. L. Sparnins, and G. Barany, “Inhibition of Af-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes,” Cancer Research, vol. 49, 1989. View at: Google Scholar
  25. S. C. Sahu, “Dual role of organosulfur compounds in foods: a review,” Journal of Environmental Science and Health, Part C, vol. 20, no. 1, pp. 61–76, 2002. View at: Publisher Site | Google Scholar
  26. A. Schmidt, W. R. Abrams, and J. A. Schiff, “Reduction of adenosine 5'-phosphosulfate to cysteine in extracts from chlorella and mutants blocked for sulfate reduction,” European Journal of Biochemistry, vol. 47, no. 3, pp. 423–434, 1974. View at: Publisher Site | Google Scholar
  27. E. Bloem, S. Haneklaus, and E. Schnug, “Significance of sulfur compounds in the protection of plants against pests and diseases,” Journal of Plant Nutrition, vol. 28, no. 5, pp. 763–784, 2005. View at: Publisher Site | Google Scholar
  28. M. Burow, U. Wittstock, and J. Gershenzon, “Sulfur-Containing Secondary Metabolites and Their Role in Plant Defense,” in Sulfur Metabolism in Phototrophic Organisms, pp. 201–222, Springer, 2008. View at: Publisher Site | Google Scholar
  29. C. Jacob, “A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms,” Natural Product Reports, vol. 23, no. 6, pp. 851–863, 2006. View at: Publisher Site | Google Scholar
  30. T. K. Korendyaseva, D. N. Kuvatov, V. A. Volkov et al., “An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism,” PLoS Computational Biology, vol. 4, no. 5, article e1000076, 2008. View at: Publisher Site | Google Scholar
  31. M. Giordano and L. Prioretti, “Sulphur and algae: metabolism, ecology and evolution,” in The Physiology of Microalgae, pp. 185–209, Springer, Cham, 2016. View at: Publisher Site | Google Scholar
  32. R. Montaser and H. Luesch, “Marine natural products: a new wave of drugs?” Future Medicinal Chemistry, vol. 3, no. 12, pp. 1475–1489, 2011. View at: Publisher Site | Google Scholar
  33. M. R. Prinsep, “Sulfur-containing natural products from marine invertebrates,” in Studies in Natural Products Chemistry, A. Rahman, Ed., vol. 28, pp. 617–751, Elsevier, 2003. View at: Publisher Site | Google Scholar
  34. P. H. Yancey, J. Ishikawa, B. Meyer, P. R. Girguis, and R. W. Lee, “Thiotaurine and hypotaurine contents in hydrothermal-vent polychaetes without thiotrophic endosymbionts: correlation with sulfide exposure,” Journal of Experimental Zoology Part A: Ecological Genetics and Physiology, vol. 311A, no. 6, pp. 439–447, 2009. View at: Publisher Site | Google Scholar
  35. N. K. Rosenberg, R. W. Lee, and P. H. Yancey, “High contents of hypotaurine and thiotaurine in hydrothermal-vent gastropods without thiotrophic endosymbionts,” Journal of Experimental Zoology Part A: Comparative Experimental Biology, vol. 305A, no. 8, pp. 655–662, 2006. View at: Publisher Site | Google Scholar
  36. J. A. Ortega, J. M. Ortega, and D. Julian, “Hypotaurine and sulfhydryl-containing antioxidants reduce H2S toxicity in erythrocytes from a marine invertebrate,” Journal of Experimental Biology, vol. 211, no. 24, pp. 3816–3825, 2008. View at: Publisher Site | Google Scholar
  37. A. Baseggio Conrado, E. Capuozzo, L. Mosca, A. Francioso, and M. Fontana, “Thiotaurine: from chemical and biological properties to role in H2S signaling,” in Advances in Experimental Medicine and Biology, pp. 755–771, Springer, 2019. View at: Publisher Site | Google Scholar
  38. T. M. Hildebrandt and M. K. Grieshaber, “Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria,” FEBS Journal, vol. 275, no. 13, pp. 3352–3361, 2008. View at: Publisher Site | Google Scholar
  39. T. Corsello, N. Komaravelli, and A. Casola, “Role of hydrogen sulfide in NRF2- and sirtuin-dependent maintenance of cellular redox balance,” Antioxidants, vol. 7, no. 10, p. 129, 2018. View at: Publisher Site | Google Scholar
  40. O. Kabil and R. Banerjee, “Redox biochemistry of hydrogen sulfide,” Journal of Biological Chemistry, vol. 285, no. 29, pp. 21903–21907, 2010. View at: Publisher Site | Google Scholar
  41. I. Castellano and F. P. Seebeck, “On ovothiol biosynthesis and biological roles: from life in the ocean to therapeutic potential,” Natural Product Reports, vol. 35, no. 12, pp. 1241–1250, 2018. View at: Publisher Site | Google Scholar
  42. G. Nardi and H. Steinberg, “Isolation and distribution of adenochrome (s) in Octopus vulgaris Lam,” Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, vol. 48, no. 3, pp. 453–461, 1974. View at: Publisher Site | Google Scholar
  43. F. P. Seebeck, “In vitro reconstitution of mycobacterial ergothioneine biosynthesis,” Journal of the American Chemical Society, vol. 132, no. 19, pp. 6632-6633, 2010. View at: Publisher Site | Google Scholar
  44. F. Leisinger, R. Burn, M. Meury, P. Lukat, and F. P. Seebeck, “Structural and mechanistic basis for anaerobic ergothioneine biosynthesis,” Journal of the American Chemical Society, vol. 141, no. 17, pp. 6906–6914, 2019. View at: Publisher Site | Google Scholar
  45. R. Burn, L. Misson, M. Meury, and F. P. Seebeck, “Anaerobic origin of ergothioneine,” Angewandte Chemie, vol. 129, no. 41, pp. 12682–12685, 2017. View at: Publisher Site | Google Scholar
  46. K. V. Goncharenko, A. Vit, W. Blankenfeldt, and F. P. Seebeck, “Structure of the sulfoxide synthase EgtB from the ergothioneine biosynthetic pathway,” Angewandte Chemie International Edition, vol. 54, no. 9, pp. 2821–2824, 2015. View at: Publisher Site | Google Scholar
  47. S. Nachimuthu, R. Kandasamy, R. Ponnusamy, J. Deruiter, M. Dhanasekaran, and S. Thilagar, “L-Ergothioneine: a potential bioactive compound from edible mushrooms,” in Medicinal Mushrooms, pp. 391–407, Springer, 2019. View at: Publisher Site | Google Scholar
  48. B. Halliwell, I. K. Cheah, and R. M. Y. Tang, “Ergothioneine – a diet-derived antioxidant with therapeutic potential,” FEBS Letters, vol. 592, no. 20, pp. 3357–3366, 2018. View at: Publisher Site | Google Scholar
  49. S. De, T. P. A. Devasagayam, S. Adhikari, and V. P. Menon, “Antioxidant properties of a novel marine analogue of dendrodoine,” BARC Newsletter, vol. 273, pp. 123–133, 2006. View at: Google Scholar
  50. N. Helbecque, C. Moquin, J. L. Bernier, E. Morel, M. Guyot, and J. P. Henichart, “Grossularine-1 and grossularine-2, alpha carbolines from Dendrodoa grossularia, as possible intercalative agents,” Cancer Biochemistry Biophysics, vol. 9, no. 3, pp. 271–279, 1987. View at: Google Scholar
  51. C. Ireland and P. J. Scheuer, “Ulicyclamide and ulithiacyclamide, two new small peptides from a marine tunicate,” Journal of the American Chemical Society, vol. 102, no. 17, pp. 5688–5691, 1980. View at: Publisher Site | Google Scholar
  52. P. Rose, P. K. Moore, M. Whiteman, and Y. Z. Zhu, “An appraisal of developments in allium sulfur chemistry: expanding the pharmacopeia of garlic,” Molecules, vol. 24, no. 21, p. 4006, 2019. View at: Publisher Site | Google Scholar
  53. C. Shang, S.-Y. Cao, X.-Y. Xu et al., “Bioactive compounds and biological functions of garlic (Allium sativum L.),” Foods, vol. 8, no. 7, p. 246, 2019. View at: Publisher Site | Google Scholar
  54. N. Baenas, D. Villaño, C. García-Viguera, and D. A. Moreno, “Optimizing elicitation and seed priming to enrich broccoli and radish sprouts in glucosinolates,” Food Chemistry, vol. 204, pp. 314–319, 2016. View at: Publisher Site | Google Scholar
  55. E. Glawischnig, M. D. Mikkelsen, and B. A. Halkier, “Glucosinolates: biosynthesis and metabolism,” in Sulphur in Plants, pp. 145–162, Springer Netherlands, 2003. View at: Publisher Site | Google Scholar
  56. H. Zukalova and D. B. J. Vasak, “Glucosinolates–secondary plant products as important complex interaction in our biosphere,” Current Nutrition & Food Science, vol. 6, no. 4, pp. 281–289, 2010. View at: Publisher Site | Google Scholar
  57. Y. Zhang, “Allyl isothiocyanate as a cancer chemopreventive phytochemical,” Molecular Nutrition and Food Research, vol. 54, no. 1, pp. 127–135, 2010. View at: Publisher Site | Google Scholar
  58. A. Alfieri, S. Srivastava, R. C. M. Siow et al., “Sulforaphane preconditioning of the Nrf 2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke,” Free Radical Biology and Medicine, vol. 65, pp. 1012–1022, 2013. View at: Publisher Site | Google Scholar
  59. K. Morita and S. Kobayashi, “Isolation, structure, and synthesis of lenthionine and its Analogs,” Chemical & Pharmaceutical Bulletin, vol. 15, no. 7, pp. 988–993, 1967. View at: Publisher Site | Google Scholar
  60. E. Block and R. Deorazio, “Chemistry in a salad bowl: comparative organosulfur chemistry of garlic, onion and shiitake mushrooms,” Pure and Applied Chemistry, vol. 66, no. 10–11, pp. 2205-2206, 1994. View at: Publisher Site | Google Scholar
  61. J. Luis Gómez-Ariza, T. García-Barrera, F. Lorenzo, and A. Arias, “Analytical characterization of bioactive metal species in the cellular domain (metallomics) to simplify environmental and biological proteomics,” International Journal of Environmental Analytical Chemistry, vol. 85, no. 4–5, pp. 255–266, 2005. View at: Publisher Site | Google Scholar
  62. A. J. L. Cooper, “Biochemistry of sulfur-containing amino acids,” Annual Review of Biochemistry, vol. 52, no. 1, pp. 187–222, 1983. View at: Publisher Site | Google Scholar
  63. M. H. Stipanuk, “Metabolism of sulfur-containing amino acids,” Annual Review of Nutrition, vol. 6, no. 1, pp. 179–209, 1986. View at: Publisher Site | Google Scholar
  64. L. P. Laura Betti, “Sulfur metabolism and sulfur-containing amino acids: I-molecular effectors,” Biochemistry & Pharmacology: Open Access, vol. 4, no. 1, 2015. View at: Publisher Site | Google Scholar
  65. O. Kabil, V. Vitvitsky, and R. Banerjee, “Sulfur as a signaling nutrient through hydrogen sulfide,” Annual Review of Nutrition, vol. 34, no. 1, pp. 171–205, 2014. View at: Publisher Site | Google Scholar
  66. M. A. Pajares and D. Pérez-Sala, “Mammalian sulfur amino acid metabolism: a nexus between redox regulation, nutrition, epigenetics, and detoxification,” Antioxidants and Redox Signaling, vol. 29, no. 4, pp. 408–452, 2018. View at: Publisher Site | Google Scholar
  67. G. Kim, S. J. Weiss, and R. L. Levine, “Methionine oxidation and reduction in proteins,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1840, no. 2, pp. 901–905, 2014. View at: Publisher Site | Google Scholar
  68. Y.-M. Go, J. D. Chandler, and D. P. Jones, “The cysteine proteome,” Free Radical Biology and Medicine, vol. 84, pp. 227–245, 2015. View at: Publisher Site | Google Scholar
  69. M. H. Stipanuk, “SULFUR AMINO ACID METABOLISM: Pathways for production and removal of homocysteine and cysteine,” Annual Review of Nutrition, vol. 24, no. 1, pp. 539–577, 2004. View at: Publisher Site | Google Scholar
  70. M. J. MacCoss, N. K. Fukagawa, and D. E. Matthews, “Measurement of intracellular sulfur amino acid metabolism in humans,” American Journal of Physiology-Endocrinology And Metabolism, vol. 280, no. 6, pp. E947–E955, 2001. View at: Publisher Site | Google Scholar
  71. R. J. Huxtable, “The Chemistry of sulfur,” in Biochemistry of Sulfur, Springer US, Boston, MA, 1986. View at: Publisher Site | Google Scholar
  72. M. Velayutham, C. F. Hemann, A. J. Cardounel, and J. L. Zweier, “Sulfite oxidase activity of cytochrome c: role of hydrogen peroxide,” Biochemistry and Biophysics Reports, vol. 5, pp. 96–104, 2016. View at: Publisher Site | Google Scholar
  73. A. P. Landry, D. P. Ballou, and R. Banerjee, “H2S oxidation by nanodisc-embedded human sulfide quinone oxidoreductase,” Journal of Biological Chemistry, vol. 292, no. 28, pp. 11641–11649, 2017. View at: Publisher Site | Google Scholar
  74. E. Lagoutte, S. Mimoun, M. Andriamihaja, C. Chaumontet, F. Blachier, and F. Bouillaud, “Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes,” Biochimica et Biophysica Acta (BBA) - Bioenergetics, vol. 1797, no. 8, pp. 1500–1511, 2010. View at: Publisher Site | Google Scholar
  75. K. Módis, C. Coletta, K. Erdélyi, A. Papapetropoulos, and C. Szabo, “Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics,” The FASEB Journal, vol. 27, no. 2, pp. 601–611, 2012. View at: Publisher Site | Google Scholar
  76. M. Goubern, M. Andriamihaja, T. Nübel, F. Blachier, and F. Bouillaud, “Sulfide, the first inorganic substrate for human cells,” The FASEB Journal, vol. 21, no. 8, pp. 1699–1706, 2007. View at: Publisher Site | Google Scholar
  77. L. M. Stead, J. T. Brosnan, M. E. Brosnan, D. E. Vance, and R. L. Jacobs, “Is it time to reevaluate methyl balance in humans?” American Journal of Clinical Nutrition, vol. 83, no. 1, pp. 5–10, 2006. View at: Publisher Site | Google Scholar
  78. I. Ishii, N. Akahoshi, H. Yamada, S. Nakano, T. Izumi, and M. Suematsu, “Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury,” Journal of Biological Chemistry, vol. 285, no. 34, pp. 26358–26368, 2010. View at: Publisher Site | Google Scholar
  79. S. Mani, G. Yang, and R. Wang, “A critical life-supporting role for cystathionine γ-lyase in the absence of dietary cysteine supply,” Free Radical Biology and Medicine, vol. 50, no. 10, pp. 1280–1287, 2011. View at: Publisher Site | Google Scholar
  80. J. A. Martin, J. Sastre, J. G. de la Asunción, F. V. Pallardó, and J. Viña, “Hepatic γ-cystathionase deficiency in patients with AIDS,” Journal of the American Medical Association, vol. 285, no. 11, pp. 1444-1445, 2001. View at: Publisher Site | Google Scholar
  81. I. Quéré, V. Paul, C. Rouillac et al., “Spatial and temporal expression of the cystathionine β-synthase gene during early human development,” Biochemical and Biophysical Research Communications, vol. 254, no. 1, pp. 127–137, 1999. View at: Publisher Site | Google Scholar
  82. S. H. Mudd, J. D. Finkelstein, F. Irreverre, and L. Laster, “Transsulfuration in mammals. Microassays and tissue distributions of three enzymes of the pathway,” Journal of Biological Chemistry, vol. 240, no. 11, pp. 4382–4392, 1965. View at: Google Scholar
  83. I. Ishii, N. Akahoshi, X.-N. Yu et al., “Murine cystathionine γ-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression,” Biochemical Journal, vol. 381, no. 1, pp. 113–123, 2004. View at: Publisher Site | Google Scholar
  84. V. Vitvitsky, M. Thomas, A. Ghorpade, H. E. Gendelman, and R. Banerjee, “A functional transsulfuration pathway in the brain links to glutathione homeostasis,” Journal of Biological Chemistry, vol. 281, no. 47, pp. 35785–35793, 2006. View at: Publisher Site | Google Scholar
  85. L. Diwakar and V. Ravindranath, “Inhibition of cystathionine-γ-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS,” Neurochemistry International, vol. 50, no. 2, pp. 418–426, 2007. View at: Publisher Site | Google Scholar
  86. E. Mosharov, M. R. Cranford, and R. Banerjee, “The Quantitatively Important Relationship between Homocysteine Metabolism and Glutathione Synthesis by the Transsulfuration Pathway and Its Regulation by Redox Changes†,” Biochemistry, vol. 39, no. 42, pp. 13005–13011, 2000. View at: Publisher Site | Google Scholar
  87. C. Desiderio, R. A. Cavallaro, A. De Rossi, F. D’Anselmi, A. Fuso, and S. Scarpa, “Evaluation of chemical and diastereoisomeric stability of S-adenosylmethionine in aqueous solution by capillary electrophoresis,” Journal of Pharmaceutical and Biomedical Analysis, vol. 38, no. 3, pp. 449–456, 2005. View at: Publisher Site | Google Scholar
  88. J. L. Hoffman, “Chromatographic analysis of the chiral and covalent instability of S-adenosyl-L-methionine,” Biochemistry, vol. 25, no. 15, pp. 4444–4449, 1986. View at: Publisher Site | Google Scholar
  89. S. H. MUDD, “Enzymatic cleavage of S-adenosylmethionine,” Journal of Biological Chemistry, vol. 34, no. 1, pp. 87–92, 1959. View at: Google Scholar
  90. P. Laurino and D. S. Tawfik, “Spontaneous emergence of S-adenosylmethionine and the evolution of methylation,” Angewandte Chemie International Edition, vol. 56, no. 1, pp. 343–345, 2017. View at: Publisher Site | Google Scholar
  91. A. E. Pegg, H. Xiong, D. J. Feith, and L. M. Shantz, “S-Adenosylmethionine decarboxylase: structure, function and regulation by polyamines,” Biochemical Society Transactions, vol. 26, no. 4, pp. 580–586, 1998. View at: Publisher Site | Google Scholar
  92. B. J. Landgraf, E. L. McCarthy, and S. J. Booker, “RadicalS-Adenosylmethionine enzymes in human health and disease,” Annual Review of Biochemistry, vol. 85, no. 1, pp. 485–514, 2016. View at: Publisher Site | Google Scholar
  93. J. E. Cronan, “Advances in synthesis of biotin and assembly of lipoic acid,” Current Opinion in Chemical Biology, vol. 47, pp. 60–66, 2018. View at: Publisher Site | Google Scholar
  94. M. Lotierzo, B. Tse Sum Bui, D. Florentin, F. Escalettes, and A. Marquet, “Biotin synthase mechanism: an overview,” Biochemical Society Transactions, vol. 33, no. 4, pp. 820–823, 2005. View at: Publisher Site | Google Scholar
  95. A. Marquet, B. Tse Sum Bui, and D. Florentin, “Biosynthesis of biotin and lipoic acid,” Vitamins and Hormones, vol. 61, pp. 51–101, 2001. View at: Publisher Site | Google Scholar
  96. J. T. Jarrett, “The generation of 5-deoxyadenosyl radicals by adenosylmethionine-dependent radical enzymes,” Current Opinion in Chemical Biology, vol. 7, no. 2, pp. 174–182, 2003. View at: Publisher Site | Google Scholar
  97. S. Ollagnier, E. Mulliez, P. P. Schmidt et al., “Activation of the anaerobic ribonucleotide reductase from Escherichia coli. The essential role of the iron-sulfur center for S-adenosylmethionine reduction,” Journal of Biological Chemistry, vol. 272, no. 39, pp. 24216–24223, 1997. View at: Publisher Site | Google Scholar
  98. C. CABRERO, J. PUERTA, and S. ALEMANY, “Purification and comparison of two forms of S-adenosyl-l-methionine synthetase from rat liver,” European Journal of Biochemistry, vol. 170, no. 1–2, pp. 299–304, 1987. View at: Publisher Site | Google Scholar
  99. J. D. Finkelstein, “Pathways and regulation of homocysteine metabolism in mammals,” Seminars in Thrombosis and Hemostasis, vol. 26, no. 3, pp. 219–226, 2000. View at: Publisher Site | Google Scholar
  100. A. L. Pey, T. Majtan, J. M. Sanchez-Ruiz, and J. P. Kraus, “Human cystathionine β-synthase (CBS) contains two classes of binding sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM,” Biochemical Journal, vol. 449, no. 1, pp. 109–121, 2013. View at: Publisher Site | Google Scholar
  101. T. Majtan, A. L. Pey, and J. P. Kraus, “Kinetic stability of cystathionine beta-synthase can be modulated by structural analogs of S-adenosylmethionine: potential approach to pharmacological chaperone therapy for homocystinuria,” Biochimie, vol. 126, pp. 6–13, 2016. View at: Publisher Site | Google Scholar
  102. Q. Li, J. Cui, C. Fang, M. Liu, G. Min, and L. Li, “S-Adenosylmethionine Attenuates Oxidative Stress and Neuroinflammation Induced by Amyloid-β Through Modulation of Glutathione Metabolism,” Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 549–558, 2017. View at: Publisher Site | Google Scholar
  103. G. L. Case and N. J. Benevenga, “Significance of formate as an intermediate in the oxidation of the methionine, S-methyl-L-cysteine and sarcosine methyl carbons to CO2 in the rat,” The Journal of Nutrition, vol. 107, no. 9, pp. 1665–1676, 1977. View at: Google Scholar
  104. R. D. Steele and N. J. Benevenga, “Identification of 3-methylthiopropionic acid as an intermediate in mammalian methionine metabolism in vitro,” Journal of Biological Chemistry, vol. 253, no. 21, pp. 7844–7850, 1978. View at: Google Scholar
  105. A. Finkelstein and N. J. Benevenga, “The effect of methanethiol and methionine toxicity on the activities of cytochrome c oxidase and enzymes involved in protection from peroxidative damage,” The Journal of Nutrition, vol. 116, no. 2, pp. 204–215, 1986. View at: Google Scholar
  106. J. T. Dever and A. A. Elfarra, “L-Methionine toxicity in freshly isolated mouse hepatocytes is gender-dependent and mediated in part by transamination,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 3, pp. 809–817, 2008. View at: Google Scholar
  107. H. Yamada, N. Akahoshi, S. Kamata et al., “Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria,” Free Radical Biology and Medicine, vol. 52, no. 9, pp. 1716–1726, 2012. View at: Google Scholar
  108. P. G. Marchesini, E. Bugianesi, G. Bianchi et al., “Defective methionine metabolism in cirrhosis: relation to severity of liver disease. Hepatology,” vol. 16, no. 1, pp. 149–155, 1992. View at: Publisher Site | Google Scholar
  109. P. J. Garlick, “Toxicity of methionine in humans,” The Journal of Nutrition, vol. 136, pp. 1722S–1725S, 2006. View at: Google Scholar
  110. M. Costa, B. Pensa, M. Fontana, C. Foppoli, and D. Cavallini, “Transamination of L-cystathionine and related compounds by a bovine liver enzyme. Possible identification with glutamine transaminase,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 881, no. 3, pp. 314–320, 1986. View at: Google Scholar
  111. B. Pensa, M. Achilli, M. Fontana, A. M. Caccuri, and D. Cavallini, “S-Aminoethyl-l-cysteine transaminase from bovine brain: purification to homogeneity and assay of activity in different regions of the brain,” Neurochemistry International, vol. 15, no. 3, pp. 285–291, 1989. View at: Google Scholar
  112. M. H. Stipanuk and P. W. Beck, “Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat,” Biochemical Journal, vol. 206, no. 2, pp. 267–277, 1982. View at: Google Scholar
  113. B. D. Paul and S. H. Snyder, “H2S signalling through protein sulfhydration and beyond,” Nature Reviews Molecular Cell Biology, vol. 13, no. 8, pp. 499–507, 2012. View at: Google Scholar
  114. B. D. Paul and S. H. Snyder, “Gasotransmitter hydrogen sulfide signaling in neuronal health and disease,” Biochemical Pharmacology, vol. 149, pp. 101–109, 2018. View at: Google Scholar
  115. M. H. Stipanuk and I. Ueki, “Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur,” Journal of Inherited Metabolic Disease, vol. 34, no. 1, pp. 17–32, 2011. View at: Google Scholar
  116. N. Shibuya, M. Tanaka, M. Yoshida et al., “3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain,” Antioxidants & Redox Signaling, vol. 11, no. 4, pp. 703–714, 2009. View at: Google Scholar
  117. Y. Mikami, N. Shibuya, Y. Kimura, N. Nagahara, Y. Ogasawara, and H. Kimura, “Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide,” Biochemical Journal, vol. 439, no. 3, pp. 479–485, 2011. View at: Google Scholar
  118. P. M. Ueland, M. A. Mansoor, A. B. Guttormsen et al., “Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status—a possible element of the extracellular antioxidant defense system,” The Journal of Nutrition, vol. 126, Supplement 4, pp. 1281S–1284S, 1996. View at: Publisher Site | Google Scholar
  119. H. Sato, A. Shiiya, M. Kimata et al., “Redox imbalance in cystine/glutamate transporter-deficient mice,” Journal of Biological Chemistry, vol. 280, no. 45, pp. 37423–37429, 2005. View at: Publisher Site | Google Scholar
  120. D. Cavallini, C. De Marco, B. Mondovì, and B. G. Mori, “The cleavage of cystine by cystathionase and the transulfuration of hypotaurine,” Enzymologia, vol. 22, pp. 161–173, 1960. View at: Google Scholar
  121. D. Cavallini, B. Mondovì, C. De Marco, and A. Scioscia-Santoro, “The mechanism of desulphhydration of cysteine,” Enzymologia, vol. 24, pp. 253–266, 1962. View at: Google Scholar
  122. T. Chiku, D. Padovani, W. Zhu, S. Singh, V. Vitvitsky, and R. Banerjee, “H2S biogenesis by human cystathionine γ-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia,” Journal of Biological Chemistry, vol. 284, no. 17, pp. 11601–11612, 2009. View at: Google Scholar
  123. T. Yamanishi and S. Tuboi, “The mechanism of the L-cystine cleavage reaction catalyzed by rat liver γ-cystathionase1,” The Journal of Biochemistry, vol. 89, no. 6, pp. 1913–1921, 1981. View at: Google Scholar
  124. M. Orlowski and A. Meister, “Isolation of highly purified γ-glutamylcysteine synthetase from rat kidney,” Biochemistry, vol. 10, no. 3, pp. 372–380, 1971. View at: Google Scholar
  125. R. Dringen, B. Pfeiffer, and B. Hamprecht, “Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of Cys Gly as precursor for neuronal glutathione,” The Journal of Neuroscience, vol. 19, no. 2, pp. 562–569, 1999. View at: Google Scholar
  126. J. E. Snoke, “Isolation and properties of yeast glutathione synthetase,” Journal of Biological Chemistry, vol. 213, no. 2, pp. 813–824, 1955. View at: Google Scholar
  127. S. C. Lu, “Regulation of glutathione synthesis,” Molecular Aspects of Medicine, vol. 30, no. 1–2, pp. 42–59, 2009. View at: Google Scholar
  128. M. H. Hanigan, “Gamma-glutamyl transpeptidase: redox regulation and drug resistance,” in Advances in Cancer Research, vol. 122, pp. 103–141, Academic Press, 2014. View at: Google Scholar
  129. A. K. Bachhawat and A. Kaur, “Glutathione degradation,” Antioxidants & Redox Signaling, vol. 27, no. 15, pp. 1200–1216, 2017. View at: Google Scholar
  130. M. Inoue, “Glutathionists in the battlefield of gamma-glutamyl cycle,” Archives of Biochemistry and Biophysics, vol. 595, pp. 61–63, 2016. View at: Google Scholar
  131. G. J. McBean, M. Aslan, H. R. Griffiths, and R. C. Torrão, “Thiol redox homeostasis in neurodegenerative disease,” Redox Biology, vol. 5, pp. 186–194, 2015. View at: Google Scholar
  132. B. D. Paul, J. I. Sbodio, and S. H. Snyder, “Cysteine metabolism in neuronal redox homeostasis,” Trends in Pharmacological Sciences, vol. 39, no. 5, pp. 513–524, 2018. View at: Google Scholar
  133. R. Leonardi, Y. M. Zhang, C. O. Rock, and S. Jackowski, “Coenzyme A: back in action,” Progress in Lipid Research, vol. 44, no. 2–3, pp. 125–153, 2005. View at: Google Scholar
  134. D. Cavallini, S. Dupre, M. T. Graziani, and M. G. Tinti, “Identification of pantethinase in horse kidney extract,” FEBS Letters, vol. 1, no. 2, pp. 119–121, 1968. View at: Google Scholar
  135. B. Maras, D. Barra, S. Duprè, and G. Pitari, “Is pantetheinase the actual identity of mouse and human vanin-1 proteins?” FEBS Letters, vol. 461, no. 3, pp. 149–152, 1999. View at: Google Scholar
  136. R. Scandurra, V. Consalvi, C. De Marco, L. Politi, and D. Cavallini, “Lanthionine decarboxylation by animal tissues,” Life Sciences, vol. 24, no. 21, pp. 1925–1930, 1979. View at: Google Scholar
  137. M. Besouw, H. Blom, A. Tangerman, A. de Graaf-Hess, and E. Levtchenko, “The origin of halitosis in cystinotic patients due to cysteamine treatment,” Molecular Genetics and Metabolism, vol. 91, no. 3, pp. 228–233, 2007. View at: Google Scholar
  138. M. Besouw and E. Levtchenko, “Pharmacokinetics of cysteamine in a cystinosis patient treated with hemodialysis,” Pediatric Nephrology, vol. 26, pp. 639-640, 2011. View at: Google Scholar
  139. C. A. O’Brian and F. Chu, “Post-translational disulfide modifications in cell signaling - role of inter-protein, intra-protein, S-glutathionyl, and S-cysteaminyl disulfide modifications in signal transmission,” Free Radical Research, vol. 39, no. 5, pp. 471–480, 2005. View at: Google Scholar
  140. G. Pitari, F. Malergue, F. Martin et al., “Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice,” FEBS Letters, vol. 483, no. 2–3, pp. 149–154, 2000. View at: Google Scholar
  141. L. Di Leandro, B. Maras, M. E. Schininà et al., “Cystamine restores GSTA3 levels in Vanin-1 null mice,” Free Radical Biology and Medicine, vol. 44, no. 6, pp. 1088–1096, 2008. View at: Google Scholar
  142. M. Besouw, R. Masereeuw, L. Van Den Heuvel, and E. Levtchenko, “Cysteamine: an old drug with new potential,” Drug Discovery Today, vol. 18, no. 15-16, pp. 785–792, 2013. View at: Google Scholar
  143. C. Gibrat and F. Cicchetti, “Potential of cystamine and cysteamine in the treatment of neurodegenerative diseases,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 35, no. 2, pp. 380–389, 2011. View at: Publisher Site | Google Scholar
  144. L. Gallego-Villar, L. Hannibal, J. Häberle et al., “Cysteamine revisited: repair of arginine to cysteine mutations,” Journal of Inherited Metabolic Disease, vol. 40, no. 4, pp. 555–567, 2017. View at: Google Scholar
  145. R. J. Huxtable, “Physiological actions of taurine,” Physiological Reviews, vol. 72, no. 1, pp. 101–164, 1992. View at: Google Scholar
  146. J. E. Dominy, C. R. Simmons, L. L. Hirschberger, J. Hwang, R. M. Coloso, and M. H. Stipanuk, “Discovery and characterization of a second mammalian thiol dioxygenase, cysteamine dioxygenase,” Journal of Biological Chemistry, vol. 282, no. 35, pp. 25189–25198, 2007. View at: Google Scholar
  147. B. Sarkar, M. Kulharia, and A. K. Mantha, “Understanding human thiol dioxygenase enzymes: structure to function, and biology to pathology,” International Journal of Experimental Pathology, vol. 98, no. 2, pp. 52–66, 2017. View at: Google Scholar
  148. L. Ewetz and B. Sörbo, “Characteristics of the cysteinesulfinate-forming enzyme system in rat liver,” Biochimica et Biophysica Acta (BBA) - Enzymology and Biological Oxidation, vol. 128, no. 2, pp. 296–305, 1966. View at: Google Scholar
  149. D. Cavallini, R. Scandurra, and C. De Marco, “The enzymatic oxidation of cysteamine to hypotaurine in the presence of,” Journal of Biological Chemistry, vol. 238, pp. 2999–3005, 1963. View at: Google Scholar
  150. M. H. Stipanuk, J. E. Dominy, J.-I. Lee, and R. M. Coloso, “Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism,” The Journal of Nutrition, vol. 136, no. 6, pp. 1652S–1659S, 2006. View at: Google Scholar
  151. J. Dominy, S. Eller, and R. Dawson, “Building biosynthetic schools: reviewing compartmentation of CNS taurine synthesis,” Neurochemical Research, vol. 29, pp. 97–103, 2004. View at: Google Scholar
  152. C. E. Wright, H. H. Tallan, and Y. Y. Lin, “Taurine: biological update,” Annual Review of Biochemistry, vol. 55, no. 1, pp. 427–453, 1986. View at: Google Scholar
  153. L. Pecci, M. Costa, G. Montefoschi, A. Antonucci, and D. Cavallini, “Oxidation of hypotaurine to taurine with photochemically generated singlet oxygen: the effect of azide,” Biochemical and Biophysical Research Communications, vol. 254, no. 3, pp. 661–665, 1999. View at: Google Scholar
  154. M. Fontana, D. Amendola, E. Orsini, A. Boffi, and L. Pecci, “Oxidation of hypotaurine and cysteine sulphinic acid by peroxynitrite,” Biochemical Journal, vol. 389, no. 1, pp. 233–240, 2005. View at: Google Scholar
  155. M. Fontana, S. Duprè, and L. Pecci, “The reactivity of hypotaurine and cysteine sulfinic acid with peroxynitrite,” in Taurine 6, vol. 583, pp. 15–24, Springer, 2006. View at: Google Scholar
  156. A. Baseggio Conrado, M. D’Angelantonio, M. D’Erme, L. Pecci, and M. Fontana, “The interaction of hypotaurine and other sulfinates with reactive oxygen and nitrogen species: a survey of reaction mechanisms,” in Advances in Experimental Medicine and Biology, vol. 975, pp. 573–583, Springer, 2017. View at: Google Scholar
  157. A. Baseggio Conrado, M. D’Angelantonio, A. Torreggiani, L. Pecci, and M. Fontana, “Reactivity of hypotaurine and cysteine sulfinic acid toward carbonate radical anion and nitrogen dioxide as explored by the peroxidase activity of Cu, Zn superoxide dismutase and by pulse radiolysis,” Free Radical Research, vol. 48, no. 11, pp. 1300–1310, 2014. View at: Google Scholar
  158. A. Baseggio Conrado, L. Pecci, E. Capuozzo, and M. Fontana, “Oxidation of hypotaurine and cysteine sulfinic acid by peroxidase-generated reactive species,” in Taurine 9, vol. 803, pp. 41–51, Springer, 2015. View at: Google Scholar
  159. A. Baseggio Conrado, L. Pecci, and M. Fontana, “Effects of hypotaurine on carbonate radical anion and nitrogen dioxide radical generated by peroxidase activity of Cu, Zn-superoxide dismutase,” Free Radical Biology and Medicine, vol. 65, pp. S23–S24, 2013. View at: Google Scholar
  160. S. Veeravalli, I. R. Phillips, R. T. Freire, D. Varshavi, J. R. Everett, and E. A. Shephard, “Flavin-containing monooxygenase 1 catalyzes the production of taurine from hypotaurine,” Drug Metabolism and Disposition, vol. 48, pp. 378–385, 2020. View at: Google Scholar
  161. J. T. Brosnan, K. C. Man, D. E. Hall, S. A. Colbourne, and M. E. Brosnan, “Interorgan metabolism of amino acids in streptozotocin-diabetic ketoacidotic rat,” American Journal of Physiology-Endocrinology and Metabolism, vol. 244, no. 2, pp. E151–E158, 1983. View at: Google Scholar
  162. A. Francioso, S. Fanelli, D. Vigli et al., “HPLC determination of bioactive sulfur compounds, amino acids and biogenic amines in biological specimens,” Advances in Experimental Medicine and Biology, vol. 975, pp. 535–549, 2017. View at: Google Scholar
  163. H. Ripps and W. Shen, “Review: taurine: a “very essential” amino acid,” Molecular Vision, vol. 18, pp. 2673–2686, 2012. View at: Google Scholar
  164. K. C. Hayes and J. A. Sturman, “Taurine in metabolism,” Annual Review of Nutrition, vol. 1, pp. 401–425, 1981. View at: Google Scholar
  165. N. Froger, R. R. Sahel, and S. Picaud, “Taurine deficiency and the eye,” Handbook of Nutrition, Diet and the Eye, Preedy Academic Press Inc, pp. 505–512, 2014. View at: Google Scholar
  166. V. Vitvitsky, S. K. Garg, and R. Banerjee, “Taurine biosynthesis by neurons and astrocytes,” Journal of Biological Chemistry, vol. 286, no. 37, pp. 32002–32010, 2011. View at: Google Scholar
  167. R. Banerjee, V. Vitvitsky, and S. K. Garg, “The undertow of sulfur metabolism on glutamatergic neurotransmission,” Trends in Biochemical Sciences, vol. 33, no. 9, pp. 413–419, 2008. View at: Google Scholar
  168. M. F. Olive, “Interactions between taurine and ethanol in the central nervous system,” Amino Acids, vol. 23, no. 4, pp. 345–357, 2002. View at: Google Scholar
  169. A. El Idrissi, “Taurine increases mitochondrial buffering of calcium: role in neuroprotection,” Amino Acids, vol. 34, no. 2, pp. 321–328, 2008. View at: Google Scholar
  170. O. I. Aruoma, B. Halliwell, B. M. Hoey, and J. Butler, “The antioxidant action of taurine, hypotaurine and their metabolic precursors,” Biochemical Journal, vol. 256, no. 1, pp. 251–255, 1988. View at: Google Scholar
  171. M. Fontana, F. Giovannitti, and L. Pecci, “The protective effect of hypotaurine and cysteine sulphinic acid on peroxynitrite-mediated oxidative reactions,” Free Radical Research, vol. 42, no. 4, pp. 320–330, 2008. View at: Google Scholar
  172. M. Fontana, L. Pecci, S. Duprè, and D. Cavallini, “Antioxidant properties of sulfinates: protective effect of hypotaurine on peroxynitrite-dependent damage,” Neurochemical Research, vol. 29, no. 1, pp. 111–116, 2004. View at: Google Scholar
  173. J. A. Sturman, “Formation and accumulating of hypotaurine in rat liver regenerating after partial hepatectomy,” Life Sciences, vol. 26, no. 4, pp. 267–272, 1980. View at: Google Scholar
  174. D. B. Learn, V. A. Fried, and E. L. Thomas, “Taurine and hypotaurine content of human leukocytes,” Journal of Leukocyte Biology, vol. 48, no. 2, pp. 174–182, 1990. View at: Google Scholar
  175. R. P. Holmes, H. O. Goodman, Z. K. Shihabi, and J. Jarow, “The taurine and hypotaurine content of human semen,” Journal of Andrology, vol. 13, no. 3, pp. 289–292, 1992. View at: Google Scholar
  176. A. B. Conrado, S. Maina, H. Moseley et al., “Carbonate anion radical generated by the peroxidase activity of copper-zinc superoxide dismutase: scavenging of radical and protection of enzyme by hypotaurine and cysteine sulfinic acid,” in Advances in Experimental Medicine and Biology, vol. 975, pp. 551–561, Springer, 2017. View at: Google Scholar
  177. A. K. Mustafa, M. M. Gadalla, N. Sen et al., “H2S signals through protein S-sulfhydration,” Science Signaling, vol. 2, no. 96, article ra72, 2009. View at: Google Scholar
  178. M. R. Filipovic, J. Zivanovic, B. Alvarez, and R. Banerjee, “Chemical biology of H2S signaling through persulfidation,” Chemical Reviews, vol. 118, pp. 1253–1337, 2018. View at: Google Scholar
  179. T. Ida, T. Sawa, H. Ihara et al., “Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling,” Proceedings of the National Academy of Sciences, vol. 111, no. 21, pp. 7606–7611, 2014. View at: Google Scholar
  180. T. V. Mishanina, M. Libiad, and R. Banerjee, “Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways,” Nature Chemical Biology, vol. 11, pp. 457–464, 2015. View at: Google Scholar
  181. J. I. Toohey, “Sulfur signaling: is the agent sulfide or sulfane?” Analytical Biochemistry, vol. 413, no. 1, pp. 1–7, 2011. View at: Google Scholar
  182. N. E. Francoleon, S. J. Carrington, and J. M. Fukuto, “The reaction of H 2S with oxidized thiols: generation of persulfides and implications to H 2S biology,” Archives of Biochemistry and Biophysics, vol. 516, pp. 146–153, 2011. View at: Google Scholar
  183. M. R. Jackson, S. L. Melideo, and M. S. Jorns, “Human sulfide: quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite,” Biochemistry, vol. 51, no. 34, pp. 6804–6815, 2012. View at: Google Scholar
  184. M. Libiad, P. K. Yadav, V. Vitvitsky, M. Martinov, and R. Banerjee, “Organization of the human mitochondrial hydrogen sulfide oxidation pathway,” Journal of Biological Chemistry, vol. 289, no. 45, pp. 30901–30910, 2014. View at: Google Scholar
  185. O. Kabil and R. Banerjee, “Enzymology of H2S biogenesis, decay and signaling,” Antioxidants & Redox Signaling, vol. 20, no. 5, pp. 770–782, 2014. View at: Google Scholar
  186. P. K. Yadav, M. Martinov, V. Vitvitsky et al., “Biosynthesis and reactivity of cysteine persulfides in signaling,” Journal of the American Chemical Society, vol. 138, no. 1, pp. 289–299, 2016. View at: Google Scholar
  187. P. K. Yadav, K. Yamada, T. Chiku, M. Koutmos, and R. Banerjee, “Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase,” Journal of Biological Chemistry, vol. 288, no. 27, pp. 20002–20013, 2013. View at: Google Scholar
  188. Y. Kimura, S. Koike, N. Shibuya, D. Lefer, Y. Ogasawara, and H. Kimura, “3-Mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine- and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S,” Scientific Reports, vol. 7, 2017. View at: Google Scholar
  189. T. Akaike, T. Ida, F.-Y. Wei et al., “Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics,” Nature Communications, vol. 8, no. 1, p. 1177, 2017. View at: Publisher Site | Google Scholar
  190. G. X. Luo and P. M. Horowitz, “The sulfurtransferase activity and structure of rhodanese are affected by site-directed replacement of Arg-186 or Lys-249,” Journal of Biological Chemistry, vol. 269, no. 11, pp. 8220–8225, 1994. View at: Google Scholar
  191. D. Cavallini, C. De Marco, and B. Mondovì, “Chromatographic evidence on the occurrence of thiotaurine in the urine of rats fed with cystine,” Journal of Biological Chemistry, vol. 234, no. 4, pp. 854–857, 1959. View at: Google Scholar
  192. B. Sörbo, “Enzymic transfer of sulfur from mercaptopyruvate to sulfite or sulfinates,” Biochimica et Biophysica Acta, vol. 24, no. C, pp. 324–329, 1957. View at: Google Scholar
  193. T. R. Chauncey and J. Westley, “The catalytic mechanism of yeast thiosulfate reductase,” Journal of Biological Chemistry, vol. 258, no. 24, pp. 15037–15045, 1983. View at: Google Scholar
  194. E. Capuozzo, L. Pecci, A. Baseggio Conrado, and M. Fontana, “Thiotaurine prevents apoptosis of human neutrophils: a putative role in inflammation,” in Advances in Experimental Medicine and Biology, vol. 775, pp. 227–236, Springer, 2013. View at: Google Scholar
  195. E. Capuozzo, A. Baseggio Conrado, and M. Fontana, “Thiotaurine modulates human neutrophil activation,” in Advances in Experimental Medicine and Biology, vol. 803, pp. 145–155, Springer, 2015. View at: Google Scholar
  196. E. Capuozzo, A. Giorgi, S. Canterini et al., “A proteomic approach to study the effect of thiotaurine on human neutrophil activation,” in Advances in Experimental Medicine and Biology, vol. 975, pp. 563–571, Springer, 2017. View at: Google Scholar
  197. J. Dragotto, E. Capuozzo, M. Fontana, A. Curci, M. T. Fiorenza, and S. Canterini, “Thiotaurine protects mouse cerebellar granule neurons from potassium deprivation-induced apoptosis by inhibiting the activation of caspase-3,” in Advances in Experimental Medicine and Biology, vol. 803, pp. 513–523, Springer, 2015. View at: Google Scholar
  198. M. Costa, B. Pensa, B. Di Costanzo, R. Coccia, and D. Cavallini, “Transamination of l-cystathionine and related compounds by bovine brain glutamine transaminase,” Neurochemistry International, vol. 10, no. 3, pp. 377–382, 1987. View at: Google Scholar
  199. M. Costa, B. Pensa, C. Blarzino, and D. Cavallini, “New enzymatic changes of L-cystathionine catalyzed by bovine tissue extracts,” Physiological Chemistry and Physics and Medical NMR, vol. 17, no. 1, pp. 107–111, 1985. View at: Google Scholar
  200. T. S. Soper and J. M. Manning, “β Elimination of β-halo substrates by d-amino acid transaminase associated with inactivation of the enzyme. Trapping of a key intermediate in the reaction,” Biochemistry, vol. 17, no. 16, pp. 3377–3384, 1978. View at: Google Scholar
  201. G. Ricci, L. Santoro, M. Achilli, R. M. Matarese, M. Nardini, and D. Cavallini, “Similarity of the oxidation products of L-cystathionine by L-amino acid oxidase to those excreted by cystathioninuric patients,” Journal of Biological Chemistry, vol. 258, no. 17, pp. 10511–10517, 1983. View at: Google Scholar
  202. D. Cavallini, G. Ricci, and G. Federici, “The ketamine derivatives of thialysine, lanthionine, cystathionine, cystine: preparation and properties,” Progress in Clinical and Biological Research, vol. 125, pp. 355–363, 1983. View at: Google Scholar
  203. L. Pecci, M. Costa, F. Pinnen, A. Antonucci, and D. Cavallini, “Properties of the phenylthiohydantoin derivatives of some sulfur-containing cyclic amino acids,” Physiological Chemistry and Physics and Medical NMR, vol. 20, no. 3, pp. 199–203, 1988. View at: Google Scholar
  204. M. Nardini, G. Ricci, L. Vesci, L. Pecci, and D. Cavallini, “Bovine brain ketimine reductase,” Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, vol. 957, no. 2, pp. 286–292, 1988. View at: Google Scholar
  205. R. M. Matarese, S. P. Solinas, G. Montefoschi, G. Ricci, and D. Cavallini, “Identification of 1, 4-thiomorpholine-3-carboxylic acid (TMA) in normal human urine,” FEBS Letters, vol. 250, no. 1, pp. 75–77, 1989. View at: Google Scholar
  206. D. Cavallini, R. M. Matarese, L. Pecci, and G. Ricci, “1, 4-Thiomorpholine-3, 5-dicarboxylic acid, a novel cyclic imino acid detected in bovine brain,” FEBS Letters, vol. 192, no. 2, pp. 247–250, 1985. View at: Google Scholar
  207. M. Nardini, R. M. Matarese, L. Pecci, A. Antonucci, G. Ricci, and D. Cavallini, “Detection of 2H-1, 4-thiazine-5, 6-dihydro-3-carboxylic acid (aminoethylcysteine ketimine) in the bovine brain,” Biochemical and Biophysical Research Communications, vol. 166, no. 3, pp. 1251–1256, 1990. View at: Google Scholar
  208. S. Yu, K. Sugahara, J. Zhang et al., “Simultaneous determination of urinary cystathionine, lanthionine, S-(2-aminoethyl)-L-cysteine and their cyclic compounds using liquid chromatography-mass spectrometry with atmospheric pressure chemical ionization,” Journal of Chromatography B: Biomedical Sciences and Applications, vol. 698, no. 1–2, pp. 301–307, 1997. View at: Google Scholar
  209. M. Fontana, A. Brunori, M. Costa, and A. Antonucci, “Detection of cystathionine ketimine and lanthionine ketimine in human brain,” Neurochemical Research, vol. 22, no. 7, pp. 821–824, 1997. View at: Google Scholar
  210. K. Hensley, K. Venkova, and A. Christov, “Emerging biological importance of central nervous system lanthionines,” Molecules, vol. 15, no. 8, pp. 5581–5594, 2010. View at: Publisher Site | Google Scholar
  211. N. Marangoni, K. Kowal, Z. Deliu, K. Hensley, and D. L. Feinstein, “Neuroprotective and neurotrophic effects of lanthionine ketimine ester,” Neuroscience Letters, vol. 664, pp. 28–33, 2018. View at: Google Scholar
  212. J. L. Dupree, P. E. Polak, K. Hensley, D. Pelligrino, and D. L. Feinstein, “Lanthionine ketimine ester provides benefit in a mouse model of multiple sclerosis,” Journal of Neurochemistry, vol. 134, no. 2, pp. 302–314, 2015. View at: Google Scholar
  213. K. Hensley, S. P. Gabbita, K. Venkova et al., “A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3×Tg-AD mouse model of Alzheimer disease,” Journal of Neuropathology & Experimental Neurology, vol. 72, no. 10, pp. 955–969, 2013. View at: Google Scholar
  214. A. C. Hensley, S. Kamat, X. C. Zhang, K. W. Jackson, S. Snow, and J. Post, “Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures,” Journal of Neuroscience, vol. 30, no. 8, pp. 2979–2988, 2010. View at: Google Scholar
  215. C. J. Bataille, M. B. Brennan, S. Byrne et al., “Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family,” Bioorganic & Medicinal Chemistry, vol. 25, no. 9, pp. 2657–2665, 2017. View at: Google Scholar
  216. A. Ahmad, A. Ahmad, R. Sudhakar et al., “Designing, synthesis, and antimicrobial action of oxazoline and thiazoline derivatives of fatty acid esters,” Journal of Biomolecular Structure and Dynamics, vol. 35, no. 15, pp. 3412–3431, 2017. View at: Google Scholar
  217. W. Suvachittanont, Y. Kurashima, H. Esumi, and M. Tsuda, “Formation of thiazolidine-4-carboxylic acid (thioproline), an effective nitrite-trapping agent in human body, in Parkia speciosa seeds and other edible leguminous seeds in Thailand,” Food Chemistry, vol. 55, no. 4, pp. 359–363, 1996. View at: Google Scholar
  218. D. Cavallini, B. Mondovì, and C. De Marco, “Thiazoline carboxylic acid from formylcysteine,” Experientia, vol. 13, no. 11, pp. 436–438, 1957. View at: Google Scholar
  219. H. Kumagai, K. I. Mukaisho, H. Sugihara, K. Miwa, G. Yamamoto, and T. Hattori, “Thioproline inhibits development of esophageal adenocarcinoma induced by gastroduodenal reflux in rats,” Carcinogenesis, vol. 25, no. 5, pp. 723–727, 2004. View at: Google Scholar
  220. H. U. Weber, J. F. Fleming, and J. Miquel, “Thiazolidine-4-carboxylic acid, a physiologic sulfhydryl antioxidant with potential value in geriatric medicine,” Archives of Gerontology and Geriatrics, vol. 1, pp. 299–310, 1982. View at: Google Scholar
  221. K. R. Martin, “The bioactive agent ergothioneine, a key component of dietary mushrooms, inhibits monocyte binding to endothelial cells characteristic of early cardiovascular disease,” Journal of Medicinal Food, vol. 13, no. 6, pp. 1340–1346, 2010. View at: Google Scholar
  222. I. Petrikovics, D. E. Thompson, G. A. Rockwood et al., “Organ-distribution of the metabolite 2-aminothiazoline-4-carboxylic acid in a rat model following cyanide exposure,” Biomarkers, vol. 16, no. 8, pp. 686–690, 2011. View at: Google Scholar
  223. D. Cavallini, C. De Marco, and B. Mondovi, “The oxidation of cystamine and other sulfur-diamines by diamine-oxidase preparations,” Experientia, vol. 12, no. 10, pp. 377–379, 1956. View at: Google Scholar
  224. D. Cavallini, G. Federici, S. Dupre, C. Cannella, and R. Scandurra, “Ambiguities in the enzymology of sulfur-containing compounds,” Pure and Applied Chemistry, vol. 52, no. 1, pp. 147–155, 1980. View at: Google Scholar
  225. I. Winge, K. Teigen, A. Fossbakk et al., “Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression,” Neurochemistry International, vol. 90, pp. 173–184, 2015. View at: Google Scholar
  226. Q. Shi, J. E. Savage, S. J. Hufeisen et al., “L-Homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists,” Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 1, pp. 131–142, 2003. View at: Google Scholar
  227. M. Costa, L. Vesci, M. Fontana, S. P. Solinas, S. Dupre, and D. Cavallini, “Displacement of [3H] GABA binding to bovine brain receptors by sulfur-containing analogues,” Neurochemistry International, vol. 17, no. 4, pp. 547–551, 1990. View at: Google Scholar
  228. A. Khan, Y. Choi, J. H. Back, S. Lee, S. H. Jee, and Y. H. Park, “High-resolution metabolomics study revealing l-homocysteine sulfinic acid, cysteic acid, and carnitine as novel biomarkers for high acute myocardial infarction risk,” Metabolism, vol. 104, article 154051, 2020. View at: Google Scholar
  229. K. S. McCully, “Homocysteine, vitamins, and vascular disease prevention,” The American Journal of Clinical Nutrition, vol. 86, no. 5, pp. 1563S–1568S, 2007. View at: Google Scholar
  230. S. Seshadri, A. Beiser, J. Selhub et al., “Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease,” New England Journal of Medicine, vol. 346, no. 7, pp. 476–483, 2002. View at: Google Scholar
  231. N. Fillon-Emery, A. Chango, C. Mircher et al., “Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms,” The American Journal of Clinical Nutrition, vol. 80, pp. 1551–1557, 2004. View at: Google Scholar
  232. B. Chadefaux, I. Ceballos, M. Hamet et al., “Is absence of atheroma in Down syndrome due to decreased homocysteine levels?” The Lancet, vol. 332, no. 8613, p. 741, 1988. View at: Google Scholar
  233. P. Kamoun, M.-C. Belardinelli, A. Chabli, K. Lallouchi, and B. Chadefaux-Vekemans, “Endogenous hydrogen sulfide overproduction in Down syndrome,” American Journal of Medical Genetics, vol. 116A, no. 3, pp. 310-311, 2003. View at: Google Scholar
  234. M. Pogribna, S. Melnyk, I. Pogribny, A. Chango, P. Yi, and S. J. James, “Homocysteine metabolism in children with down syndrome: in vitro modulation,” The American Journal of Human Genetics, vol. 69, no. 1, pp. 88–95, 2001. View at: Google Scholar
  235. T. Majtan, J. Krijt, J. Sokolová et al., “Biogenesis of hydrogen sulfide and thioethers by cystathionine beta-synthase,” Antioxidants & Redox Signaling, vol. 28, no. 4, pp. 311–323, 2018. View at: Google Scholar
  236. V. Kožich, J. Krijt, J. Sokolová et al., “Thioethers as markers of hydrogen sulfide production in homocystinurias,” Biochimie, vol. 126, pp. 14–20, 2016. View at: Google Scholar
  237. W. Shen, M. K. McGath, R. Evande, and D. B. Berkowitz, “A continuous spectrophotometric assay for human cystathionine beta-synthase,” Analytical Biochemistry, vol. 342, no. 1, pp. 103–110, 2005. View at: Google Scholar
  238. J. T. Pinto, T. Khomenko, S. Szabo et al., “Measurement of sulfur-containing compounds involved in the metabolism and transport of cysteamine and cystamine. Regional differences in cerebral metabolism,” Journal of Chromatography B, vol. 877, no. 28, pp. 3434–3441, 2009. View at: Google Scholar
  239. G. I. Giles and C. Jacob, “Reactive sulfur species: an emerging concept in oxidative stress,” Biological Chemistry, vol. 383, no. 3–4, pp. 375–388, 2002. View at: Google Scholar
  240. G. I. Giles, K. M. Tasker, and C. Jacob, “Hypothesis: the role of reactive sulfur species in oxidative stress,” Free Radical Biology and Medicine, vol. 31, no. 10, pp. 1279–1283, 2001. View at: Google Scholar
  241. J. Li, F. L. Huang, and K. P. Huang, “Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione. Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43,” Journal of Biological Chemistry, vol. 276, no. 5, p. 3098, 2001. View at: Google Scholar
  242. T. Okamoto, T. Akaike, T. Sawa, Y. Miyamoto, A. Van der Vliet, and H. Maeda, “Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation,” Journal of Biological Chemistry, vol. 276, no. 31, pp. 29596–29602, 2001. View at: Google Scholar
  243. B. C. Smith and M. A. Marletta, “Mechanisms of S-nitrosothiol formation and selectivity in nitric oxide signaling,” Current Opinion in Chemical Biology, vol. 16, pp. 498–506, 2012. View at: Google Scholar
  244. R. J. Singh, N. Hogg, J. Joseph, and B. Kalyanaraman, “Mechanism of nitric oxide release from S-nitrosothiols,” Chemical Communications, vol. 271, no. 31, pp. 18596–18603, 1996. View at: Google Scholar
  245. H. AL-SA’DONI and A. FERRO, “S-Nitrosothiols: a class of nitric oxide-donor drugs,” Clinical Science, vol. 98, no. 5, pp. 507–520, 2000. View at: Google Scholar
  246. D. R. Arnelle and J. S. Stamler, “NO+, NO, and NO−donation by S-nitrosothiols: implications for regulation of physiological functions by S-nitrosylation and acceleration of disulfide formation,” Archives of Biochemistry and Biophysics, vol. 318, no. 2, pp. 279–285, 1995. View at: Google Scholar
  247. T. Nauser, W. H. Koppenol, and C. Schöneich, “Protein thiyl radical reactions and product formation: a kinetic simulation,” Free Radical Biology and Medicine, vol. 80, pp. 158–163, 2015. View at: Google Scholar
  248. H. D. Venters, L. E. Bonilla, T. Jensen et al., “Heme from Alzheimer’s brain inhibits muscarinic receptor binding via thiyl radical generation,” Brain Research, vol. 764, no. 1-2, pp. 93–100, 1997. View at: Google Scholar
  249. K. R. Maples, C. H. Kennedy, S. J. Jordan, and R. P. Mason, “In vivo thiyl free radical formation from hemoglobin following administration of hydroperoxides,” Archives of Biochemistry and Biophysics, vol. 277, no. 2, pp. 402–409, 1990. View at: Google Scholar
  250. M. D. Sevilla, D. Becker, and M. Yan, “The formation and structure of the sulfoxyl radicals RSO· RSOO· RSO2· and RSO2OO· from the reaction of cysteine, glutathione and penicillamine thiyl radicals with molecular oxygen,” International Journal of Radiation Biology, vol. 57, no. 1, pp. 65–81, 1990. View at: Google Scholar
  251. D. P. Jones, “Redox potential of GSH/GSSG couple: assay and biological significance,” Methods in Enzymology, vol. 348, pp. 93–112, 2002. View at: Google Scholar
  252. O. Zitka, S. Skalickova, J. Gumulec et al., “Redox status expressed as GSH: GSSG ratio as a marker for oxidative stress in paediatric tumour patients,” Oncology Letters, vol. 4, no. 6, pp. 1247–1253, 2012. View at: Google Scholar
  253. W. Maret, C. Jacob, B. L. Vallee, and E. H. Fischer, “Inhibitory sites in enzymes: zinc removal and reactivation by thionein,” Proceedings of the National Academy of Sciences, vol. 96, no. 5, pp. 1936–1940, 1999. View at: Google Scholar
  254. E. M. Hanschmann, J. R. Godoy, C. Berndt, C. Hudemann, and C. H. Lillig, “Thioredoxins, glutaredoxins, and peroxiredoxins-molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling,” Antioxidants and Redox Signaling, vol. 19, no. 13, pp. 1539–1605, 2013. View at: Google Scholar
  255. M. Conrad, G. W. Bornkamm, and M. Brielmeier, “Mitochondrial and cytosolic thioredoxin reductase knockout mice,” in Selenium: Its Molecular Biology and Role in Human Health, pp. 195–206, Springer US, Boston, MA, 2nd edition, 2006. View at: Google Scholar
  256. H. Nakamura, “Extracellular functions of thioredoxin,” in The Biology of Extracellular Molecular Chaperones, pp. 184–195, Wiley, 2008. View at: Google Scholar
  257. Y. Matsuo and J. Yodoi, “Extracellular thioredoxin: a therapeutic tool to combat inflammation,” Cytokine and Growth Factor Reviews, vol. 24, pp. 345–353, 2013. View at: Google Scholar
  258. A. P. Fernandes and A. Holmgren, “Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system,” Antioxidants and Redox Signaling, vol. 6, pp. 63–74, 2004. View at: Google Scholar

Copyright © 2020 Antonio Francioso et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views3415
Downloads674
Citations

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.