Manganese superoxide dismutase mechanism

Quint P et al (2006) Crystal structure of nitrated human manganese superoxide dismutase mechanism of inactivation. Free Radio Biol Med 40 453-458 PDBID 2ADQ... 

Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 1996 93(19) 10417-22. 

Hence, (ClgTPP)Fell (ClgTPP)Mnll facilitate the disproportionation of O2 -, which is equivalent to the function of the iron and manganese superoxide dismutase proteins. Whether the mechanism of Eq. (7-28) is relevant to those for the proteins is unknown, but the absence of electron transfer from their metal centers to O2 - is a reasonable expectation (as is radical-radical coupling of 02"-and the protein in the primary step of the disproportionation mechanism). 

The reactions of TTHA (Mn -triethylenetetraminehexaacetate) complexes with H02-02 radicals were studied (pH 2.5-9.S), and a mechanism was suggested that involves the formation of a transient Mn tthaH( 02 f complex. At low pH, this complex is protonated, with the release of H2O2. At higher pH, the dismutation of 02 from the equilibrium complex (Mn TTHA(02 f Mn TTHA + Os") is competitive with protonation. At low pH, the results indicate that there is a rapid first-order process that may be an isomerization from end-bound to side-bound of the attached superoxide radical. In contrast, the kinetics of the dismutation of superoxide radical by Escherichia coh MnSOD (manganese superoxide dismutase) were measured and shown to fit a mechanism involving the rapid reduction of Mn SOD by superoxide followed by both the direct reoxidation of Mn SOD by superoxide and the formation of a Mn SOD(02 ) complex. The differences in the mechanisms are discussed. 

The mechanisms by which manganese complexes and manganese superoxide dismutase react with superoxide radicals are of interest as knowledge of the kinetic parameters and the reaction pathways may allow the synthesis of model compounds with specific chemical features. These compounds may then have clinical application or may allow the control of specific redox chemistry in catalytic processes. 

Knockout mice lacking the gene encoding the mitochondrial manganese superoxide dismutase develop metabolic acidosis and die a few days after birth of severe heart failure due to dilated cardiomyopathy (Li etal. 1995). Several lines of evidence demonstrate a decline of mitochobdrial enzyme activities with age, particularly complex I (Trounce etal. 1989). Lack of an efficient repair mechanism and absence of histones make mtDNA more susceptible to the toxic effects of free radicals. Accumulation of mtDNA mutations are proposed to cause progressive impairment of mitochondrial respiration. Deletion of mtDNA accumulate with age in the human heart (Hattori et al. 1991). 

TNF-a elicits a wide range of responses in cells and tissues. Apart from causing the lysis of certain tumours (by mechanisms probably related to the ability of the target to induce the synthesis of the mitochondrial manganese-dependent superoxide dismutase, Mn-SOD), it can also kill normal cells. These effects on normal cells are more apparent when biosynthesis is blocked - for example, by the addition of inhibitors of macromolecular bio-... 

Pick M, Rabani J, Yost F, Fridovich I (1974) The catalytic mechanism of the manganese-containing superoxide dismutase of Escherichia coli studied by pulse radiolysis. J Am Chem Soc 96 7329-7333... 

Manganese compounds of biologic importance are examined by pulse radiolysis e.g., the rate of dismutation of radiation-generated Of is catalyzed by Escherichia coli, Mn-containing superoxide dismutase involving electron transfer in which enzymes with Mn(IV), Mn(IIl), Mn(II) and Mn(I) oxidation states are involved. A kinetic model for the reaction mechanism of an Mn dismutase from Bacillus stearothermophilus accounts for the variation of the rate of decay on the concentrations of Oj, enzyme, HjOj, NaNj, KCN and H+. 

Biochemically, manganese is considered an essential trace element, participating in a number of hiomolecules superoxide dismutase (Mn-SOD), catalase, Mn-ribonucleotide reductase, Mn-peroxidase, ligninase, the o>ygen-evolving centre (OEC) of photosystem ii (PS-ii), and Mn-thiosulfate oxidase. The enzymes mechanisms are very diverse and include oxo-atom transfer (four-electron oxidation of water to diojygen in PS-ii, extradiol dioxygenase), electron transfer (SOD, catalase), reduction of ribonucleotides to water and deoxyribonucleotides and oxidation of thiosulfate to sulfate. ... 

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