Sulfur and Selenium Catalysis as Paradigms for Redox Regulations

Flohé, Leopold

doi:10.1007/0-306-48412-9_2

Cited by 3 publications

(3 citation statements)

References 49 publications

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“…It has been shown that the selenenic acid (E-SeOH) produced in the GPx cycle reacts readily with a yet undefined X−H group with elimination of H 2 O to produce an oxygen-free Se(II) compound that instantly reacts with thiols . Flohé has proposed that the E-SeOH intermediate may react with proximal Gln residue to form an Se−N bond . The assumption that a selenenyl amide could be generated in proteins is further supported by the recent reports that the redox regulation of protein tyrosine phosphatase 1B (PTP1B; Figure ) involves a sulfenyl amide intermediate. , In this redox mechanism, the sulfenic acid generated in response to PTP1B oxidation by H 2 O 2 is rapidly converted to a sulfenyl amide species (Scheme ).…”

Section: Gpx Activity Of Ebselen and Related Compoundsmentioning

confidence: 96%

Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants

2010

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Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the biological system's ability to detoxify these reactive intermediates. Mammalian cells have elaborate antioxidant defense mechanisms to control the damaging effects of ROS. Glutathione peroxidase (GPx), a selenoenzyme, plays a key role in protecting the organism from oxidative damage by catalyzing the reduction of harmful hydroperoxides with thiol cofactors. The selenocysteine residue at the active site forms a "catalytic triad" with tryptophan and glutamine, which activates the selenium moiety for an efficient reduction of peroxides. After the discovery that ebselen, a synthetic organoselenium compound, mimics the catalytic activity of GPx both in vitro and in vivo, several research groups developed a number of small-molecule selenium compounds as functional mimics of GPx, either by modifying the basic structure of ebselen or by incorporating some structural features of the native enzyme. The synthetic mimics reported in the literature can be classified in three major categories: (i) cyclic selenenyl amides having a Se-N bond, (ii) diaryl diselenides, and (iii) aromatic or aliphatic monoselenides. Recent studies show that ebselen exhibits very poor GPx activity when aryl or benzylic thiols such as PhSH or BnSH are used as cosubstrates. Because the catalytic activity of each GPx mimic largely depends on the thiol cosubstrates used, the difference in the thiols causes the discrepancies observed in different studies. In this Account, we demonstrate the effect of amide and amine substituents on the GPx activity of various organoselenium compounds. The existence of strong Se···O/N interactions in the selenenyl sulfide intermediates significantly reduces the GPx activity. These interactions facilitate an attack of thiol at selenium rather than at sulfur, leading to thiol exchange reactions that hamper the formation of catalytically active selenol. Therefore, any substituent capable of enhancing the nucleophilic attack of thiol at sulfur in the selenenyl sulfide state would enhance the antioxidant potency of organoselenium compounds. Interestingly, replacement of the sec-amide substituent by a tert-amide group leads to a weakening of Se···O interactions in the selenenyl sulfide intermediates. This modification results in 10- to 20-fold enhancements in the catalytic activities. Another strategy involving the replacement of tert-amide moieties by tert-amino substituents further increases the activity by 3- to 4-fold. The most effective modification so far in benzylamine-based GPx mimics appears to be either the replacement of a tert-amino substituent by a sec-amino group or the introduction of an additional 6-methoxy group in the phenyl ring. These strategies can contribute to a remarkable enhancement in the GPx activity. In addition to enhancing catalytic activity, a change in the substituents near the selenium moiety alters the catalytic mechanisms. The mechanistic investigations of functional mimics are useful not...

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Section: Gpx Activity Of Ebselen and Related Compoundsmentioning

confidence: 96%

Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants

2010

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“…with H 2 O 2 is ϳ10 5 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., ϳ10 M Ϫ1 ⅐ s Ϫ1 ), which is quite slow. Thus the question is raised whether a nonenzymatic reaction can account for the formation of the sulfenate.…”

Section: Protein Tyrosine Phosphatases and H2o2mentioning

confidence: 99%

Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers

Forman¹,

Fukuto²,

Torrès³

2004

American Journal of Physiology-Cell Physiology

490

345

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. Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol 287: C246 -C256, 2004; 10.1152/ ajpcell.00516.2003.-Except for the role of NO in the activation of guanylate cyclase, which is well established, the involvement of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in signal transduction remains controversial, despite a large body of evidence suggestive of their participation in a variety of signaling pathways. Several problems have limited their acceptance as signaling molecules, with the major one being the difficulty in identifying the specific targets for each pathway and the chemical reactions supporting reversible oxidation of these signaling components, consistent with a second messenger role for ROS and RNS. Nevertheless, it has become clear that cysteine residues in the thiolate (i.e., ionized) form that are found in some proteins can be specific targets for reaction with H 2O2 and RNS. This review focuses on the chemistry of the reversible oxidation of those thiolates, with a particular emphasis on the critical thiolate found in protein tyrosine phosphatases as an example. hydrogen peroxide; thiolate; nitrosothiol; nitric oxide; signal transduction ALTHOUGH THE INVOLVEMENT OF FREE RADICALS in biology was assumed for many years to be restricted to damaging reactions, the discovery of the endogenous generation of NO in mammalian systems and the finding that this small, freely diffusing, chemically unique species participates in specific signal transduction pathways represented an important new paradigm and expanded views of the possible nature of cell communication and/or signaling processes. This novel role in signal transduction for ⅐NO and other reactive nitrogen species (RNS) now extends to reactive oxygen species (ROS) such as H 2 O 2 and is gaining greater acceptance. The skepticism that still exists about these molecules acting as second messengers in various signaling pathways may vanish with better understanding of their chemistry, particularly regarding the differences in reactivity at high concentrations (mainly associated with pathology and toxicology) from those at low concentrations generated under physiological conditions in response to stimuli. Several excellent reviews have been published regarding evidence supporting a role for ROS and RNS in signaling (26,32,75,82,87,117,119), and we (35, 36) previously described the general properties that define a second messenger and showed how ROS and RNS fit into this role. In this review, the main focus is on the chemistry that may provide specificity, a necessary property of second messengers that has remained the most elusive in the study of ROS and RNS. REACTIVE SPECIES AS SECOND MESSENGERSSecond messengers are generated at the time of receptor activation, are short-lived, and act specifically on effectors to transiently alter their activity. Indeed, ROS and RNS can be generated at the time of receptor activation and are short-lived, as a...

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“…A sensor's competence to sense ROOH or an alkylant selectively would certainly be enhanced if its sensing sulfur were replaced by the super-sulfur selenium (120). Many selenoproteins display signatures of redox proteins (146) and most of those with an established enzymatic function are indeed oxidoreductases with selenocysteine (Sec) as pivotal catalytic entity (122).…”

Section: Sensing By Selenocysteine-containing Proteins?mentioning

confidence: 99%

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Brigelius‐Flohé

Flohé

2011

Antioxidants & Redox Signaling

Self Cite

497

431

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Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NFjB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O 2 -and NO and can be excluded for fast reacting radicals such as OH, OR, or Cl ; (ii) oxidant signals are H 2 O 2 , enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)-and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-jB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed. Antioxid. Redox Signal. 15, 2335-2381.

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Sulfur and Selenium Catalysis as Paradigms for Redox Regulations

Cited by 3 publications

References 49 publications

Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants

Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants

Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

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