Research conducted during the last two decades has provided evidence for the existence of an extensive intracellular redox signalling, control and feedback network based on different cysteine-containing proteins and enzymes. Together, these proteins enable the living cell to sense and respond towards external and internal redox changes in a measured, gradual, appropriate and mostly reversible manner. The (bio)chemical basis of this regulatory ‘thiolstat’ is provided by the complex redox chemistry of the amino acid cysteine, which occurs in vivo in various sulfur chemotypes and is able to participate in different redox processes. Although our knowledge of the biological redox behaviour of sulfur (i.e. cysteine or methionine) is expanding, numerous questions still remain. Future research will need to focus on the individual proteins involved in this redox system, their particular properties and specific roles in cellular defence and survival. Once it is more fully understood, the cellular thiolstat and its individual components are likely to form prominent targets for drug design.

Introduction

Among the various intracellular signalling networks operational within the living cell, the ones based on phosphorylation and dephosphorylation may be the best known and understood. Nonetheless, other post-translational protein modifications play an equally important role in the control and regulation of protein function and enzyme activity. Among the different amino acid modifications, redox changes of cysteine residues are of particular interest. In biology, the thiol group of cysteine is a true ‘redox chameleon’, which can occur in over ten different formal oxidation states in vivo (from −2 in thiols to +6 in sulfate and including several fractional oxidation states) [1,2]. This results in the formation of numerous different sulfur ‘chemotypes’ and allows cysteine to participate in several distinct redox mechanisms (e.g. electron and atom transfer, radical reactions, hydride transfer, nucleophilic exchange reactions). Aspects of the resulting cysteine-centred cellular redox control system, which is frequently involved in OS (oxidative stress) responses and ‘life and death’ decisions, are slowly emerging (Figure 1). Nonetheless, little is known about the proteins and enzymes involved, or details regarding the formation, extent, reversibility and overall biochemical impact of such post-translational cysteine modifications. In the present paper, I map out the basic features of cysteine-based redox control and discuss the cellular thiolstat as an overarching, fairly ‘intelligent’ redox control system enabling the cell to respond to redox changes in a gradual, measured, appropriate and reversible manner.

The cellular thiolstat

Figure 1
The cellular thiolstat

(A) Schematic overview of sulfur-centred cellular redox control (‘thiolstat’). This scheme is based on our currently available, limited, knowledge of redox-sensitive cysteine proteins and highlights some elements of redox control. (B) Similarities between the thiolstat and a conventional thermostat. T, temperature.

Figure 1
The cellular thiolstat

(A) Schematic overview of sulfur-centred cellular redox control (‘thiolstat’). This scheme is based on our currently available, limited, knowledge of redox-sensitive cysteine proteins and highlights some elements of redox control. (B) Similarities between the thiolstat and a conventional thermostat. T, temperature.

The hidden chemistry of cysteine modifications

Before I discuss post-translational cysteine modifications, I need to address a few factors complicating the detection and subsequent analysis of cysteine modifications in vivo. This discussion is necessary in order to illustrate the inherent methodological difficulties faced by chemists and biochemists dealing with the various cysteine-based sulfur chemotypes. First of all, sulfur, unlike most elements, is a redox chameleon under in vivo conditions (see above). Sulfur chemotypes observed in cysteine proteins and enzymes over the years include thiols and disulfides, but also many ‘exotic’ RSS (reactive sulfur species), such as thiyl radicals, S-nitrosothiols, sulfenic, sulfinic and sulfonic acids, thiosulfinates and thiosulfonates to name just a few [1] (see also Table 1). As a result, most bioanalytical techniques available to date have been overwhelmed by the number and diversity of possible post-translational cysteine modifications. Matters are complicated further by the fact that the sulfur atom is generally extraordinarily silent as far as its analytically useful properties are concerned. It is therefore very hard to pinpoint cysteine modifications inside the cell, for instance by dyes or spectroscopic methods. At the same time, most of these modifications are only transiently formed and are unstable. Their detection inside the cell is difficult, whereas detection outside the cell is marred by artefacts, such as rapid decomposition and oxidation under aerobic conditions. Mapping out the various cysteine modification pathways inside cells is therefore a truly daunting task. In addition, traditional biochemistry has long considered post-translational cysteine modifications inside the cell, i.e. in the presence of vast amounts of reduced glutathione (GSH), as mostly marginal, accidental and of little consequence.

Table 1
A selection of important post-translational cysteine modifications which have been identified in mammalian proteins and enzymes

There is mounting evidence that most of these modifications occur inside the living cell, especially under conditions of OS. Owing to the extensive redox activity of sulfur, and its ability to occur in many different chemotypes in vivo, this list of modifications is neither complete nor final (for details and references, see the text. Pr, protein.

Post-translational cysteine modification Formula Possible function 
S-glutathiolation PrSSG Regulation of protein function and enzyme activity 
Protein disulfide PrSSPr' Regulation of function/activity, protein–protein interactions 
S-nitrosation PrSNO Regulation of function/activity 
Sulfenic acid PrSOH Catalysis, redox switch 
Sulfinic acid PrS(O)OH (Irreversible) redox switch 
Thiosulfinate PrS(O)SPr' Intermediate in enzyme-based redox processes 
Sulfinic phospho ester PrS(O)OPO32− Intermediate in enzyme-based redox processes 
Post-translational cysteine modification Formula Possible function 
S-glutathiolation PrSSG Regulation of protein function and enzyme activity 
Protein disulfide PrSSPr' Regulation of function/activity, protein–protein interactions 
S-nitrosation PrSNO Regulation of function/activity 
Sulfenic acid PrSOH Catalysis, redox switch 
Sulfinic acid PrS(O)OH (Irreversible) redox switch 
Thiosulfinate PrS(O)SPr' Intermediate in enzyme-based redox processes 
Sulfinic phospho ester PrS(O)OPO32− Intermediate in enzyme-based redox processes 

Without the apparent need to hunt for post-translational cysteine modifications, and the lack of appropriate trapping and hunting gear, it is hardly surprising that research in this area has long been considered as ‘exotic’. This situation has changed dramatically during the last decade, fuelled by several key discoveries in the field of sulfur redox biochemistry [3].

The last decade: unravelling some of the mysteries

These changes have been brought about by several key developments which together have slowly, but irreversibly, shifted the traditional paradigm of cysteine as occurring exclusively in the thiol or disulfide oxidation state. The notion that sulfur occurs in biology either as thiol or disulfide has given way to the concept of RSS, which predicts the coexistence of a number of distinct post-translational cysteine modifications in vivo, each with its own formation pathway, reactivity and biochemical impact [4]. Such cysteine modifications include sulfur-centred radicals, sulfenic, sulfinic and sulfonic acids, sulfenylamides and various disulfide S-oxides, all of which have been observed in biological systems, even if only in small quantities and mostly as highly reactive, unstable and transient species. Let us just consider two prominent examples: a sulfinic acid was observed at the active site of human decameric TPx-B (thioredoxin peroxidase B), a two-cysteine type II Prdx (peroxiredoxin) in 2000 [5]. Around the same time, a sulfenylamide was detected at the active site of PTP1B (protein tyrosine phosphatase 1B) [6,7]. [It must be emphasized that, throughout the last 60 years, there have been several key discoveries of unusual cysteine modifications in proteins and enzymes, including thiyl radicals, disulfides and sulfenic acids. These discoveries have been highly important for our understanding of cysteine biochemistry and ultimately have laid the foundation for the landmark discoveries witnessed since 2000. Without intending to ignore these efforts, the present paper is focused on the developments of the last decade, and especially on the shift of paradigm being witnessed today.]

Although many of these modifications may still have been considered as artefacts at the time, the discovery of the protein Srx (sulfiredoxin) in 2003 has irreversibly changed our perception of ‘exotic’ sulfur chemotypes: Srx is able to reduce the cysteine sulfinic acid in Prdx to the sulfenic acid in the presence of a suitable thiol-based reducing agent and ATP and via several unusual sulfur oxidation states (including a sulfinic phosphoryl ester and a thiosulfinate) [8]. In essence, the discovery of Srx confirms the occurrence of the sulfinic acid in Prdx. It also confirms the presence of unusual sulfur chemotypes, such as thiosulfinates, in proteins, where these modifications play an integral and valuable part of normal function and catalytic activity. Indeed, Prdx, by relying on a total of six different sulfur chemotypes at a time, highlights the diversity and complexity, but also the power, elegance and virtuosity of cysteine sulfur chemistry inside the living cell [9].

Nonetheless, the discovery of the Prdx/Srx pair, and its involvement in redox sensing and control, does not answer the question of how widespread such cysteine modifications in mammalian cells really are. From a sceptical point of view, it may well be possible that the Prdx/Srx pair represents an interesting, yet rare, example of unusual intracellular cysteine chemistry. Not surprisingly, the last decade has witnessed an intense, often cumbersome and certainly still ongoing, hunt for cysteine modifications in various proteins and enzymes.

So far, ‘cysteine hunters’ such as Phil Eaton at King's College London, Leslie Poole at Wake Forest University School of Medicine or Kate Carroll at the Scripps Research Institute have been able to trap and ultimately hunt down several protein-based cysteine modifications [1022]. Their findings to date include numerous S-thiolated (S-glutathiolated) cysteine proteins, widespread intermolecular protein disulfide formation and the presence of sulfenic acids in various proteins (mostly under conditions of OS). The presence of the sulfenic acid chemotype in proteins is particularly stimulating, since it opens up a whole (new) field of sulfur biochemistry and control associated with it. Indeed, some authors even refer to sulfenic acid-modified proteins as the cellular ‘sulfenome’ [14].

Time for tricky questions – and answers

Despite the stunning results many of these studies have already delivered, several pieces in the cysteine redox puzzle remain missing. I therefore turn my attention to these ‘tricky’ issues, some of which have only been addressed by research conducted during the last couple of years.

First of all, most mammalian cells contain millimolar cytosolic concentrations of reduced glutathione (GSH). Surely, this would be enough to sequester most oxidants, alleviate OS and also prevent any significant cysteine oxidation in proteins and enzymes under ‘normal conditions’? The reply to this objection is based on fairly significant differences in cysteine thiol oxidation potentials (Epa) which exist between GSH on the one hand and various redox sensitive proteins on the other. Such distinct oxidation potentials allow a gradual oxidation of specific cysteine residues in specific proteins and enzymes, and despite the presence of a vast excess of GSH.

Within this context, Jakob Winther and colleagues from the University of Copenhagen published a key paper in 2009 on the ‘global cellular thiol-disulfide status’ describing the processes surrounding cysteine oxidation in a (diamide) stressed cell [23]. Although this study was conducted under unusual stress conditions, and its findings therefore may not apply to all cells at all times, it nonetheless provides some insight into cellular redox processes and their prime targets. In HEK (human embryonic kidney)-293 cells, and under normal conditions, only approximately 8.5% of total glutathione is present as glutathione disulfide (GSSG), and only approximately 5.8% of protein thiols are present as protein disulfides (PrSSPr). As expected, the vast majority of glutathione is present as GSH, and proteins are in the PrSH state. Importantly, virtually no protein S-glutathiolation occurs under those conditions, with a cellular PrSSG content as low as 0.037% of all protein thiols. This situation changes dramatically, however, when (external) OS in form of diamide is applied. Widespread oxidation of cysteine thiols results in disulfides, which ultimately account for more than 50% of the total overall thiol/disulfide content (i.e. 47% of thiols reduced in RSH, 53% oxidized in RSSR). Importantly, most of the cysteine residues oxidized by diamide are found in proteins (56%), and not in GSH (44%). The preferred formation of protein-based disulfides is even more pronounced in HeLa cells, where 67% of oxidized cysteine residues are found in proteins and only 33% in glutathione.

These findings are of considerable significance: GSH apparently does not act as the major intracellular thiol-redox buffer under these conditions, and its presence certainly does not prevent the formation of widespread cysteine modifications in proteins and enzymes. Despite its high abundance, the Epa of cysteine in GSH is rather positive, i.e. GSH is not a particularly good reducing agent. [Literature values for the redox potential of glutathione vary depending on the systems and analytical methods employed; the E1/2 (redox potential) of glutathione is mostly found to be approximately −230 to −240 mV compared with the NHE (normal hydrogen electrode).] Several proteins contain cysteine residues which are considerably more reactive, and hence may be oxidized preferably. Indeed, it appears that the catalytic cysteine residues, which usually feature a rather low pKa value, are also particularly prone to oxidative modification. [Although a low pKa value of a given thiol is often used as a measure of its redox sensitivity, equating acidity (pKa) with reducing power (Epa) is only superficially correct. A low pKa value implies that the deprotonated form of cysteine, i.e. the thiolate, dominates over the thiol form. Since the thiolate is also a good nucleophile, and many (but not all) of the redox reactions involving cysteine proceed via nucleophilic exchange reactions, a low pKa value and excess of thiolate over protonated thiol indeed often, but not always, mirror a more reactive cysteine residue and a more reducing redox behaviour.] Ironically, the fact that high reactivity comes at the cost of extreme sensitivity towards oxidation provides an ideal basis for redox control of protein function and enzyme activity.

Within this context, one may wonder which of the intracellular proteins are indeed the most sensitive towards cysteine modifications, and which modifications may occur depending on the severity of the (oxidative) stress signal. To be honest, very little is known regarding the individual Epa values of specific cysteine residues in particular proteins or enzymes. Such potentials are difficult to measure experimentally, since most methods available for this purpose today, such as equilibrium redox titrations or cyclic voltammetry, require considerable amounts of protein, cannot distinguish between individual cysteine residues within the same protein and often are just too imprecise.

One may hope that future research will be able to assign specific potentials to the cysteine residues in question, ultimately providing a (semi-)quantitative ranking of redox sensitive proteins and enzymes. Such a list would represent a major step forward. It would allow us to understand which proteins are modified under specific conditions, and to which extent these modifications occur. Importantly, such a ‘ranking’ would also indicate which cellular events are under redox control, and under which redox conditions these control mechanisms (gradually) take effect.

At this point, another critical question arises, which concerns the biochemical impact of such modifications: although it may well be the case that some proteins become oxidized (albeit only under severe conditions of OS), such oxidative modification may still be of little consequence. Does it really matter if one or two cysteine residues in a particular enzyme are S-thiolated or oxidized to a sulfenic or sulfinic acid? The enzyme may not even be affected by this change, and in any case, there will be thousands of copies of the same enzyme within a given cell which surely will continue with their business as usual?

Here, the last decade has witnessed the slow but steady, and still continuing, identification of key players in cellular regulation and signalling as cysteine-containing proteins. [It should be pointed out that not all cysteine residues in proteins necessarily have to be redox-sensitive. Some cysteine residues are fairly resistant towards oxidation. It is therefore (still) not possible to simply use genetic information or the protein structure in order to decide that a given protein is a cysteine protein and therefore necessarily under redox control.]

It now appears that numerous proteins and enzymes involved in various cellular signalling cascades contain active-site or regulatory cysteine residues. Besides the Prdx proteins (which as ‘hydrogen peroxide floodgate keepers’ take and execute life-and-death decisions), examples of (redox) regulated cysteine proteins include transcription factors [e.g. NF-κB (nuclear factor κB)], some of the enzymes of the cell cycle (e.g. Cdc25) and proteins and enzymes involved in apoptosis (e.g. certain caspases). Indeed, there are probably numerous proteins and enzymes positioned at critical locations in cellular signalling networks, whose activity can be ‘fine-tuned’ or even switched off by modification of specific cysteine residues [24]. Although it is impossible to discuss all of these proteins, and their various biochemical functions, as part of the present review, it is important to emphasize that the cysteine residues in these proteins are often modified in a reversible manner. Reversibility of the post-translational modification, of course, is essential for the signal to be generated and relayed, but also to be ‘switched off’ once the initial stimulus has subsided or has been reversed.

Towards the concept of the intracellular thiolstat

Taken together, the developments, discoveries and concepts described in the previous sections sketch out the picture of rather complex overarching intracellular redox control based on redox-sensitive cysteine proteins. This cellular thiolstat is based on an extensive, diverse and often little understood chemistry centred around the amino acid cysteine which forms a redox feedback and control cycle and apparently enables the cell to respond to gradual changes of the intracellular redox environment in a gradual, measured, appropriate, effective and reversible manner (Figure 1). [Recent studies also point towards the involvement of methionine residues. The latter are redox-sensitive and the sulfide in question, under appropriate conditions, may be oxidized to sulfoxide (reversible) and sulfone (irreversible). The full implications of these methionine modifications, especially in the context of redox control, are still not fully apparent, yet the presence of methionine sulfoxide reductases in most organisms hints at a rather significant role in redox signalling and control.]

As mentioned above, a gradual response is possible since cysteine residues tend to differ in their Epa values: different cysteine residues in proteins exhibit different susceptibility towards oxidation, hence modification of cysteine residues occurs selectively and gradually, often following the Epa trend of the residue (and hence protein) involved. In turn, gradual modification of proteins in response to gradual changes to the redox environment enables the cell to respond gradually to these changes. Such a response may be measured and appropriate: it may initially involve the activation of antioxidant pathways, e.g. via activation of NF-κB and an increased expression of antioxidant proteins and enzymes. More extreme shifts in redox potential, for instance under conditions of severe OS, may then (de-)activate additional proteins, a process which may result in cell-cycle arrest and apoptosis.

Interestingly, oxidation of cysteine thiols may lead to a range of oxidation products, which adds further to the ability of proteins to react gradually to shifts in the cellular redox potential: whereas disulfide formation (S-thiolation, S-glutathiolation, and intra- and inter-molecular disulfide formation) is likely to dominate under mild OS, other sulfur species, such as sulfenic acids, sulfenylamides and ultimately sulfinic and sulfonic acids, may accumulate under more severe conditions. As a consequence, the extent of the redox change in the cell can be ‘measured’ not only by oxidation of particular cysteine residues (and here according to their Epa values), but also by the type of modification ultimately formed (Figure 2). Here, some modifications, such as S-nitrosation, S-thiolation and sulfenic acid formation, are reversible and, upon normalization of the cell, lead to the restoration of the initial protein and its function. Such modifications allow the instigation of temporary actions. Other modifications, in contrast, are usually encountered only under severe OS conditions, are irreversible and trigger unidirectional processes, often resulting in cell death (e.g. sulfinic and sulfonic acid formation).

Post-translational modifications of cysteine

Figure 2
Post-translational modifications of cysteine

Different post-translational modifications with a distinct biochemical impact are possible at the same cysteine residue in a given enzyme. Although some of these modifications may result in the sensing of oxidants, others may play a role in protein–protein interactions or in cell signalling.

Figure 2
Post-translational modifications of cysteine

Different post-translational modifications with a distinct biochemical impact are possible at the same cysteine residue in a given enzyme. Although some of these modifications may result in the sensing of oxidants, others may play a role in protein–protein interactions or in cell signalling.

Formation of different sulfur oxidation states under different redox conditions has been studied, for instance, in the case of Prdx, where over-oxidation of the sulfenic acid to the sulfinic acid provides a (sometimes) irreversible trigger to open the ‘peroxide floodgate’. The ability of cysteine to occur in different sulfur oxidation states under different redox conditions obviously represents a major advantage of cysteine-centred cellular control which requires further attention in the near future, especially in the context of the cellular ‘sulfenome’ [14,24].

Nonetheless, the thiolstat is not a classical cellular signalling pathway as such. The thiolstat is rather a cellular control mechanism which senses and responds to externally inflicted or internally generated redox changes via different pathways in order to maintain a suitable intracellular redox homoeostasis. Here, it is comparable with a system of strategically placed thermostats in different rooms across a building, which together sense the extent of temperature changes at different places and times and activate, tune or deactivate the different heating and cooling systems in the various rooms in order to provide the desired temperature(s). Like the thermostat, the thiolstat is composed of strategically placed proteins and enzymes at critical positions within existing signalling and control networks of the cell. It is able to sense the existing redox status of the cell via the type and extent of thiol oxidation. The thiolstat subsequently activates, tunes or deactivates the various proteins and enzymes involved, which affects various cellular processes and results in an overall effect (e.g. activation of antioxidant defence, cell-cycle arrest or cell death). Like the thermostat, which maintains a given temperature, the thiolstat maintains a suitable intracellular redox environment, primarily based on reduced and oxidized thiols. Unlike a conventional thermostat, however, the thiolstat not only controls the cysteine redox state in peptides and proteins, but also uses these cysteine residues for sensing and control purposes. The redox state of cysteine therefore serves three roles: It is the sensor, trigger and also the ultimate target of redox changes and regulation in form of a complex redox signalling circuit and feedback loop (Figure 1).

Conclusions and outlook

Whereas the basic aspects of intracellular redox control, post-translational cysteine modification and the intracellular thiolstat are slowly emerging, numerous questions remain. To conclude, I highlight some of the issues which in my opinion deserve urgent attention in form of future research.

First of all, it is still not entirely understood which cysteine proteins and enzymes are affected by (oxidative) post-translational modification, and under which conditions these modifications occur. In order to resolve this issue, and to provide a more quantitative measure of redox sensitivity, the determination of reliable Epa values for different cysteine residues within various proteins is of paramount importance. Future studies in this field need to focus on the development and use of refined and reliable techniques to measure these potentials. Within this context, proteins most susceptible towards oxidation are of particular interest, since these proteins are likely to be preferably modified, and hence should play a major part in cellular redox control.

Secondly, questions surrounding the different sulfur oxidation states found inside the cell are of increasing importance. Besides S-nitrosothiols, disulfides and sulfenic acids, other modifications may also play a role in redox control, for instance sulfur-centred radicals, sulfinic acids, various sulfur-nitrogen species (including S-nitrothiols) and, to some extent, disulfide-S-oxides. Little is known about the formation, presence and biochemical impact (if any) of such modifications. The discovery of sulfenic acids in proteins and enzymes has illustrated, however, that such modifications are not inherently ‘exotic’: they may well occur in vivo and fulfil important roles in catalysis or in controlling key cellular processes. Furthermore, it now appears that the sulfur atom in methionine is also redox-active, and that sulfoxides, sulfones and some follow-on products may be involved in control and signalling processes as well.

On the basis of the answers to these questions, it would then be necessary to investigate (i) which particular cysteine residues in proteins and enzymes are modified, (ii) to which sulfur oxidation state (and chemotype) they are modified, and (iii) under which conditions such modifications occur. On the basis of our present knowledge regarding the redox behaviour of the thiol group, one may predict that the initial oxidation processes would result in a disulfide, whereas more extreme conditions may lead to higher oxidation states, such as sulfenic acids. This rule of thumb has, however, some limitations. It appears that the type of oxidant involved also plays a major role. Whereas some oxidants seem to cause disulfide formation, others lead to sulfur-centred radicals and sulfenic acids [24]. In a way, the thiol group may therefore differentiate not only between the overall severity of OS, but also between individual oxidants. It may even be possible that the very same cysteine residue is sometimes modified by S-thiolation, sometimes by S-nitrosation and sometimes by oxidation to a sulfenic or even sulfinic acid, depending on the nature and amount of oxidant present.

There are also limited data available regarding the modification of individual cysteine residues in proteins containing two or more of these residues. Although we have a comprehensive knowledge concerning the particular features of specific phosphorylation sites, we still know very little about the characteristics of prospective S-thiolation, S-nitrosation or sulfur oxidation sites, if any, apart from specific Epa values.

And finally, our currently available list of cysteine proteins affected by redox control is still vastly incomplete. Here, we need to focus on several closely related issues, including (i) which cysteine-containing proteins and enzymes are sensitive to cysteine modifications, (ii) under which conditions these modifications occur, (iii) how widespread these modifications are within the cell, (iv) how these modifications affect the protein/enzyme in question, and (v) whether these effects actually have a wider impact on cellular processes. Indeed, it is possible that such modifications occur specifically in individual cellular compartments, such as mitochondria, the endoplasmic reticulum (one may take note of endoplasmic reticulum stress) and the nucleus, which complicates these issues further.

The cellular thiolstat with its numerous redox-regulated and -regulating proteins and enzymes clearly provides ample opportunities for exciting future research projects at the interface of chemistry, biochemistry and (cell) biology. Ultimately, the high selectivity inherent in the chemistry of sulfur species will also provide stimulating new targets for the design of innovative drugs and pesticides.

Analysis of Free Radicals, Radical Modifications and Redox Signalling: A Biochemical Society Focused Meeting held at Aston University, Birmingham, U.K., 18–19 April 2011. Organized and Edited by Helen Griffiths (Aston University, U.K.), Corinne Spickett (Aston University, U.K.) and Paul Winyard (Exeter, U.K.).

Abbreviations

     
  • Epa

    oxidation potential

  •  
  • NF-κB

    nuclear factor κB

  •  
  • OS

    oxidative stress

  •  
  • Prdx

    peroxiredoxin

  •  
  • PTP1B

    protein tyrosine phosphatase 1B

  •  
  • RSS

    reactive sulfur species

  •  
  • Srx

    sulfiredoxin

Funding

I acknowledge the financial support of the University of Saarland, the Ministry of Economics and Science of Saarland, the Deutsche Forschungsgemeinschaft (DFG) [grant number JA1741/2-1], the European Community Seventh Framework Programme (FP7/2007–2013) [grant number 215009 RedCat] and the Corena Interreg IVa Programme.

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