Capillary electrophoresis study on the dimeric SOD enzyme in the presence of ascorbic acid.

A Notable decrease of the peak intensity of the capillary electrophoregram due to the dimeric SOD molecule was observed when a solution containing copper(II) chloride and ascorbic acid was added to the SOD solution, indicating that the capillary electrophoresis method is useful to detect the dissociation of the dimeric SOD molecule in solution, and that dissociation of the dimeric SOD molecule is induced by the presence of hydrogen peroxide. The present results may give reasonable countermeasures towards the sporadic amyotrophic lateral sclerosis in future.

Facile uptake of manganese(III) by apotransferrin: possible origin of manganism.

We have investigated the mechanism of manganese ion uptake by apo-transferrin using a capillary electrophoresis method, and obtained clear evidence that oxidation state +3 and the binuclear unit of a manganese chelate are essential factors for the facile uptake by apotransferrin, similar to that observed for Fe(III) chelates. These results may give valuable information to understand the pathogenesis of manganism and to develop new countermeasures for the neurotoxicity by manganese ions.

Origin of renal proximal tubular injuries by Fe(III)-nta chelate.

Interaction between apo-transferrin and several iron(III) chelates has been investigated in terms of the capillary electrophoresis method. Based on the results, it has been clarified that (i) a binuclear iron(III) unit with an oxo-bridge is necessary for the facile transfer of an iron atom from the iron(III) chelate to apo-transferrin, and (ii) the renal proximal tubular injuries by Fe(III)-nitrilotriacetate (Fe-nta) should be due to the unique binuclear structure of this complex, which gives a peroxide adduct of the binuclear Fe-nta in the presence of glutathione cycle and oxygen.

Detection of structural change of superoxide dismutase in solution.

We have confirmed that dissociation of the dimeric SOD molecule into a monomeric one can be readily detected in solution by the use of capillary electrophoresis (CE), which is based on the fact that the peak height in the CE profile is highly dependent on the aggregation conditions of the protein molecule. Based on this fact, it has become apparent that the hydrogen peroxide molecule induces the dissociation of the dimeric structure of SOD, and this should give reasonable explanation for the inactivation of SOD by hydrogen peroxide. Our results may give a convenient way for the early detection of the amyotrophic lateral sclerosis in patients, because we can estimate whether the SOD molecule is of a rigid or loosed dimeric structure by the use of this technique. The loosed one has been assumed to exhibit inherent toxicity of the copper center, so-called "gain-of-function" of the mutant SOD.

Oxidative renal tubular injuries induced by aminocarboxylate-type iron (III) coordination compounds as candidate renal carcinogens.

Oxidative renal tubular injuries and carcinogenesis induced by Fe(III)-nitrilotriacetate (NTA) and Fe(III)-ethylenediamine-N,N'-diacetate (EDDA) have been reported in rodent kidneys, but the identity of iron coordination structure essential for renal carcinogenesis, remains to be clarified. We compared renal tubular injuries caused by various low molecular weight aminocarboxylate type chelators with injuries due to NTA and EDDA. We found that Fe(III)-iminodiacetate (IDA), a novel iron-chelator, induced acute tubular injuries and lipid peroxidation to the same extent. We also prepared Fe(III)-IDA solutions at different pHs, and studied resultant oxidative injuries and physicochemical properties. The use of Fe(III)-IDA at pH 5.2, 6.2, and 7.2 resulted in renal tubular necrosis and apoptotic cell death, but neither tubular necrosis nor apoptosis was observed at pH 8.2. Spectrophotometric data suggested that Fe(III)-IDA had the same dimer structure from pH 6.2 to 7.2 as Fe(III)-NTA; but at a higher pH, iron polymerized and formed clusters. Fe(III)-IDA was crystallized, and this was confirmed by X-ray analysis and magnetic susceptibility measurements. These data indicated that Fe(III)-IDA possessed a linear mu-oxo bridged dinuclear iron (III) around neutral pH.

Structure of a new tetranuclear iron(III) complex with an oxo-bridge; factors to govern formation and stability of oxo-bridged iron(III) species in the L-subunit of ferritin.

We have investigated the reaction products of several iron(III) compounds with hydrogen peroxide, and have found that hydrogen peroxide promotes the formation of an oxo-bridged iron(III) species in the presence of methanol (electron donor), and carboxyl groups of the ligand systems play a role to give the tetranuclear iron(III) compound containing a bent Fe-O-Fe unit (O: oxo oxygen atom). Based on the present results and the facts that L-chains of human ferritins lack ferroxidase activity, but are richer in carboxyl groups (glutamates) exposed on the cavity surface, it seems reasonable to conclude that (i) the hydrogen peroxide released in the H-subunit may contribute to the formation of a diferric oxo-hydrate in the L-subunit, (ii) the formation of a bent oxo-bridged iron(III) species is essentially important in the L-subunit, and (iii) rich carboxyl groups in L-subunits contribute to facilitate iron nucleation and mineralization through the capture and activation of the peroxide ion, and formation of a stable bent oxo-bridged iron(III) species.

Elucidation of endemic neurodegenerative diseases--a commentary.

Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al(III) and Mn(II) ions soluble in the subterranean aquifers.

Four copper(II) complexes with potentially tetradentate tripodal ligands.

The four title Cu(II) compounds are chloro[(2-furylmethyl)bis(2-pyridylmethyl)amine-N,N',N"]copper(II) perchlorate, [CuCl(C(17)H(17)N(3)O)]ClO(4), (I), chloro{2-[bis(2-pyridylmethyl)amino]ethanolato-N,N',N",O}copper(II) hemi[tetrachlorocopper(II)], [CuCl(C(14)H(17)N(3)O)][CuCl(4)](1/2), (II), chloro[(2-morpholinoethyl)bis(2-pyridylmethyl)amine-N,N',N",N"']copper(II) perchlorate, [CuCl(C(18)H(24)N(4)O)]ClO(4), (III), and chloro[(2-piperidinylethyl)bis(2-pyridylmethyl)amine-N,N',N",N"']copper(II) hexafluorophosphate, [CuCl(C(19)H(26)N(4))]PF(6), (IV). They have tripodal potentially tetradentate ligands. In (I), the O atom of the furan moiety weakly coordinates to the Cu atom at a distance of 2.750 (3) A.

micro-Acetato-O:O'-bis{[bis(salicylidene)ethylenediaminato]manganese(III)} perchlorate.

In the title complex, [Mn(2)(C(16)H(14)N(2)O(2))(2)(C(2)H(3)O(2))]ClO(4), two [Mn(salen)] moieties [salen is bis(salicylidene)ethylenediamine] are connected through a micro-acetate bridge in a syn-anti fashion. The Mn.Mn distance is 5.365 (1) A.

micro-Chloro-bis{[benzylbis(2-pyridylmethyl)amine-kappa(3)N]chlorocopper(II)} perchlorate hemihydrate.

In the title dinuclear Cu(II) compound, [Cu(2)Cl(3)(C(19)H(19)N(3))(3)]ClO(4).0.5H(2)O, the coordination geometry around the Cu atoms is square pyramidal, with the bridging Cl atom at the apical positions. The Cu-Cl-Cu angle is 136.9 (1) degrees and the Cu.Cu distance is 4.961 (1) A.

Redetermination of bis{[(2-hydroxyphenylmethyl)bis(2-pyridylmethyl)aminato]copper(II)} diperchlorate.

The structure of the title compound, [Cu(2)(C(19)H(18)N(3)O)(2)](ClO(4))(2), was reported with insufficient accuracy because of a twinning problem by Adams, Bailey, Campbell, Fenton & He [J. Chem. Soc. Dalton Trans. (1996), pp. 2233-2237]. The dinuclear phenolate-bridged Cu(II) complex has an inversion centre.

Iron(III) Complexes with Hydrogen Peroxide which Can Discriminate Two Reaction Types; Oxidation (H-Atom Abstraction) and Oxygenation Reaction.

Iron(III)-NTA (nitrilotriacetic acid) solution shows high activity for oxidative degradation of 2'-deoxyribose in the presence of hydrogen peroxide, whereas its activity of Fe(III)-TFDA (2-aminomethyltetrahydrofuran-N,N-diacetic acid) is negligible under the same experimental conditions; however the latter solution exhibits abnormally higher reactivity for oxygenation reaction at 8-position of 2'-deoxyguanosine than other iron(III) chelates examined. These results suggest that oxidative degradation of deoxyribose and the oxygenation of deoxyguanosine are caused by a different iron(III)-peroxide species.