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Space-filling model of the antioxidant metabolite glutathione. The yellow sphere is the redox-active sulfur atom that provides antioxidant activity, while the red, blue, white, and dark grey spheres represent oxygen, nitrogen, hydrogen, and carbon atoms, respectively.
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols or polyphenols.
Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells.
As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect any benefit for the formulations tested, and excess supplementation may occasionally be harmful. In addition to these uses in medicine, antioxidants have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline.
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The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines.Matill HA (1947). Antioxidants. Annu Rev Biochem 16: 177–192.
Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity.German J (1999). "Food processing and lipid oxidation". Adv Exp Med Biol 459: 23–50. PMID 10335367. Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in biochemistry of living organisms.Jacob R (1996). "Three eras of vitamin C discovery". Subcell Biochem 25: 1–16. PMID 8821966. Knight J (1998). "Free radicals: their history and current status in aging and disease". Ann Clin Lab Sci 28 (6): 331-46. PMID 9846200.
The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized.Moreau and Dufraisse, (1922) Comptes Rendus des Séances et Mémoires de la Société de Biologie, 86, 321. Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells.Wolf G (2005). "The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill". J Nutr 135 (3): 363-6. PMID 15735064.
The structure of the antioxidant vitamin ascorbic acid (vitamin C).
A paradox in metabolism is that while the vast majority of complex life requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.Davies K (1995). "Oxidative stress: the paradox of aerobic life". Biochem Soc Symp 61: 1–31. PMID 8660387. Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids.Sies H (1997). "Oxidative stress: oxidants and antioxidants". Exp Physiol 82 (2): 291-5. PMID 9129943. Vertuani S, Angusti A, Manfredini S (2004). "The antioxidants and pro-antioxidants network: an overview". Curr Pharm Des 10 (14): 1677–94. PMID 15134565. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.
The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M, Telser J (2007). "Free radicals and antioxidants in normal physiological functions and human disease". Int J Biochem Cell Biol 39 (1): 44–84. PMID 16978905. The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction.Stohs S, Bagchi D (1995). "Oxidative mechanisms in the toxicity of metal ions". Free Radic Biol Med 18 (2): 321-36. PMID 7744317. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,Nakabeppu Y, Sakumi K, Sakamoto K, Tsuchimoto D, Tsuzuki T, Nakatsu Y (2006). "Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids". Biol Chem 387 (4): 373-9. PMID 16606334. Valko M, Izakovic M, Mazur M, Rhodes C, Telser J (2004). "Role of oxygen radicals in DNA damage and cancer incidence". Mol Cell Biochem 266 (1–2): 37–56. PMID 15646026. while damage to proteins causes enzyme inhibition, denaturation and protein degradation.Stadtman E (1992). "Protein oxidation and aging". Science 257 (5074): 1220–4. PMID 1355616.
The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.Raha S, Robinson B (2000). "Mitochondria, oxygen free radicals, disease and aging". Trends Biochem Sci 25 (10): 502-8. PMID 11050436. In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.Lenaz G (2001). "The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology". IUBMB Life 52 (3–5): 159-64. PMID 11798028. Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q·−). This unstable intermediate can lead to electron "leakage", when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain.Finkel T, Holbrook NJ (2000). "Oxidants, oxidative stress and the biology of aging". Nature 408 (6809): 239-47. PMID 11089981. In a similar set of reactions in plants, reactive oxygen species are also produced during photosynthesis under conditions of high light intensity.Krieger-Liszkay A (2005). "Singlet oxygen production in photosynthesis". J Exp Bot 56 (411): 337-46. PMID 15310815. This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.Szabó I, Bergantino E, Giacometti G (2005). "Light and oxygenic photosynthesis: energy dissipation as a protection mechanism against photo-oxidation". EMBO Rep 6 (7): 629-34. PMID 15995679.
Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. These compounds may be synthesized in the body or obtained from the diet. The different antioxidants are present at a wide range of concentrations in body fluids and tissues, with some such as glutathione or ubiquinone mostly present within cells, while others such as uric acid are more evenly distributed (see table below).
The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another.Chaudière J, Ferrari-Iliou R (1999). "Intracellular antioxidants: from chemical to biochemical mechanisms". Food Chem Toxicol 37 (9–10): 949 – 62. PMID 10541450. Sies H (1993). "Strategies of antioxidant defense". Eur J Biochem 215 (2): 213 – 9. PMID 7688300. The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. The amount of protection provided by any one antioxidant will also depend on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts.
Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin.Imlay J (2003). "Pathways of oxidative damage". Annu Rev Microbiol 57: 395–418. PMID 14527285. Selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes, as is discussed below.
Ascorbic acid or "vitamin C" is a monosaccharide antioxidant found in both animals and plants. As it cannot be synthesised in humans and must be obtained from the diet, it is a vitamin.Smirnoff N (2001). "L-ascorbic acid biosynthesis". Vitam Horm 61: 241 – 66. PMID 11153268. Most other animals are able to produce this compound in their bodies and do not require it in their diets.Linster CL, Van Schaftingen E (2007). "Vitamin C. Biosynthesis, recycling and degradation in mammals". FEBS J. 274 (1): 1-22. PMID 17222174. In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins.Meister A (1994). "Glutathione-ascorbic acid antioxidant system in animals". J Biol Chem 269 (13): 9397 – 400. PMID 8144521. Wells W, Xu D, Yang Y, Rocque P (1990). "Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity". J Biol Chem 265 (26): 15361 – 4. PMID 2394726. Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide.Padayatty S, Katz A, Wang Y, Eck P, Kwon O, Lee J, Chen S, Corpe C, Dutta A, Dutta S, Levine M (2003). "Vitamin C as an antioxidant: evaluation of its role in disease prevention". J Am Coll Nutr 22 (1): 18 – 35. PMID 12569111. In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the antioxidant enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants.Shigeoka S, Ishikawa T, Tamoi M, Miyagawa Y, Takeda T, Yabuta Y, Yoshimura K (2002). "Regulation and function of ascorbate peroxidase isoenzymes". J Exp Bot 53 (372): 1305 – 19. PMID 11997377.
The free radical mechanism of lipid peroxidation.
Glutathione is a cysteine-containing peptide found in most forms of aerobic life.Meister A, Anderson M (1983). "Glutathione". Annu Rev Biochem 52: 711 – 60. PMID 6137189. It is not required in the diet and is instead synthesized in cells from its constituent amino acids.Meister A (1988). "Glutathione metabolism and its selective modification". J Biol Chem 263 (33): 17205 – 8. PMID 3053703. Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants. Due to its high concentration and its central role in maintaining the cell\'s redox state, glutathione is one of the most important cellular antioxidants.
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.Reiter RJ, Carneiro RC, Oh CS (1997). "Melatonin in relation to cellular antioxidative defense mechanisms". Horm. Metab. Res. 29 (8): 363-72. PMID 9288572. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000). "Significance of melatonin in antioxidative defense system: reactions and products". Biological signals and receptors 9 (3–4): 137-59. PMID 10899700.
Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties.Herrera E, Barbas C (2001). "Vitamin E: action, metabolism and perspectives". J Physiol Biochem 57 (2): 43 – 56. PMID 11579997. Packer L, Weber SU, Rimbach G (2001). "Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling". J. Nutr. 131 (2): 369S–73S. PMID 11160563. Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolising this form.Brigelius-Flohé R, Traber M (1999). "Vitamin E: function and metabolism". FASEB J 13 (10): 1145 – 55. PMID 10385606.
It has been claimed that the α-tocopherol form is the most important lipid-soluble antioxidant, and that it protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.Traber MG, Atkinson J (2007). "Vitamin E, antioxidant and nothing more". Free Radic. Biol. Med. 43 (1): 4–15. PMID 17561088. This removes the free radical intermediates and prevents the propagation reaction from continuing. This reaction produces oxidised α-tocopheroxyl radicals that can be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol.Wang X, Quinn P (1999). "Vitamin E and its function in membranes". Prog Lipid Res 38 (4): 309 – 36. PMID 10793887.
However, the roles and importance of the various forms of vitamin E are presently unclear,Brigelius-Flohé R, Davies KJ (2007). "Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a \'junk\' food? Comments on the two accompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E, antioxidant and nothing more" by M. Traber and J. Atkinson". Free Radic. Biol. Med. 43 (1): 2–3. PMID 17561087. Atkinson J, Epand RF, Epand RM (2007). "Tocopherols and tocotrienols in membranes: A critical review". Free Radic. Biol. Med. 44 (5): 739-764. PMID 18160049. and it has even been suggested that the most important function of α-tocopherol is as a signaling molecule, with this molecule having no significant role in antioxidant metabolism.Azzi A (2007). "Molecular mechanism of alpha-tocopherol action". Free Radic. Biol. Med. 43 (1): 16–21. PMID 17561089. Zingg JM, Azzi A (2004). "Non-antioxidant activities of vitamin E". Curr. Med. Chem. 11 (9): 1113–33. PMID 15134510. The functions of the other forms of vitamin E are even less well-understood, although γ-tocopherol is a nucleophile that may react with electrophilic mutagens, and tocotrienols may be important in protecting neurons from damage.Sen C, Khanna S, Roy S (2006). "Tocotrienols: Vitamin E beyond tocopherols". Life Sci 78 (18): 2088 – 98. PMID 16458936.
Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,Duarte TL, Lunec J (2005). "Review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C". Free Radic. Res. 39 (7): 671-86. PMID 16036346. however, it can also reduce metal ions which leads to the generation of free radicals through the Fenton reaction.Carr A, Frei B (1999). "Does vitamin C act as a pro-oxidant under physiological conditions?". FASEB J. 13 (9): 1007-24. PMID 10336883. Stohs SJ, Bagchi D (1995). "Oxidative mechanisms in the toxicity of metal ions". Free Radic. Biol. Med. 18 (2): 321-36. PMID 7744317.
The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.Valko M, Morris H, Cronin MT (2005). "Metals, toxicity and oxidative stress". Curr. Med. Chem. 12 (10): 1161-208. PMID 15892631. However, less data is available for other dietary antioxidants, such as polyphenol antioxidants,Halliwell B (2007). "Dietary polyphenols: good, bad, or indifferent for your health?". Cardiovasc. Res. 73 (2): 341-7. PMID 17141749. zinc,Hao Q, Maret W (2005). "Imbalance between pro-oxidant and pro-antioxidant functions of zinc in disease". J. Alzheimers Dis. 8 (2): 161-70; discussion 209-15. PMID 16308485. and vitamin E.Schneider C (2005). "Chemistry and biology of vitamin E". Mol Nutr Food Res 49 (1): 7-30. PMID 15580660.
Enzymatic pathway for detoxification of reactive oxygen species.
As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes. Here, the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalysing the first step and then catalases and various peroxidases removing hydrogen peroxide. As with antioxidant metabolites, the contributions of these enzymes can be hard to separate from one another, but the generation of transgenic mice lacking just one antioxidant enzyme can be informative.Ho Y, Magnenat J, Gargano M, Cao J (9788901). "The nature of antioxidant defense mechanisms: a lesson from transgenic studies". Environ Health Perspect 106 Suppl 5: 1219–28. PMID 9788901.
Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide.Zelko I, Mariani T, Folz R (2002). "Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression". Free Radic Biol Med 33 (3): 337-49. PMID 12126755. Bannister J, Bannister W, Rotilio G (1987). "Aspects of the structure, function, and applications of superoxide dismutase". CRC Crit Rev Biochem 22 (2): 111-80. PMID 3315461. SOD enzymes are present in almost all aerobic cells and in extracellular fluids.Johnson F, Giulivi C (2005). "Superoxide dismutases and their impact upon human health". Mol Aspects Med 26 (4–5): 340-52. PMID 16099495. Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be copper, zinc, manganese or iron. In humans, the copper/zinc SOD is present in the cytosol, while manganese SOD is present in the mitochondrion. There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites.Nozik-Grayck E, Suliman H, Piantadosi C (2005). "Extracellular superoxide dismutase". Int J Biochem Cell Biol 37 (12): 2466–71. PMID 16087389. The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth.Melov S, Schneider J, Day B, Hinerfeld D, Coskun P, Mirra S, Crapo J, Wallace D (1998). "A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase". Nat Genet 18 (2): 159-63. PMID 9462746. In contrast, the mice lacking copper/zinc SOD are viable but have lowered fertility, while mice without the extracellular SOD have minimal defects.Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W (1996). "Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury". Nat Genet 13 (1): 43-7. PMID 8673102. In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in chloroplasts that is absent from vertebrates and yeast.Van Camp W, Inzé D, Van Montagu M (1997). "The regulation and function of tobacco superoxide dismutases". Free Radic Biol Med 23 (3): 515-20. PMID 9214590.
Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.Chelikani P, Fita I, Loewen P (2004). "Diversity of structures and properties among catalases". Cell Mol Life Sci 61 (2): 192–208. PMID 14745498. Zámocký M, Koller F (1999). "Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis". Prog Biophys Mol Biol 72 (1): 19–66. PMID 10446501. This protein is localized to peroxisomes in most eukaryotic cells.del Río L, Sandalio L, Palma J, Bueno P, Corpas F (1992). "Metabolism of oxygen radicals in peroxisomes and cellular implications". Free Radic Biol Med 13 (5): 557-80. PMID 1334030. Catalase is an unusual enzyme since, although hydrogen peroxide is its only substrate, it follows a ping-pong mechanism. Here, its cofactor is oxidised by one molecule of hydrogen peroxide and then regenerated by transferring the bound oxygen to a second molecule of substrate.Hiner A, Raven E, Thorneley R, García-Cánovas F, Rodríguez-López J (2002). "Mechanisms of compound I formation in heme peroxidases". J Inorg Biochem 91 (1): 27–34. PMID 12121759. Despite its apparent importance in hydrogen peroxide removal, humans with genetic deficiency of catalase — "acatalasemia" — or mice genetically engineered to lack catalase completely, suffer few ill effects.Mueller S, Riedel H, Stremmel W (1997). "Direct evidence for catalase as the predominant H2O2 -removing enzyme in human erythrocytes". Blood 90 (12): 4973–8. PMID 9389716. Ogata M (1991). "Acatalasemia". Hum Genet 86 (4): 331-40. PMID 1999334.
Decameric structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.Parsonage D, Youngblood D, Sarma G, Wood Z, Karplus P, Poole L (2005). "Analysis of the link between enzymatic activity and oligomeric state in AhpC, a bacterial peroxiredoxin". Biochemistry 44 (31): 10583-92. PMID 16060667. PDB 1YEX
Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite.Rhee S, Chae H, Kim K (2005). "Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling". Free Radic Biol Med 38 (12): 1543–52. PMID 15917183. They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.Wood Z, Schröder E, Robin Harris J, Poole L (2003). "Structure, mechanism and regulation of peroxiredoxins". Trends Biochem Sci 28 (1): 32–40. PMID 12517450. These enzymes share the same basic catalytic mechanism, in which a redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a sulfenic acid by the peroxide substrate.Claiborne A, Yeh J, Mallett T, Luba J, Crane E, Charrier V, Parsonage D (1999). "Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation". Biochemistry 38 (47): 15407-16. PMID 10569923. Peroxiredoxins seem to be important in antioxidant metabolism, as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from hemolytic anaemia, while plants use peroxiredoxins to remove hydrogen peroxide generated in chloroplasts.Neumann C, Krause D, Carman C, Das S, Dubey D, Abraham J, Bronson R, Fujiwara Y, Orkin S, Van Etten R (2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature 424 (6948): 561-5. PMID 12891360. Lee T, Kim S, Yu S, Kim S, Park D, Moon H, Dho S, Kwon K, Kwon H, Han Y, Jeong S, Kang S, Shin H, Lee K, Rhee S, Yu D (2003). "Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice". Blood 101 (12): 5033–8. PMID 12586629. Dietz K, Jacob S, Oelze M, Laxa M, Tognetti V, de Miranda S, Baier M, Finkemeier I (2006). "The function of peroxiredoxins in plant organelle redox metabolism". J Exp Bot 57 (8): 1697-709. PMID 16606633.
The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase.Nordberg J, Arner ES (2001). "Reactive oxygen species, antioxidants, and the mammalian thioredoxin system". Free Radic Biol Med 31 (11): 1287-312. PMID 11728801. Proteins related to thioredoxin are present in all sequenced organisms, with plants such as Arabidopsis thaliana having a particularly great diversity of isoforms.Vieira Dos Santos C, Rey P (2006). "Plant thioredoxins are key actors in the oxidative stress response". Trends Plant Sci 11 (7): 329-34. PMID 16782394. The active site of thioredoxin consists of two neighboring cysteines, as part of a highly-conserved CXXC motif, that can cycle between an active dithiol form (reduced) and an oxidized disulfide form. In its active state, thioredoxin acts as an efficient reducing agent, scavenging reactive oxygen species and maintaining other proteins in their reduced state.Arnér E, Holmgren A (2000). "Physiological functions of thioredoxin and thioredoxin reductase". Eur J Biochem 267 (20): 6102–9. PMID 11012661. After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.Mustacich D, Powis G (2000). "Thioredoxin reductase". Biochem J 346 Pt 1: 1–8. PMID 10657232.
The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases. This system is found in animals, plants and microorganisms.Creissen G, Broadbent P, Stevens R, Wellburn A, Mullineaux P (1996
