1School of Natural Sciences, University of California, Merced 95344; 2Department of Pharmacology, University of California, Los Angeles 90095; 3The Saban Research Institute of Childrens Hospital Los Angeles and 4Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90027
Submitted 19 November 2003 ; accepted in final form 13 January 2004
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ABSTRACT |
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hydrogen peroxide; thiolate; nitrosothiol; nitric oxide; signal transduction
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REACTIVE SPECIES AS SECOND MESSENGERS |
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REDOX SIGNALING VS. STRESS RESPONSE TO OXIDANTS |
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Both reversible and irreversible modifications of second messengers and proteins participate in signal transduction. Reversible reactions include phosphorylation of inositol and proteins, while irreversible reactions often involve the degradation of proteins such as that which occurs with an inhibitor of nuclear factor- (I
) during NF-
activation or with cyclin proteins during the cell cycle. Irreversible oxidation of the target molecule is common during oxidative stress. In contrast, redox signaling entails at least one reaction, which is usually reversible and involves the oxidation of a signaling molecule by a reactive species. In other words, in redox signaling, the reaction of the ROS or the RNS with the target is more reminiscent of on-off signaling associated with phosphorylation than it is of nonenzymatic lipid peroxidation. An exception to the reversibility rule is the situation in which irreversible oxidation is enzymatically catalyzed, such as that which occurs in the cyclooxygenase reaction. Thus, according to our definition, redox signaling occurs when at least one step in a signaling pathway involves one of its components being specifically modified by a reactive species through a reaction that is chemically reversible under physiological conditions and/or enzymatically catalyzed.
During oxidative stress, the ensuing stress response is likely to involve both redox signaling as defined above and nonenzymatic irreversible reactions, although the extent to which each of these processes contributes to the ultimate outcome varies with the concentration and chemical nature of the species. The rest of this review focuses largely on those reversible redox reactions.
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GLUTATHIONE AND THIOREDOXIN AS TARGETS AND CONTROLLERS |
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![]() | (1) |
Four seleno-glutathione peroxidases have been identified that have differential specificity toward H2O2 or lipid and other hydroperoxides (for review of glutathione peroxidases and a different perspective on redox state, see Ref. 33).
Glutathione disulfide reductase can restore GSH
![]() | (2) |
The GSSG-2GSH ratio, however, is also partially determined by export of GSH and GSSG, GSH synthesis, glutathione S-transferase catalyzed conjugation (Reaction 3), and disulfide exchange with proteins (Reaction 4)
![]() | (3) |
![]() | (4) |
The global GSSG-2GSH ratio is thought to play a major role in maintaining the reduced state of most cellular molecules. Nonetheless, as signal transduction reactions are not global but localized processes, we argue that there is not a direct connection between the global GSSG-2GSH ratio and any specific redox signaling reaction. The importance of localized events in signaling is well illustrated by the sudden increase in cAMP that can occur after stimulation and activate a small portion of the cellular protein kinase A (PKA), even though enough phosphodiesterase is present in the cell to rapidly decrease cAMP to its prestimulation concentration. Thus cAMP activates a PKA molecule only within the distance allowed by the phosphodiesterase. Similarly, it seems that for H2O2 to play a role in signaling, its targets must be localized near its site of production because of the high cellular activity of glutathione peroxidase, catalase, and other enzymes that rapidly eliminate H2O2. Just as phosphatase activity is one factor in defining cAMP signaling, GSSG/2GSH is just one factor in determining H2O2 signaling. Therefore, the local concentration of H2O2 is as important as the global GSSG-2GSH ratio, if not more so.
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CHEMISTRY OF H2O2 REACTIONS |
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Before giving up on the idea of similarity between the chemistry of redox signaling and H2O2 elimination, we next briefly consider the chemistry of thiols on the basis of current knowledge about thiols and disulfides (33, 38, 52, 118). We also describe the mechanisms by which thiols may provide the specificity required for signaling as we discuss the extensive work of the Rhee and Poole laboratories with members of the peroxiredoxin (Prx) family, which are nonselenium peroxidases that use either Trx or GSH as a substrate (for review, see Refs. 83, 84, 88, 123).
A thiol (SH) does not react at physiologically significant rates with a hydroperoxide, such as H2O2, unless the reaction is catalyzed. Thiolates (S), however, react with hydroperoxides at rates varying from 10105 M1·s1, depending on their local environment. In the active sites of some proteins, such as Prx and Trx, one cysteine is in the thiolate form, which can potentially react with H2O2. The general reaction series below defines thiolate-H2O2 chemistry where RSH is a thiol, RS is a thiolate, and RSO is a sulfenate [the ionized form of a sulfenic acid (SOH)]
![]() | (5) |
![]() | (6) |
The original thiolate can then be restored by exchange with another thiolate
![]() | (7) |
All Prx except one (Prx VI, also known as 1-cys Prx) contain two cysteines in their active sites, with one being a thiolate (S) residue. They demonstrate the following chemistry that is analogous to Reaction 5 and in which Prx-(SH)(S) represents a 2-cys Prx
![]() | (8) |
Evidence for the formation of the sulfenate intermediate was clearly provided by work on a bacterial Prx (AhpC) in which a second cysteine was mutated, allowing the formation of a stable SOH (27). Similar studies with mammalian Prx have not been conducted yet.
In the next step, the second thiol acts in a manner analogous to that of R'SH in Reaction 6 but results in the formation of a Prx intramolecular disulfide [Prx-(S)2]
![]() | (9) |
In the final reaction, all Prx except the mammalian Prx VI use Trx [formally written as Trx-(SH)(S), while the disulfide form is written as Trx(S)2] to restore the original thiolate
![]() | (10) |
An intermediate disulfide between Prx and Trx is likely to be formed, but because of the high propensity of Trx to form an intramolecular disulfide, the reaction appears to occur in one step. Trx disulfide does not readily exchange with other thiols or thiolates and must be reduced by Trx reductase with the addition of NADPH
![]() | (11) |
TrxS2 also may be formed by direct reaction of Trx with H2O2 (15). Nonetheless, the nonenzymatic reaction of Trx with H2O2 may be too slow to account for Trx oxidation under physiological conditions. It was demonstrated that Prx profoundly enhance the rate of reaction between Trx and H2O2 (15). Considering the ubiquitous and abundant presence of Prx in cells (16, 89), it is possible that all Trx(S2) may be formed through catalysis by the Trx-specific Prx isoforms.
As mentioned earlier, Prx VI/1-cys Prx has been found to use other thiols, most likely GSH under physiological conditions (72). The initial reaction of 1-cys Prx with H2O2 is similar to that of the other Prx, except that it forms a mixed disulfide instead of the intramolecular disulfide
![]() | (12) |
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Because disulfide exchange is relatively slow for a biological reaction, even when GSH is dissociated to the thiolate, we propose that reduction of PrxVI-SSG requires an enzyme-catalyzed reaction with GSH. Recently, Fisher and coworkers (72) showed that Prx VI activity requires the presence of glutathione S-transferase-. Hence it is possible that this enzyme functions as a catalyst in Reaction 14 under physiological conditions.
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THIOLATE TARGETS IN REDOX SIGNALING |
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Nevertheless, recent data indicate that signaling proteins containing critical cysteines that must be retained for activity are potential targets for ROS and RNS in various pathways. For some of these signaling proteins, the cysteine has been clearly shown to be a thiolate [e.g., protein tyrosine phosphatase (PTP) (24), Trx (51)]. For others, the relative ease of their oxidation and rereduction strongly suggests that their critical thiols are in the thiolate form [e.g., the bacterial transcription factor OxyR (6), the eukaryotic transcription factors AP-1 (59) and NF- (80), caspases (12)]. Similarly, the cysteines in the regulatory site of some protein kinase C isoforms are bound to zinc in such a way that the negative character of their sulfur atoms renders them susceptible to H2O2 oxidation, thereby altering the regulation of these important signaling proteins (40). Oxidation of the thiolate or substitution by site-directed mutagenesis suppresses the activity of these proteins. Nonetheless, although thiolates rather than thiols react with H2O2, the rate constants for some thiolates are still relatively slow and may require catalysis to form the sulfenate. This issue is addressed in the next section.
Table 1 lists the signaling proteins that have been clearly shown to be modified by ROS and RNS via thiol chemistry. Ras, a member of a family of small GTPases that plays a critical role in the activation of several signaling pathways (47), was one of the first such well-defined signaling proteins to be identified as a target for ·NO and H2O2, resulting in its activation (25, 62, 63, 115). However, the first evidence of reversibility of thiol oxidation by ROS and RNS was demonstrated with PTPs at the time these were being recognized as important players in signaling. The redox-mediated regulation of PTPs is supported by several in vivo studies (see below); thus our focus in this article is on the reversible inactivation of PTPs to illustrate both the chemical principles and the unanswered questions that will be the source material for investigations into redox signaling that are currently underway in many laboratories.
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PROTEIN TYROSINE PHOSPHATASES AND H2O2 |
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As mentioned above, all PTPs have a critical thiolate cysteine in a CX5R motif that participates in the dephosphorylation reaction (24, 31, 65). Therefore, the oxidation of the thiolate to a sulfenate, which cannot function in the catalytic process, would likely account for inhibition of PTP activity by H2O2. Although several studies provided some evidence suggesting the formation of an intermediate sulfenate in the active sites of PTPs, the rate of reaction of a PTP with H2O2 is 105 times slower than the Prx reaction (24, 33, 118) or the rate of oxidation of a critical cysteine in the bacterial transcription factor OxyR (6) (i.e.,
10 M1·s1), which is quite slow. Thus the question is raised whether a nonenzymatic reaction can account for the formation of the sulfenate. In Fig. 2, two possible mechanisms are depicted: 1) H2O2 is generated by a NADPH oxidase closely neighboring the PTP so that the concentration of H2O2 is high enough to make the rate of the nonenzymatic reaction physiologically significant, and/or 2) another enzyme, essentially a cysteine oxidase, catalyzes the reaction. Supporting evidence for these mechanisms awaits better knowledge of compartmentalization and the identification of a cysteine oxidase, which would be of great importance in advancing the understanding of redox signaling. The PTP-sulfenate intermediate (analogous to the Prx VI reaction displayed in Reaction 12) can react with GSH to form a mixed disulfide (analogous to the Prx VI reaction displayed in Reaction 13), which also is catalytically inactive.
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Others (9) suggested that reversible inhibition of PTPs occurs via the reaction of the active site cysteine with O2·. The argument presented was that the relative rate constants for cysteine in its thiol form with O2· and H2O2 favored O2·. Nonetheless, this reaction is rather unlikely, as the active site cysteine has clearly been shown to be a thiolate created by a high pH environment in the PTP active site and superoxide radical is an anion with a pKa of 4.7. Furthermore, the reaction of O2· with a thiol, while significantly faster than that of H2O2, is 106 times slower than the rate of dismutation of O2· by superoxide dismutase, which is abundant in the cytosol.
The reversibility of inactivation of most PTPs occurs via reduction of the mixed disulfide to the thiolate (Fig. 2). This again raises the question of a role for an enzymatically catalyzed reaction, as nonenzymatic thiol/disulfide exchange with GSH is slow. The enzyme glutaredoxin, which is found in the cytosol and contains a Trx motif in its active site, may be involved in this reaction (Fig. 2). Glutaredoxin is related to PDI, most of which are found in the lumen of the endoplasmic reticulum, where they are involved in protein folding (107), although some PDI activity is associated with the plasma membrane (60) (for review of glutaredoxin, see Refs. 50, 52). Interestingly, in the case of low-molecular-weight PTP, which has a second cysteine in proximity to the active site, an intramolecular disulfide rather than a mixed disulfide is formed upon reaction with H2O2 (14). The reduction of an intramolecular disulfide is unlikely to occur without catalysis that may be accomplished by a PDI, glutaredoxin, or perhaps an NADPH-requiring enzyme such as Trx reductase. Thus we suggest that the recovery of the phosphatase activity may in all cases necessitate an enzymatic reaction under physiological conditions.
Further complexity in the reversible inactivation of PTP activity by H2O2 has been suggested by recent studies with isolated PTP1B, demonstrating the formation of an intermediate sulfenamide from reaction of the SOH intermediate with an amide in the PTP backbone in proximity to the active site (91, 109). This sulfenamide is reactive with GSH and could be an intermediate in the formation of the mixed disulfide. Nonetheless, whether the reaction of the sulfenate with the amide occurs faster than the reaction of the sulfenate with GSH under in vivo conditions of high GSH concentration is uncertain. Thus the mechanisms of formation of sulfenates and mixed disulfides are still far from well understood. The readers are referred to reviews by Poole et al. (84) and Claiborne et al. (21), which provide a more in-depth analysis of the current understanding of sulfenate formation in biology than that provided herein. To further complicate the picture, Woo et al. (122) recently showed that Prx I can be reversibly oxidized to sulfinic acid (SO2H), although oxidation to that state had previously been viewed as irreversible. A recent publication (11) described an ATP- and thiol-dependent reduction of the sulfinic acid form of yeast 2-cys Prx (Tsa1) catalyzed by a newly discovered yeast enzyme called sulfiredoxin. In the same article, the authors reported that sequences homologous to sulfiredoxin can be found in higher eukaryotes. While a role for reversible inactivation of PTP by H2O2 in redox signaling is gaining support, it is clear that further investigations are needed to fully understand the underlying mechanisms.
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S-NITROSOTHIOL FORMATION AND ITS ROLE IN REDOX SIGNALING |
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Myriad reports allude to the involvement of S-nitrosylation in cell signaling. For example, the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors (69), the calcium channel ryanodine receptor (30), caspase activity (58, 67), metalloproteinase (45), PTPs (68), NF- (74), Trx (46), and the Trx-ASK1 pathway (101) have been reported to be at least partially regulated by S-nitrosylation. In fact, nearly 100 proteins have been reported to be S-nitrosylated (49), making the comprehensive listing of all proteins potentially affected by S-nitrosylation beyond the scope of this review. Nevertheless, the partial listing above is indicative of the diverse array of systems that may be affected by S-nitrosylation. While it is clear that S-nitrosylation is a potentially important signaling process, knowledge of the mechanisms by which protein thiols are nitrosylated and denitrosylated in biological systems is far more tenuous.
The generation of S-nitrosothiols can occur via several mechanisms that are dictated by the cellular environment. In the following sections, we present various possibilities that have been established in purely chemical systems. Most of them, however, have not yet been firmly shown to occur in vivo. The most well-known and chemically accessible pathways involve ·NO-O2 reaction products (113, 116, 117). The reaction of ·NO with O2 generates nitrogen dioxide (NO2) as an initial product
![]() | (15) |
Further reaction of ·NO2 with ·NO forms dinitrogen trioxide (N2O3)
![]() | (16) |
Both ·NO2 and N2O3 are capable of reacting with thiols. ·NO2 is a fairly potent one-electron oxidant that can oxidize thiols by a single electron to form nitrite and the thiyl radical that can directly react with ·NO to produce an S-nitrosothiol
![]() | (17) |
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This mechanism via initial NO2 oxidation and a thiyl radical intermediate have been proposed to be significant in vivo. Nonphysiological O2 concentration decreases RSNO formation because O2 and ROS can remove both thiyl radicals and ·NO. In contrast, the low O2 tension in tissues allows an increase in steady-state thiyl radical formation that may involve ·NO2 (55). Moreover, others (34) suggested that ·NO2 generated in the cytoplasm is unlikely to react with ·NO to form N2O3, owing to the rapid reaction of ·NO2 with thiols and urate. Thus there is the distinct possibility that nitrosation chemistry in the cytoplasm is dominated by rapid reactions of ·NO2.
An S-nitrosothiol also can be generated by the reaction of a thiol with N2O3
![]() | (19) |
The chemistry outlined above can explain the endogenous generation of nitrosothiols from ·NO in an aerobic environment, although the reaction kinetics of these processes may preclude a role in vivo. The generation of ·NO2 is an overall third-order reaction (first order in O2 and second order in ·NO). Thus significant levels of ·NO2 are generated only in conditions of significant ·NO concentration. As "signaling" levels of ·NO are likely to be submicromolar, the rate of ·NO2 generation is slow. Nevertheless, Liu et al. (71) showed that ·NO and O2 favorably partition and accumulate in lipid membranes, increasing the likelihood of ·NO2-N2O3 chemistry. Although not yet established as the primary mechanism in vivo, the S-nitrosylation of protein thiols residing in membrane or hydrophobic environments may in fact occur via ·NO2-N2O3-mediated chemistry.
Metals have been shown to participate in ·NO-mediated nitrosation chemistry in chemical studies. For example, binding of ·NO to a ferric species generates an intermediate with significant nitrosonium ion (+NO) "character." This intermediate species can further react with a nucleophile (e.g., a thiol), generating a nitrosated nucleophile and a ferrous species (110)
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Of course, this metal-mediated chemistry requires the existence of an oxidized metal (Fe3+) in proximity to a nucleophilic thiol species to make a nitrosothiol, since other nucleophiles (including water) can also react with the ferrous nitrosonium intermediate. The in vivo relevance of this metal-mediated chemistry, however, remains speculative. It is worth noting that O2-dependent oxidation of ·NO is not the only way to generate ·NO2. Peroxidase-mediated oxidation of nitrite (NO2) can also form ·NO2, which can lead to thiyl radical formation and subsequent S-nitrosothiol generation, as described above (108)
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Although the peroxidase-catalyzed process outlined above requires NO2, which may come from O2-mediated oxidation of ·NO (and ·NO2 intermediacy), NO2 levels in cells can potentially be much higher than levels of ·NO. Thus, under cellular conditions in which significant NO2 has accumulated in the presence of H2O2 and a peroxidase, even low levels of ·NO can react with a thiyl radical (first order in ·NO) and lead to S-nitrosylation. It has been reported (43) that S-nitrosothiol formation can occur via a direct reaction of ·NO with a thiol followed by oxidation of the intermediate NO-thiol radical adduct. This intriguing report provides a first-order process (in ·NO) for the generation of S-nitrosothiols. However, the validity of this reaction remains to be established. Thus it is clear that S-nitrosothiols are formed in vivo; however, the mechanism by which they are formed requires further investigation, and a variety of factors, such as the proximity of an appropriate metal, the cellular environment of the thiol, the presence of peroxidases, and/or the concentration of the reacting species, dictate which of the described mechanisms are relevant for signaling in vivo.
As most biological signals need to be transient, the involvement of S-nitrosothiol in signaling pathways calls for mechanisms for its degradation. One such possible mechanism involves the attack of the nucleophilic thiol species at the sulfur atom of the S-nitrosothiol, resulting in the generation of nitroxyl (HNO) and the corresponding disulfide (3, 121)
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Another possible mechanism involves transnitrosation (i.e., transfer) of the equivalent of +NO from one thiol to another (7, 8). This does not directly result in the degradation of the S-nitrosothiol function but merely transfers it to another thiol
![]() | (24) |
The relative rates of these two processes are certainly a function of the accessibility of the attacking nucleophilic thiol to the two sites of attack as well as the relative electrophilicity of the sulfur and nitrogen atoms of the S-nitrosothiol. To date, the degree to which these factors dictate the reaction pathway has not been examined rigorously. Significantly, disulfide bond formation is the likely mechanism by which PTPs are inhibited by nitrosothiol species, since only reagents capable of reducing disulfide bonds regenerate activity (68).
S-nitrosothiols are also redox active and, indeed, can be destroyed by redox chemistry, with the most studied of such reactions being that with the cuprous ion (114). Cuprous ion reduces S-nitrosothiols to generate ·NO, thiolate, and cupric ion
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The prevalence of the chemistry in a biological system is dependent on the availability and accessibility of the reducing copper species. Since "free" levels of copper are extremely low in cells, the likelihood of this process occurring is highly dependent on the biological juxtaposition of the reducing copper with the S-nitrosothiol. O2· has been shown to react with S-nitrosothiols in a reaction that is second order in S-nitrosothiol, forming an oxidant and disulfide (56). As with mechanisms of their formation, the biologically relevant mechanisms by which S-nitrosothiols are degraded remains unclear and are a function of a variety of factors that are strictly defined by the nature of the chemical process (e.g., metal, thiol proximity, ROS generation).
One of the most important questions to ask when speculating about the importance and/or the existence of S-nitrosylation in cell signaling is that of specificity, as RSNO would be formed in a "sea of thiols." Considering that glutathione can exceed millimolar concentrations in cells, the rate of reaction of the nitrosylating event must be significantly greater than the rate of reaction with other cellular thiols. The rate of thiol reaction with electrophilic and/or oxidizing species such as N2O3 or ·NO2 is determined in part by the thiol protonation state, as thiolates are much more reactive with RNS (and ROS, as mentioned above) than with thiols. Thus proteins with deprotonated regulatory thiols react at a faster rate with relevant RNS, a chemistry reminiscent of that with H2O2. Moreover, metal thiolates may also possess increased reactivity compared with simple thiols. For example, Chen et al. (18) reported that transnitrosation chemistry with the Zn thiolate functions of metallothionein is extremely facile. With respect to this issue, Stamler (99) also proposed that protein thiols in a consensus motif whereby the thiol is adjacent to a basic and acidic residue confer special reactivity conducive to S-nitrosothiol formation via nitrosation chemistry. Indeed, this motif has predicted thiol nitrosation in several systems containing multiple thiol targets (73). The proximity of a redox metal to a target thiol may be an important factor in thiol nitrosylation. Espey et al. (29) hypothesized that nitrosylation chemistry may occur in discrete domains or compartments on the basis of the compartmentalization or local levels of antioxidants such as ascorbate or glutathione.
The above discussion of the chemistry of potential signaling processes involving the interaction of RNS with thiol species merely describes possible mechanistic scenarios that have not been firmly established. Nevertheless, in spite of the current mechanistic ambiguities, it is clear that RNS-mediated signaling via thiol modification is a potentially important process that needs to be considered as a fundamental signaling paradigm.
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SUMMARY |
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Because the intermediates purportedly formed during the oxidation reaction are highly unstable, a characteristic that is favorable for the reversibility of the reaction, it has been difficult to definitely prove their formation. While several "trapping" methods have allowed the identification of S-nitrosylated proteins in vivo, the formation of sulfenate by H2O2 has been mostly inferred (37). The reduction of sulfenate or S-nitrosothiols to thiolate is likely to involve the formation of mixed disulfide with GSH followed by disulfide exchange, as mentioned above. Although all of these reactions can occur nonenzymatically, enzymatic catalysis may be required to proceed rapidly enough in vivo (17, 37, 98). Other intermediates, such as a sulfenamide, may also be formed, but the general three-step process (see Reactions 57) includes the essential reversible steps required to fit the currently available evidence (Fig. 2). Thus the possible involvement of enzymes such as cysteine oxidase or glutaredoxin in this three-step process merits investigation.
Finally, one aspect that has not received careful attention to date is the timing and/or duration of the reversible inhibition. Some studies (76) have implied correlation between reversible inhibition of a target and downstream events; however, the mechanisms by which this process can be tightly controlled have not been put forth. Some (22, 96) have suggested compartmentalization of glutathione, protein S-glutathionylation, and mixed disulfides in cells with the use of fluorescence microscopy. Spatiotemporal recruitment of the target to these areas in the cells could be envisioned as a control mechanism. Better tools allowing in vivo observation of signaling events are forthcoming (106, 125) and will be of great benefit to the area of redox signaling as well as to other areas of signal transduction.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Some confusion exists regarding the terms "nitrosation" and "nitrosylation." In the purest chemical sense, nitrosation refers to chemical processes involving the nitrosonium cation (+NO). Thus nitrosation of a thiol with the use of +NO (or a species with +NO "character") can be termed S-nitrosation. This term is mechanistically defined. The term "nitrosyl" has been used by inorganic chemists to describe an NO function associated with, for example, metals. In the case of metal nitrosyls, this term does not describe the chemical process by which the metal-NO bond is formed. Another term, actually a prefix, often used in the literature is "nitroso-." Like the term "nitrosyl," "nitroso-" merely describes an NO function associated with another functional group. For example, organic chemists refer to a phenyl group with covalent attachment to NO as nitrosobenzene. Thus the prefix "nitroso-" is not mechanistically defined but describes only the connectivity of the atoms, and the term S-nitrosothiols is used to describe the S-NO function. The term "S-nitrosylation" has been adopted by many who do not want to be specific regarding how the functional group was chemically formed. Moreover, many researchers use the term "S-nitrosylation" as a means of drawing an analogy to other signaling phenomena such as phosphorylation and prenylation. Thus, for the sake of consistency, the term "nitrosylation" is used in this review to indicate the formation of an S-NO bond without regard to its mechanism. When the term "nitrosation" is used, we are indicating the involvement of +NO (or the equivalent).
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