Hypothesis: the role of reactive sulfur species in oxidative stress

Giles, Gregory I.; Tasker, Karen M.; Jacob, Claus

doi:10.1016/s0891-5849(01)00710-9

Cited by 267 publications

(200 citation statements)

References 26 publications

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“…The relevant oxidation states are the thiol (-SH), disulfide (-SS-), sulfenate (-SO Ϫ ), sulfinate (-SO 2 Ϫ ), and sulfonate (-SO 3 Ϫ ), of which the thiol and disulfide are most common. Thiyl radicals (-RS⅐) generated from thiols in the presence of oxygen-centered radicals (197), as well as other reactive sulfur species (50), have also been considered as toxic species involved in oxidative stress. Thiyl radicals rapidly react to form disulfides (171), and this may serve as a convergence point between one-electron and two-electron events.…”

Section: The Redox Hypothesismentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,032

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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Section: The Redox Hypothesismentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,032

839

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“…11,12 Hyperoxidation of Cys residues can lead to irreversible formation of sulfinic acid (-SO2H) and sulfonic acid (-SO3H). 11 In addition, protein thiols can react to form mixed disulfides with extracellular GSH (S-glutathiolation) or other small thiols, or to form S-nitrosthiol derivatives (RSNO).…”

Section: (-S -) Thiyl Radical (-S · ) Disulfides (-S-s-) Disulfidementioning

confidence: 99%

“…11 In addition, protein thiols can react to form mixed disulfides with extracellular GSH (S-glutathiolation) or other small thiols, or to form S-nitrosthiol derivatives (RSNO). 11,12 There are a variety of roles that NO plays in protein modification, such as N-nitrosation, S-nitrosation, and higher order oxidation of thiols. 13 Initial measurements of S-nitrosothiols in plasma reported levels of approximately 7 mol/L for NO present as RSNO, compared with free NO levels of 3 nmol/L.…”

Section: (-S -) Thiyl Radical (-S · ) Disulfides (-S-s-) Disulfidementioning

confidence: 99%

Redox Regulation in the Extracellular Environment

Ottaviano

Handy

Loscalzo

2008

Circ J

128

100

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Molecular oxygen is involved in the oxidation of substrates used to produce energy; however, normal metabolism can also generate harmful (bio)chemical byproducts. These deleterious products are partially reduced forms of oxygen, and include free radicals such as superoxide anion radical, hydroxyl radical, or highly oxidizing non-radical species such as hydrogen peroxide (H2O2) and lipid peroxides, which are collectively known as ROS. 1 ROS typically derive from normal metabolism, activated leukocytes, and ambient oxygen in the environment. The production and accumulation of ROS and their downstream effects can be controlled or attenuated by antioxidants. When the ability of antioxidants to eliminate harmful cellular and extracellular ROS is compromised, the balance between ROS generation and antioxidant function to eliminate ROS is shifted in favor of an accumulation of oxidants, which defines the state of oxidative stress in a cell or organism. Oxidative damage can affect DNA, lipids, and proteins, and eventually compromise cell integrity. Many studies have implicated ROS in the pathological processes leading to heart disease, cancer, aging, AIDS, and inflammatory and autoimmune diseases.Oxidants, especially free radicals, are highly reactive. Superoxide can react within milliseconds with nitric oxide (NO) to produce peroxynitrite (ONOO -), a reactive nitrogen species (RNS). The nitrosium cation and nitroxyl anion are other RNS derived from NO. 2 Peroxynitrite is a strong oxidant involved in the nitrosative modification of proteins and lipids. Owing to its rapid reaction with NO, superoxide may modulate NO bioavailability and, subsequently, regulate vascular function. 3 Circulation Journal Vol.72, January 2008The cytosol, mitochondria, peroxisomes, and plasma are all potential sites of ROS formation. 4 The major sources of ROS are enzymatic via nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), xanthine oxidase, myeloperoxidase, endothelial NO synthase (eNOS), or as a consequence of normal mitochondrial respiration. In vascular cells, other enzymatic sources of ROS include cytochrome P450 isoenzymes, lipoxygenase, cyclooxygenase, heme oxygenase, and glucose oxidase. 1,3,[5][6][7] Most reviews to date have focused on the role of intracellular antioxidants that eliminate ROS from the intracellular environment. There are, however, several extracellular antioxidants that also play an equally important role in limiting ROS accumulation in the extracellular environment. Along with limiting ROS accumulation, extracellular redox status is essential for maintaining protein stability and function.The major enzymes important for the elimination of extracellular H2O2 are glutathione peroxidase-3 (GPx-3) and peroxiredoxin IV (Prx IV). Other extracellular antioxidants involved in ROS elimination include paraoxonase (PON), thioredoxin (Trx), Trx reductase (TrxR), glutaredoxin (Grx), extracellular superoxide dismutase (EC-SOD), and extracellular glutathione (GSH).Some of these antioxidants, notably glutathione...

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“…3,5,6) In vitro, XD has been reported to be converted into XO by modification of sulfhydryl groups, or by disulfide bridge formation. 10,11,18,19) Nishino and Nishino, 10) and Nishino et al 11) have reported that DTPY is an useful tool for investigating the conversion of XD to XO by forming the disulfide bridge in XD, and have shown that, by the addition of DTT after preincubation, the XO enzyme is rapidly reconverted to XD.…”

Section: Resultsmentioning

confidence: 99%

“…[2][3][4] The physiological and pathophysiological roles of disulfide S-monoxides in the body have attracted much attention. 5,6) It is known that xanthine oxidase/xanthine dehydrogenase (XO/XD) catalyzes the conversion of hypoxanthine into xanthine and xanthine into uric acid during normal biochemical events. In physiological conditions, most XO/XD are of the XD type that utilizes NAD ϩ as an electron acceptor and does not produce ROS.…”

mentioning

confidence: 99%