Superoxide dismutase
From Wikipedia, the free encyclopedia
Superoxide dismutases (SOD, EC 1.15.1.1) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. One of the exceedingly rare exceptions is Lactobacillus plantarum and related lactobacilli, which use a different mechanism.
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[edit] Reaction
The SOD-catalysed dismutation of superoxide may be written with the following half-reactions :
- M(n+1)+ − SOD + O2− → Mn+ − SOD + O2
- Mn+ − SOD + O2− + 2H+ → M(n+1)+ − SOD + H2O2.
where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2).
In this reaction the oxidation state of the metal cation oscillates between n and n+1.
[edit] Types
[edit] General
Discovered by Irwin Fridovich and Joe McCord, SOD enzymes were previously thought to be several metalloproteins with unknown function (for example, CuZnSOD was known as erythrocuprein).[1] Several common forms of SOD exist: they are proteins cofactored with copper and zinc, or manganese, iron, or nickel. For example, Brewer (1967) identified a protein which became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique.[2]
There are three major families of superoxide dismutase, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and finally the Ni type which binds nickel.
- Copper and zinc – most commonly used by eukaryotes. The cytosols of virtually all eukaryotic cells contain an SOD enzyme with copper and zinc (Cu-Zn-SOD). (For example, Cu-Zn-SOD available commercially is normally purified from the bovine erythrocytes: The Cu-Zn enzyme is a homodimer of molecular weight 32,500. The two subunits are joined primarily by hydrophobic and electrostatic interactions. The ligands of copper and zinc are histidine side chains.
- Iron or manganese – used by prokaryotes and protists
- Iron – E. coli and many other bacteria also contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some contain both. (For the E. coli Fe-SOD: . Fe-SOD can be found in the plastids of plants. The active sites of Mn and Fe superoxide dismutases contain the same type of amino acid side chains.
- Manganese – Chicken liver (and nearly all other) mitochondria, and many bacteria (such as E. coli) contain a form with manganese (Mn-SOD). (For example, the Mn-SOD found in a human mitochondrion: The ligands of the manganese ions are 3 histidine side chains, an aspartate side chain and a water molecule or hydroxy ligand depending on the Mn oxidation state (respectively II and III).
- nickel – prokaryote
In higher plants, SOD isozymes have been localized in different cell compartments. Mn-SOD is present in mitochondria and peroxisomes. Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized in cytosol, chloroplasts, peroxisomes and apoplast.[3][4]
[edit] Human
In humans (as in all other mammals and most chordates), three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria and SOD3 is extracellular. The first is a dimer (consists of two units), while the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, while SOD2 has manganese in its reactive centre. The genes are located on chromosomes 21, 6 and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
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[edit] Biochemistry
Simply stated, SOD outcompetes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity. The reaction of superoxide with non-radicals is spin forbidden. In biological systems, this means its main reactions are with itself (dismutation) or with another biological radical such as nitric oxide (NO). The superoxide anion radical (O2-) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 M-1 s-1 at pH 7). SOD is biologically necessary because superoxide reacts even faster with certain targets such as NO radical, which makes peroxynitrite. Similarly, the dismutation rate is second order with respect to initial superoxide concentration. Thus, the half-life of superoxide, although very short at high concentrations (e.g. 0.05 seconds at 0.1mM) is actually quite long at low concentrations (e.g. 14 hours at 0.1 nM). In contrast, the reaction of superoxide with SOD is first order with respect to superoxide concentration. Moreover, superoxide dismutase has the fastest turnover number (reaction rate with its substrate) of any known enzyme (~7 x 109 M-1 s-1),[6] this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited".
[edit] Physiology
Superoxide is one of the main reactive oxygen species in the cell and as such, SOD serves a key antioxidant role. The physiological importance of SODs is illustrated by the severe pathologies evident in mice genetically engineered to lack these enzymes. Mice lacking SOD2 die several days after birth, amidst massive oxidative stress.[7] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,[8] an acceleration of age-related muscle mass loss,[9] an earlier incidence of cataracts and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan, though they are more sensitive to hyperoxic injury.[10] Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide generating drugs, such as paraquat and diquat.
Drosophila lacking SOD1 have a dramatically shortened lifespan while flies lacking SOD2 die before birth. SOD knockdowns in C. elegans do not cause major physiological disruptions. Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the yeast Sacchormyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.
Several prokaryotic SOD null mutants have been generated, including E. Coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics.
[edit] Role in disease
Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease).[11][12] The most common mutation in the U.S. is A4V while the most intensely studied is G93A. The other two types have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality[7] and inactivation of SOD1 causes hepatocellular carcinoma.[8] Mutations in SOD1 can cause familial ALS, by a mechanism that is presently not understood, but not due to loss of enzymatic activity or a decrease in the conformational stability of the SOD1 protein. Overexpression of SOD1 has been linked to Down's syndrome.[13]
SOD has proved to be highly effective in treatment of colonic inflammation in experimental colitis. Treatment with SOD decreases reactive oxygen species generation and oxidative stress and thus, inhibits endothelial activation and indicate that modulation of factors that govern adhesion molecule expression and leukocyte-endothelial interactions, such as antioxidants, may be important, new tools for the treatment of inflammatory bowel disease.[14]
[edit] Cosmetic uses
SOD is used in cosmetic products to reduce free radical damage to skin, for example to reduce fibrosis following radiation for breast cancer. Studies of this kind must be regarded as tentative however, as there were not adequate controls in the study including a lack of randomization, double-blinding or placebo.[15] Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.[16]
[edit] References
- ^ McCord JM, Fridovich I (1988). "Superoxide dismutase: the first twenty years (1968-1988)". Free Radic. Biol. Med. 5 (5-6): 363–9. doi:. PMID 2855736.
- ^ Brewer GJ (September 1967). "Achromatic regions of tetrazolium stained starch gels: inherited electrophoretic variation". Am. J. Hum. Genet. 19 (5): 674–80. PMID 4292999.
- ^ Corpas FJ, Barroso JB, del Río LA (April 2001). "Peroxisomes as a source of reactive oxygen species and nitric oxide signal molecules in plant cells". Trends Plant Sci. 6 (4): 145–50. doi:. PMID 11286918. http://linkinghub.elsevier.com/retrieve/pii/S1360-1385(01)01898-2.
- ^ Corpas FJ, Fernández-Ocaña A, Carreras A, Valderrama R, Luque F, Esteban FJ, Rodríguez-Serrano M, Chaki M, Pedrajas JR, Sandalio LM, del Río LA, Barroso JB (July 2006). "The expression of different superoxide dismutase forms is cell-type dependent in olive (Olea europaea L.) leaves". Plant Cell Physiol. 47 (7): 984–94. doi:. PMID 16766574.
- ^ Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP, Strange RW, Doucette PA, Valentine JS, Tiwari A, Hayward LJ, Padua S, Cohlberg JA, Hasnain SS, Hart PJ (June 2008). "Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis". J. Biol. Chem. 283 (23): 16169–77. doi:.
- ^ Heinrich, Peter; Georg Löffler; Petro E. Petrides (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition). Berlin: Springer. pp. 123. ISBN 3-540-32680-4.
- ^ a b Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ (December 1995). "Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase". Nat. Genet. 11 (4): 376–81. doi:. PMID 7493016.
- ^ a b Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT (January 2005). "CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life". Oncogene 24 (3): 367–80. doi:. PMID 15531919.
- ^ Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ, Csete M, Faulkner JA, Van Remmen H (June 2006). "Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy". Free Radic. Biol. Med. 40 (11): 1993–2004. doi:. PMID 16716900.
- ^ Sentman ML, Granström M, Jakobson H, Reaume A, Basu S, Marklund SL (March 2006). "Phenotypes of mice lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase". J. Biol. Chem. 281 (11): 6904–9. doi:. PMID 16377630.
- ^ Conwit RA (December 2006). "Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted?". J. Neurol. Sci. 251 (1-2): 1–2. doi:. PMID 17070848.
- ^ Al-Chalabi A, Leigh PN (August 2000). "Recent advances in amyotrophic lateral sclerosis". Curr. Opin. Neurol. 13 (4): 397–405. doi:. PMID 10970056. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1350-7540&volume=13&issue=4&spage=397.
- ^ Groner Y, Elroy-Stein O, Avraham KB, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, Yarom R, Rotshenker S (1994). "Cell damage by excess CuZnSOD and Down's syndrome". Biomed. Pharmacother. 48 (5-6): 231–40. doi:. PMID 7999984.
- ^ Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J (September 2004). "Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine". J. Leukoc. Biol. 76 (3): 537–44. doi:. PMID 15197232.
- ^ Campana F, Zervoudis S, Perdereau B, Gez E, Fourquet A, Badiu C, Tsakiris G, Koulaloglou S (2004). "Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis". J. Cell. Mol. Med. 8 (1): 109–16. doi:. PMID 15090266.
- ^ Vozenin-Brotons MC, Sivan V, Gault N, Renard C, Geffrotin C, Delanian S, Lefaix JL, Martin M (January 2001). "Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts". Free Radic. Biol. Med. 30 (1): 30–42. doi:. PMID 11134893.
[edit] See also
[edit] External links
- Online 'Mendelian Inheritance in Man' (OMIM) 105400 (ALS)
- The ALS Online Database
- A short but substantive overview of SOD and its literature.
- Damage-Based Theories of Aging Includes a discussion of the roles of SOD1 and SOD2 in aging.
- Physicians' Comm. For Responsible Med.
- SOD and Oxidative Stress Pathway Image
- Historical information on SOD research"The evolution of Free Radical Biology & Medicine: A 20-year history" and "Free Radical Biology & Medicine The last 20 years: The most highly cited papers"
- JM McCord discusses the discovery of SOD
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