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ABSTRACT: Contrary to earlier claims, the Cu(II) complex with the soluble Aβ16 peptide, and also that with Aβ28 exhibit no phenol monooxygenase (tyrosinase-like) activity; the complexes neither exhibit superoxide dismutase activity.
Chemical Communications 04/2013; · 6.17 Impact Factor
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ABSTRACT: The aggregation of α-synuclein (αS) is a critical step in the etiology of Parkinson's disease. Metal ions such as copper and iron have been shown to bind αS, enhancing its fibrillation rate in vitro. αS is also susceptible to copper-catalyzed oxidation that involves the reduction of Cu(II) to Cu(I) and the conversion of O(2) into reactive oxygen species. The mechanism of the reaction is highly selective and site-specific and involves interactions of the protein with both oxidation states of the copper ion. The reaction can induce oxidative modification of the protein, which generally leads to extensive protein oligomerization and precipitation. Cu(II) binding to αS has been extensively characterized, indicating the N terminus and His-50 as binding donor residues. In this study, we have investigated αS-Cu(I) interaction by means of NMR and circular dichroism analysis on the full-length protein (αS(1-140)) and on two, designed ad hoc, model peptides: αS(1-15) and αS(113-130). In order to identify and characterize the metal binding environment in full-length αS, in addition to Cu(I), we have also used Ag(I) as a probe for Cu(I) binding. Two distinct Cu(I)/Ag(I) binding domains with comparable affinities have been identified. The structural rearrangements induced by the metal ions and the metal coordination spheres of both sites have been extensively characterized.
Inorganic Chemistry 01/2013; · 4.60 Impact Factor
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Roberta Besio,
Roberta Gioia,
Federica Cossu, Enrico Monzani,
Stefania Nicolis,
Lucia Cucca,
Antonella Profumo,
Luigi Casella,
Ruggero Tenni,
Martino Bolognesi,
Antonio Rossi,
Antonella Forlino
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ABSTRACT: Prolidase is the only human enzyme responsible for the digestion of iminodipeptides containing proline or hydroxyproline at their C-terminal end, being a key player in extracellular matrix remodeling. Prolidase deficiency (PD) is an intractable loss of function disease, characterized by mutations in the prolidase gene. The exact causes of activity impairment in mutant prolidase are still unknown. We generated three recombinant prolidase forms, hRecProl-231delY, hRecProl-E412K and hRecProl-G448R, reproducing three mutations identified in homozygous PD patients. The enzymes showed very low catalytic efficiency, thermal instability and changes in protein conformation. No variation of Mn(II) cofactor affinity was detected for hRecProl-E412K; a compromised ability to bind the cofactor was found in hRecProl-231delY and Mn(II) was totally absent in hRecProl-G448R. Furthermore, local structure perturbations for all three mutants were predicted by in silico analysis. Our biochemical investigation of the three causative alleles identified in perturbed folding/instability, and in consequent partial prolidase degradation, the main reasons for enzyme inactivity. Based on the above considerations we were able to rescue part of the prolidase activity in patients' fibroblasts through the induction of Heath Shock Proteins expression, hinting at new promising avenues for PD treatment.
PLoS ONE 01/2013; 8(3):e58792. · 4.09 Impact Factor
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ABSTRACT: Elucidating the structure and biosynthesis of neuromelanin (NM) would be an important step towards understanding its putative role in the pathogenesis of Parkinson's disease. A useful complement to studies aimed at unraveling the origin and properties of this essentially insoluble natural substance is the preparation of synthetic derivatives that resemble NM. With this aim in mind, water-soluble conjugates between dopamine-derived melanin and bovine serum albumin (BSA) were synthesized. Melanin-BSA adducts were prepared with both eumelanic oligomers obtained through the oxidative polymerization of dopamine and pheomelanic oligomers obtained under the same conditions from dopamine and cysteine. Iron ions were added during the synthesis to understand the interaction between the pigment and this metal ion, as the NM in neurons in several human brain regions contains significant amounts of iron. The structures of the conjugates were analyzed by (1)H NMR spectroscopy and controlled proteolysis/MS experiments. The binding of iron(III) ions was evaluated by ICP analysis and EPR spectroscopy. The EPR signal from bound iron(III) indicated high-spin octahedral sites and, as also seen for NM, the signal is coupled to a signal from a radical associated with the melanic components of the conjugates. However, the intensity of the EPR signal from iron suggested a reduced fraction of the total iron, indicating that most of the iron is strongly coupled in clusters within the matrix. The amount of paramagnetic, mononuclear iron(III) was greater in the pheomelanin-BSA conjugates, suggesting that iron clustering is reduced in the sulfur-containing pigment. Thus, the melanin-BSA conjugates appear to be good models for the natural pigment.
European Journal of Biochemistry 10/2012; · 3.42 Impact Factor
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ABSTRACT: The final step of bacterial denitrification, the two-electron reduction of N2O to N2, is catalyzed by a multi-copper enzyme named nitrous oxide reductase. The catalytic centre of this enzyme is a tetranuclear
copper site called CuZ, unique in biological systems. The in vitro reconstruction of the activity requires a slow activation
in the presence of the artificial electron donor, reduced methyl viologen, necessary to reduce CuZ from the resting non-active
state (1CuII/3CuI) to the fully reduced state (4CuI), in contrast to the turnover cycle, which is very fast. In the present work, the direct reaction of the activated form of
Pseudomonas nautica nitrous oxide reductase with stoichiometric amounts of N2O allowed the identification of a new reactive intermediate of the catalytic centre, CuZ°, in the turnover cycle, characterized
by an intense absorption band at 680nm. Moreover, the first mediated electrochemical study of Ps. nautica nitrous oxide reductase with its physiological electron donor, cytochrome c-552, was performed. The intermolecular electron transfer was analysed by cyclic voltammetry, under catalytic conditions,
and a second-order rate constant of (5.5±0.9)×105M−1s−1 was determined. Both the reaction of stoichiometric amounts of substrate and the electrochemical studies show that the active
CuZ° species, generated in the absence of reductants, can rearrange to the resting non-active CuZ state. In this light, new
aspects of the catalytic and activation/inactivation mechanism of the enzyme are discussed.
KeywordsNitrous oxide reductase-Catalytic mechanism-Denitrification-Bioelectrochemistry
JBIC Journal of Biological Inorganic Chemistry 04/2012; 15(6):967-976. · 3.29 Impact Factor
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ABSTRACT: Neuromelanins (NMs) are neuronal pigments of melanic-lipidic type which accumulate during aging. They are involved in protective and degenerative mechanisms depending on the cellular context, however their structures are still poorly understood. NMs from nine human brain areas were analyzed in detail. Elemental analysis led to identification of three types of NM, while infrared spectroscopy showed that NMs from neurons of substantia nigra and locus coeruleus, which selectively degenerate in Parkinson's disease, have similar structure but different from NMs from brain regions not targeted by the disease. Synthetic melanins containing Fe and bovine serum albumin were prepared to model the natural product and help clarifying the structure of NMs. Extensive nuclear magnetic resonance spectroscopy studies showed the presence of dolichols both in the soluble and insoluble parts of NM. Diffusion measurements demonstrated that the dimethyl sulfoxide soluble components consist of oligomeric precursors with MWs in the range 1.4-52 kDa, while the insoluble part contains polymers of larger size but with a similar composition. These data suggest that the selective vulnerability of neurons of substantia nigra and locus coeruleus in Parkinson's disease might depend on the structure of the pigment. Moreover, they allow to propose a pathway for NM biosynthesis in human brain.
PLoS ONE 01/2012; 7(11):e48490. · 4.09 Impact Factor
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ABSTRACT: The influence of the positively charged N-methylpyridinium substituent on the anion binding tendencies of urea-based receptors has been investigated by comparing molecules 1 and 2. These receptors have been studied in acetonitrile, by performing UV-vis. and (1)H NMR titrations with several anions. UV-vis. titrations have also been performed in DMSO, MeOH and CHCl(3)/CH(3)CN mixture (1/1, v/v). In the case of 1, the presence of both H-donor and H-acceptor groups (urea and pyridine, respectively) favours aggregation and the formation of dimers in the solid state. In solution, this tendency to aggregate reduces affinity for anions with respect to the similar urea-based receptor 3. The methylation of the pyridyl group of 1 leads to the pyridinium-containing receptor 2. The pyridinium positive charge enhances the acidity of urea and increases anion affinity, as evidenced by the comparison of the binding constants. Both receptors (1-2) form stable adducts with all investigated anions. However, in the case of 2, the formation of 1 : 1 adducts with basic anions, such as acetate and fluoride, is followed by a proton transfer process. Quite interestingly, deprotonation does not involve the urea group, thus preserving the 1 : 1 adduct, as demonstrated by the (1)H NMR measurements. In particular, the proton transfer process takes place at the methylene group linking the pyridinium fragment to the receptor's skeleton. (1)H NMR studies indicate the formation of a stable neutral methine species, characterised by the loss of aromaticity by the pyridyl ring. These results open new perspectives in the field of anion recognition, as receptor 2 may by applied to the monitoring of both bound anion (through the urea unit) and excess anion in solution (through the development of the yellow methine species).
Organic & Biomolecular Chemistry 12/2011; 9(24):8276-83. · 3.70 Impact Factor
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ABSTRACT: Prolidase is a metallo-exopeptidase hydrolyzing X-Pro and X-Hyp dipeptides. Its absence or reduced level is typical in prolidase deficiency (PD) patients, and altered prolidase activity was reported in various diseases. Therefore, standardized and accurate measurement of prolidase activity is essential for PD diagnosis, as well as to elucidate the pathophysiology of other disorders.
Human recombinant prolidase was used to optimize a spectrophotometric enzyme activity assay. Kinetic parameters and Mn(2+) affinity were evaluated. The method was validated on blood and fibroblasts from PD patients.
An activation step consisting in prolidase incubation with 1 mmol/l MnCl(2) and 0.75 mmol/l reduced glutathione at 50°C for 20 min was necessary to obtain the maximum activity and to accurately determine, for the recombinant enzyme, V(max) (489 U/mg), K(m) (5.4 mM) and Mn(2+) affinity (54 mM(-1)). The method applied to PD diagnosis revealed an intra-assay CV=8% for blood and 9% for fibroblasts lysates. The inter-assay CV was 21% for blood and 20% for cell lysates.
We optimized a faster spectrophotometric method to measure the activity when the enzyme is fully activated, this is crucial to allow a reliable evaluation of prolidase activity from different sources.
Clinica chimica acta; international journal of clinical chemistry 06/2011; 412(19-20):1814-20. · 2.54 Impact Factor
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ABSTRACT: A mild copper-mediated halogenation reaction of phenolic rings is reported. The reaction of bis(2-hydroxybenzyl)-1,3-diaminopropane (H2bhbd) with copper(II) chloride in acetonitrile generates linear trinuclear [Cu3(bhcbd)2Cl2](CH3CN), containing modified ligands, whose phenol moieties are selectively chlorinated at the 5-position. Under comparable experimental conditions with copper(II) bromide, bromination of the ligand is observed, albeit at a slower reaction rate. In the presence of trialkylorthoformates, which are used as dehydrating agents, a ring closure of the ligand is observed after removal of copper to yield a product with a six-membered ring. This product has been isolated and characterized by NMR spectroscopy and MS. Similarly, bromination of bis(2-hydroxybenzyl)-1,3-diiminopropane (H2bhbdi) occurs in the presence of copper(II) bromide, with concomitant formation of a linear trinuclear complex. Surprisingly, an asymmetric dinuclear copper(II) coordination compound without chlorination of the ligand is obtained when the related ligand bis(2-hydroxybenzyl)-1,3-diminopropane (H2bhbdi) reacts with copper(II) chloride.
European Journal of Inorganic Chemistry 01/2011; · 3.05 Impact Factor
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ABSTRACT: A novel neutral triple-stranded hexanuclear copper(I) cluster helicate [Cu(I)(6)L(3)]·2CH(3)CN derived from a thiosemicarbazone ligand could be synthesized and crystallographically characterized. The MALDI mass spectrum of this complex suggests that the tetranuclear copper(I) cluster helicate [Cu(I)(4)L(2)] is also present in solution. These copper(I) cluster helicates are capable, in the presence of O(2), of hydroxylating the arene linker of their supporting ligand strands. The resulting dinuclear complex [Cu(II)(2)L'(OH)] is formed by two copper(II) centers, a new ligand arising from the hydroxylation reaction, and one hydroxide group. The magnetic investigation of this compound shows a strong antiferromagnetic coupling between the two Cu(II) centers. The kinetic studies for the hydroxylation process show values of ΔH(≠)=-70 kJ mol(-1), similar to those mediated by the tyrosinase enzymes.
Chemistry 10/2010; 16(47):14175-80. · 5.93 Impact Factor
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Stefano M Marino,
Stefano Fogal,
Marco Bisaglia,
Stefano Moro,
Guido Scartabelli,
Luca De Gioia,
Alessia Spada, Enrico Monzani,
Luigi Casella,
Stefano Mammi,
Luigi Bubacco
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ABSTRACT: Tyrosinase (Ty) is a copper-containing enzyme ubiquitously distributed in nature. In recent years, Ty has attracted interest as a potential detoxifying agent for xenobiotic compounds with phenolic structure. Among these, chlorophenols are particularly relevant pollutants, commonly found in waste waters. The activity of Streptomyces antibioticus tyrosinase toward isomeric monochlorophenols was studied. Tyrosinase oxidizes both 3- and 4-chlorophenol to the same product, 4-chloro-1,2-ortho-quinone, which subsequently undergoes a nucleophilic substitution reaction at the chlorine atom by excess phenol to give the corresponding phenol-quinone adduct. By contrast, 2-chlorophenol is not reactive and acts as a competitive inhibitor. Docking calculations suggest that the substrates point to one of the copper atoms of the dinuclear center (copper B) and appear to interact preferentially with one of the two coordinated oxygen atoms. The approach of the substrate toward the active site is favored by a π-stacking interaction with one of the copper-coordinated histidines (His194) and by a hydrogen bonding interaction with the O1 oxygen. With this study, we provide the first characterization of the early intermediates in the biotechnologically relevant reaction of Ty with chlorophenols. Additionally, combining experimental evidences with molecular modeling simulations, we propose a detailed reaction scheme for Ty-mediated oxidation of monochlorophenols.
Archives of Biochemistry and Biophysics 09/2010; 505(1):67-74. · 2.93 Impact Factor
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ABSTRACT: The final step of bacterial denitrification, the two-electron reduction of N(2)O to N(2), is catalyzed by a multi-copper enzyme named nitrous oxide reductase. The catalytic centre of this enzyme is a tetranuclear copper site called CuZ, unique in biological systems. The in vitro reconstruction of the activity requires a slow activation in the presence of the artificial electron donor, reduced methyl viologen, necessary to reduce CuZ from the resting non-active state (1Cu(II)/3Cu(I)) to the fully reduced state (4Cu(I)), in contrast to the turnover cycle, which is very fast. In the present work, the direct reaction of the activated form of Pseudomonas nautica nitrous oxide reductase with stoichiometric amounts of N(2)O allowed the identification of a new reactive intermediate of the catalytic centre, CuZ degrees , in the turnover cycle, characterized by an intense absorption band at 680 nm. Moreover, the first mediated electrochemical study of Ps. nautica nitrous oxide reductase with its physiological electron donor, cytochrome c-552, was performed. The intermolecular electron transfer was analysed by cyclic voltammetry, under catalytic conditions, and a second-order rate constant of (5.5 +/- 0.9) x 10(5) M(-1 )s(-1) was determined. Both the reaction of stoichiometric amounts of substrate and the electrochemical studies show that the active CuZ degrees species, generated in the absence of reductants, can rearrange to the resting non-active CuZ state. In this light, new aspects of the catalytic and activation/inactivation mechanism of the enzyme are discussed.
European Journal of Biochemistry 08/2010; 15(6):967-76. · 3.42 Impact Factor
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ABSTRACT: Nickel compounds influence carcinogenesis by interfering with a variety of cellular targets. It has been found that nickel is a potent inhibitor in vivo of histone H4 acetylation, in both yeast and mammalian cells. It has preference to specific lysine residues in the H4 N-terminal -S(1)GRGK(5)GGK(8)GLGK(12)GGAK(16)RH(18)RKVL(22) tail, in which the sites of acetylation are clustered. About the nature of the structural changes induced by histone acetylation on H4, it has been recently demonstrated that acetylation induces an increase in alpha-helical conformation of the acetylated N-terminal tail of H4. It causes a shortening of the tail and, such an effect, may have an important structural and functional implication as a mechanism of transcriptional regulation. Here we report a study on the conformational changes induced by carcinogenic nickel compounds on the histone H4 protein. From a circular dichroism study we found that nickel is able to induce a secondary structure in the protein. In particular, nickel has the same effect as acetylation: it induces an increase in alpha-helical conformation of the non-acetylated histone H4. The alpha-helical increase that occurs upon nickel interaction with histone H4 should decrease the ability of histone acetyl transferase to recognize and bind to the histone tail and thus affect the ability of the enzyme to further modify the lysine residues. The shortening of the distance between adjacent amino acids, caused by the translation from an extended to a helical conformation, could disrupt the histone recognition motif; this may eventually compromise the entire "histone code".
Dalton Transactions 01/2010; 39(3):787-93. · 3.84 Impact Factor
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ABSTRACT: The dimetallic cryptate [Cu(2)(II)(1)](4+) selectively recognizes guanosine monophosphate with respect to other nucleoside monophosphates (NMPs) in a MeOH/water solution at pH 7. Recognition is efficiently signaled through the displacement of the indicator 6-carboxyfluorescein bound to the receptor, monitoring its yellow fluorescent emission. Titration experiments evidenced the occurrence of several simultaneous equilibria involving 1:1 and 2:1 receptor/NMP and receptor/indicator complexes. It was demonstrated that the added NMP displaces the indicator from the 2:1 receptor/indicator complex, forming the 1:1 receptor/analyte inclusion complex. Recognition selectivity is thus ascribed to the nature of nucleotide donor atoms involved in the coordination and their ability to encompass the Cu(II)-Cu(II) distance within the cryptate.
Journal of the American Chemical Society 12/2009; 132(1):147-56. · 9.91 Impact Factor
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ABSTRACT: This paper shows for the first time that the spectral features of the ternary complex of tyrosinase/O2/phenol, trapped at low temperature using the very slow substrate 3,5-difluorophenol, are those of a mu-eta2:eta2-peroxidodicopper(II) species, and that this remains the only enzyme species under turnover and substrate saturation conditions.
Dalton Transactions 10/2009; · 3.84 Impact Factor
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Chemistry 10/2009; 15(47):12932-6. · 5.93 Impact Factor
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Luigi Zecca,
Chiara Bellei,
Patrizia Costi,
Alberto Albertini, Enrico Monzani,
Luigi Casella,
Mario Gallorini,
Luigi Bergamaschi,
Alberto Moscatelli,
Nicholas J Turro,
Melvin Eisner,
Pier Raimondo Crippa,
Shosuke Ito,
Kazumasa Wakamatsu,
William D Bush,
Weslyn C Ward,
John D Simon,
Fabio A Zucca
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ABSTRACT: Neuronal pigments of melanic type were identified in the putamen, cortex, cerebellum, and other major regions of human brain. These pigments consist of granules 30 nm in size, contained in organelles together with lipid droplets, and they accumulate in aging, reaching concentrations as high as 1.5-2.6 microg/mg tissue in major brain regions. These pigments, which we term neuromelanins, contain melanic, lipid, and peptide components. The melanic component is aromatic in structure, contains a stable free radical, and is synthesized from the precursor molecule cysteinyl-3,4-dihydroxyphenylalanine. This contrasts with neuromelanin of the substantia nigra, where the melanic precursor is cysteinyl-dopamine. These neuronal pigments have some structural similarities to the melanin found in skin. The precursors of lipid components of the neuromelanins are the polyunsaturated lipids present in the surrounding organelles. The synthesis of neuromelanins in the various regions of the human brain is an important protective process because the melanic component is generated through the removal of reactive/toxic quinones that would otherwise cause neurotoxicity. Furthermore, the resulting melanic component serves an additional protective role through its ability to chelate and accumulate metals, including environmentally toxic metals such as mercury and lead.
Proceedings of the National Academy of Sciences 12/2008; 105(45):17567-72. · 9.68 Impact Factor
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ABSTRACT: The multicopper enzyme nitrous oxide reductase (N 2OR) catalyzes the final step of denitrification, the two-electron reduction of N 2O to N 2. This enzyme is a functional homodimer containing two different multicopper sites: CuA and CuZ. CuA is a binuclear copper site that transfers electrons to the tetranuclear copper sulfide CuZ, the catalytic site. In this study, Pseudomonas nautica cytochrome c 552 was identified as the physiological electron donor. The kinetic data show differences when physiological and artificial electron donors are compared [cytochrome vs methylviologen (MV)]. In the presence of cytochrome c 552, the reaction rate is dependent on the ET reaction and independent of the N 2O concentration. With MV, electron donation is faster than substrate reduction. From the study of cytochrome c 552 concentration dependence, we estimate the following kinetic parameters: K m c 552 = 50.2 +/- 9.0 muM and V max c 552 = 1.8 +/- 0.6 units/mg. The N 2O concentration dependence indicates a K mN 2 O of 14.0 +/- 2.9 muM using MV as the electron donor. The pH effect on the kinetic parameters is different when MV or cytochrome c 552 is used as the electron donor (p K a = 6.6 or 8.3, respectively). The kinetic study also revealed the hydrophobic nature of the interaction, and direct electron transfer studies showed that CuA is the center that receives electrons from the physiological electron donor. The formation of the electron transfer complex was observed by (1)H NMR protein-protein titrations and was modeled with a molecular docking program (BiGGER). The proposed docked complexes corroborated the ET studies giving a large number of solutions in which cytochrome c 552 is placed near a hydrophobic patch located around the CuA center.
Biochemistry 10/2008; 47(41):10852-62. · 3.42 Impact Factor
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ABSTRACT: The generation of reactive quinone species (DAQ) from oxidation of dopamine (DA) is involved in neurodegenerative pathologies like Parkinson's disease (A. Borta, G. U. Höglinger, J. Neurochem. 2007, 100, 587-595). The oxidation of DA to DAQ can occur either in a single two-electron process or in two consecutive one-electron steps, through semiquinone radicals, giving rise to different patterns of reactions. The former type of reaction can be promoted by tyrosinase, the latter by peroxidases in the presence of H(2)O(2), which can be formed under oxidative stress conditions. Both enzymes were employed for the characterization of the thiol-catechol adducts formed by reaction of DA and cysteine or glutathione, and for the identification of specific amino acid residues modified by DAQs in two representative target proteins, human and horse heart myoglobin. Our results indicate that the cysteinyl-DA adducts are formed from the same quinone intermediate independently of the mechanism of DA oxidation, and that the hallmark of a radical mechanism is the formation of the cystine dimer. The reactivity of quinone species also controls the DA-promoted derivatization of histidine residues in proteins. However, for the modification of the cysteine residue in human myoglobin, a radical intramolecular mechanism has been proposed, in which the protein acts both as the catalyst and target of the reaction. Most importantly, the modification of myoglobins through DAQ linkages, and in particular by DA oligomers, has dramatic effects on their stability, as it induces protein unfolding and incorporation into insoluble melanic precipitates.
Chemistry 09/2008; 14(28):8661-73. · 5.93 Impact Factor
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ABSTRACT: The preparation, characterization, and NO-releasing properties of metal complexes derived from N-aminoethylpiperazine-N-diazeniumdiolate (HPipNONO), [Cu(PipNONO)Cl] and [Ni(PipNONO)Cl], and the Ni(II) complex derived from the Schiff base between HPipNONO and salicylaldehyde, [Ni(SalPipNONO)], are described. Compounds [Cu(PipNONO)Cl] and [Ni(SalPipNONO)] release NO at a much slower rate than HPipNONO in aqueous buffer in the pH range between 6.8 and 8.0. The kinetics of NO release by [Ni(SalPipNONO)] is complex, with an apparent stepwise release of NO molecules. Both [Cu(PipNONO)Cl] and [Ni(SalPipNONO)] are effective vasorelaxant agents of precontracted rabbit aorta rings, and are active in the nM concentration range. In addition, these complexes promote the proliferation of endothelial cells. Both vascular activities were inhibited by a specific inhibitor of guanylate cyclase, suggesting the involvement of the cGMP pathway. In all biological assays, the reference agent sodium nitroprusside was shown to be 10-1000-fold less potent than the two metal-NONOates.
ChemMedChem 08/2008; 3(7):1039-47. · 3.15 Impact Factor
