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Superoxide dismutase
SOD.gif
Structure of the monomeric unit of human superoxide dismutase 2.
Identifiers
EC number 1.15.1.1
CAS number 9054-89-1
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures
Gene Ontology AmiGO / EGO

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.

Contents

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.

Types

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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.[3]
  • 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).[4]
  • nickel – prokaryotic. A hexameric structure built from right-handed 4-helix bundles, each containing N-terminal hooks that chelate a Ni ion. The Ni-hook contains the motif His-Cys-X-X-Pro-Cys-Gly-X-Tyr, it provides most of the interactions critical for metal binding and catalysis and is therefore a likely diagnostic of NiSODs.[5] [6]
Copper/zinc superoxide dismutase
Identifiers
Symbol Sod_Cu
Pfam PF00080
InterPro IPR001424
PROSITE PDOC00082
SCOP 1sdy
Iron/manganese superoxide dismutases, alpha-hairpin domain
Identifiers
Symbol Sod_Fe_N
Pfam PF00081
InterPro IPR001189
PROSITE PDOC00083
SCOP 1abm
Iron/manganese superoxide dismutases, C-terminal domain
Identifiers
Symbol Sod_Fe_C
Pfam PF02777
InterPro IPR001189
PROSITE PDOC00083
SCOP 1abm
Nickel-containing superoxide dismutase
Identifiers
Symbol Sod_Ni
Pfam PF09055
InterPro IPR014123

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.[7][8]

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).

SOD1, soluble
HSOD1 2VR6.png
Crystallographic structure of the human SOD1 enzyme (rainbow colored N-terminus = blue, C-terminus = red) complexed with copper (blue-green sphere) and zinc (grey spheres).[9]
Identifiers
Symbol SOD1
Alt. symbols ALS, ALS1
Entrez 6647
HUGO 11179
OMIM 147450
RefSeq NM_000454
UniProt P00441
Other data
EC number 1.15.1.1
Locus Chr. 21 q22.1
SOD2, mitochondrial
SODsite.gif
Structure of the active site of human superoxide dismutase 2.
Identifiers
Symbol SOD2
Alt. symbols Mn-SOD; IPO-B; MVCD6
Entrez 6648
HUGO 11180
OMIM 147460
RefSeq NM_000636
UniProt P04179
Other data
EC number 1.15.1.1
Locus Chr. 6 q25
SOD3, extracellular
Identifiers
Symbol SOD3
Alt. symbols EC-SOD; MGC20077
Entrez 6649
HUGO 11181
OMIM 185490
RefSeq NM_003102
UniProt P08294
Other data
EC number 1.15.1.1
Locus Chr. 4 pter-q21

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) or a metal. The superoxide anion radical (O2) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 M−1s−1 at pH 7). SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts the NO radical, and makes toxic peroxynitrite. 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 largest kcat (reaction rate with its substrate) of any known enzyme (~7 x 109 M−1s−1),[10] this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited". Even at the subnanomolar concentrations achieved by the high concentrations of SOD within cells, superoxide inactivates the citric acid cycle enzyme aconitase, can poison energy metabolism and releases potentially toxic iron. Aconitase is one of several iron-sulfur containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.[11]

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.[12] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,[13] an acceleration of age-related muscle mass loss,[14] 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.[15] 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.

Role in disease

Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease).[16][17][18] The most common mutation in the U.S. is A4V while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality[12] and inactivation of SOD1 causes hepatocellular carcinoma.[13] 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.[19]

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.[20]

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.[21] Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.[22]

References

  1. ^ McCord JM, Fridovich I (1988). "Superoxide dismutase: the first twenty years (1968-1988)". Free Radic. Biol. Med. 5 (5-6): 363–9. doi:10.1016/0891-5849(88)90109-8. PMID 2855736. 
  2. ^ Brewer GJ (September 1967). "Achromatic regions of tetrazolium stained starch gels: inherited electrophoretic variation". Am. J. Hum. Genet. 19 (5): 674–80. PMID 4292999. 
  3. ^ Tainer JA, Getzoff ED, Richardson JS, Richardson DC (1983). "Structure and mechanism of copper, zinc superoxide dismutase.". Nature (5940): 284–7. doi:10.1038/306284a0. PMID 6316150. .
  4. ^ Borgstahl GE, Parge HE, Hickey MJ, Beyer WF Jr, Hallewell RA, Tainer JA (1992). "The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles.". Cell 71 (1): 107–18. doi:doi:10.1016/0092-8674(92)90270-M. PMID 1394426. 
  5. ^ Barondeau DP, Kassmann CJ, Bruns CK, Tainer JA, Getzoff ED (2004). "Nickel superoxide dismutase structure and mechanism". Biochemistry (25): 8038–47. doi:10.1021/bi0496081. PMID 15209499. 
  6. ^ Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K (2004). "Crystal structure of nickel-containing superoxide dismutase reveals another type of active site.". Proc Natl Acad Sci (23): 8569–74. doi:10.1073/pnas.0308514101. PMID 15173586. 
  7. ^ 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:10.1016/S1360-1385(01)01898-2. PMID 11286918. http://linkinghub.elsevier.com/retrieve/pii/S1360-1385(01)01898-2. 
  8. ^ 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:10.1093/pcp/pcj071. PMID 16766574. 
  9. ^ 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:10.1074/jbc.M801522200. 
  10. ^ Heinrich, Peter; Georg Löffler; Petro E. Petrides (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition). Berlin: Springer. pp. 123. ISBN 3-540-32680-4. 
  11. ^ Gardner PR, Raineri I, Epstein LB, White CW (June 1995). "Superoxide radical and iron modulate aconitase activity in mammalian cells". J. Biol. Chem. 270 (22): 13399–405. PMID 7768942. 
  12. ^ 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:10.1038/ng1295-376. PMID 7493016. 
  13. ^ 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:10.1038/sj.onc.1208207. PMID 15531919. 
  14. ^ 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:10.1016/j.freeradbiomed.2006.01.036. PMID 16716900. 
  15. ^ 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:10.1074/jbc.M510764200. PMID 16377630. 
  16. ^ Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP, et al. (August 1993). "Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase". Science. 261 (5124): 1047–51. doi:DOI: 10.1126/science.8351519. PMID 8351519. 
  17. ^ 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:10.1016/j.jns.2006.07.009. PMID 17070848. 
  18. ^ Al-Chalabi A, Leigh PN (August 2000). "Recent advances in amyotrophic lateral sclerosis". Curr. Opin. Neurol. 13 (4): 397–405. doi:10.1097/00019052-200008000-00006. PMID 10970056. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1350-7540&volume=13&issue=4&spage=397. 
  19. ^ 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:10.1016/0753-3322(94)90138-4. PMID 7999984. 
  20. ^ 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:10.1189/jlb.0304196. PMID 15197232. 
  21. ^ 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:10.1111/j.1582-4934.2004.tb00265.x. PMID 15090266. 
  22. ^ 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:10.1016/S0891-5849(00)00431-7. PMID 11134893. 

See also

External links


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