Impact of Cu(2+) ions on the structure of colistin and cell-free system nucleic acid degradation.

Colistin and transition metal ions are commonly used as feed additives for livestock animals. This work presents the results of an analysis of combined potentiometric and spectroscopic (UV-vis, EPR, CD, NMR) data which lead to conclude that colistin is able to effectively chelate copper(II) ions. In cell-free system the oxidative activity of the complex manifests itself in the plasmid DNA destruction with simultaneous generation of reactive OH species, when accompanied by hydrogen peroxide or ascorbic acid.

Differences in the binding of copper(I) to α- and β-synuclein.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal α-synuclein (αS) deposits in the brain. Alterations in homeostasis and metal-induced oxidative stress may play a crucial role in the progression of αS amyloid assembly and pathogenesis of PD. Contrary to αS, β-synuclein (βS) is not involved in the PD etiology.

High affinity of copper(II) towards amoxicillin, apramycin and ristomycin. Effect of these complexes on the catalytic activity of HDV ribozyme.

Three representatives of the distinct antibiotics groups: amoxicillin, apramycin and ristomycin A were studied regarding their impact on hepatitis D virus (HDV) ribozyme both in the metal-free form and complexed with copper(II) ions. Hence the Cu(II)-ristomycin A complex has been characterized by means of NMR, EPR, CD and UV-visible spectroscopic techniques and its binding pattern has been compared with the coordination modes estimated previously for Cu(II)-amoxicillin and Cu(II)-apramycin complexes. It has thus been found that all three antibiotics bind the Cu(II) ion in a very similar manner, engaging two nitrogen and two oxygen donors into coordination with the square planar symmetry in physiological conditions.

Conformation propensities of des-acyl-ghrelin as probed by CD and NMR.

Des-acyl-ghrelin is a 28 amino acid peptide secreted by both human and rat stomach. Together with ghrelin and obestatin, it is obtained by post-translational modification of a 117 aminoacid prepropeptide mainly expressed in distinct endocrine cell type in the stomach. Although its receptor has not been unambiguously identified so far, des-acyl-ghrelin is considered one of the strongest antagonists of ghrelin in activating the growth hormone secretagogue receptor (GHS-R).

Copper(I)-α-synuclein interaction: structural description of two independent and competing metal binding sites.

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 unusual stabilization of the Ni2+ and Cu2+ complexes with NSFRY.

The binding mode provided by an unprotected peptide with non-coordinating side-chains is simple and well understood. However, when particular residues are inserted into the peptide sequence, they can have a significant impact on the stability of the formed complexes. The presence of non-bonding side chains of amino acids close to the metal binding centre in the peptide/protein can provide special interactions which result in increasing the stabilization of the formed species.

NMR metabolomic investigation of astrocytes interacted with Aβ₄₂ or its complexes with either copper(II) or zinc(II).

Alzheimer's disease (AD) is the leading cause of senile dementia. One of the main hallmarks of AD is the presence of amyloid plaques in the brain, primarily formed by fibrils of the amyloid-β (Aβ) peptide. Transition metal ions, such as Cu(2+) and Zn(2+) have been found at high concentrations in senile plaques isolated from AD patients and evidence have been reached that (i) Aβ aggregation is greatly affected by Cu(2+) and Zn(2+) and (ii) Cu(2+), implicated in the formation of reactive oxygen species, leads to mitochondrial dysfunctions ultimately leading to neuronal cells death.

Capreomycin--a polypeptide antitubercular antibiotic with unusual binding properties toward copper(II).

Capreomycin is an important therapeutic agent having intriguing and diverse molecular features. Its polypeptidic structure rich in nitrogen donors makes the drug a promising chelating agent for a number of transition metal ions, especially for copper(II). The results of the model investigational studies suggest that capreomycin anchors Cu(2+) ion with an amino function of the α,β-diaminopropionic acid residue at pH around 5.

Exploring the reactions of β-amyloid (Aβ) peptide 1-28 with Al(III) and Fe(III) ions.

The reactions of human β-amyloid peptide 1-28 (Aβ28) with Al(III) and Fe(III) ions were investigated by (1)H NMR and electrospray ionization mass spectrometry (ESI-MS) under pH conditions close to physiological ones. (1)H NMR titrations, performed in the 5.3-8.

The role of His-50 of α-synuclein in binding Cu(II): pH dependence, speciation, thermodynamics and structure.

Copper interaction with alpha synuclein (αS) has been shown to accelerate aggregation and oligomerization of the protein. Three different αS copper binding domains have been proposed: (i) the N-terminal residues (1-9) that represent the minimal copper binding domain; (ii) the His-50 imidazole and (iii) the Asp and Glu residues within the acidic C-terminal domain. The copper coordination at the N-terminus has been extensively characterized and it is generally accepted that it provides the highest affinity site.

Bioinorganic chemistry of Parkinson's disease: structural determinants for the copper-mediated amyloid formation of alpha-synuclein.

The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD). A central, unresolved question in the pathophysiology of PD relates to the role of AS-metal interactions in amyloid fibril formation and neurodegeneration. Our previous works established a hierarchy in alpha-synuclein-metal ion interactions, where Cu(II) binds specifically to the protein and triggers its aggregation under conditions that might be relevant for the development of PD.

Coordination pattern, solution structure and DNA damage studies of the copper(II) complex with the unusual aminoglycoside antibiotic hygromycin B.

The aminoglycosidic antibiotic hygromycin B presents a peculiar chemical structure, characterized by two sugar rings joined via a spiro connection. The Cu(ii) complex of hygromycin B in water solution was characterized by (1)H-NMR, UV-Vis, EPR and CD spectroscopy, combined with potentiometric measurements. The spin-lattice relaxation enhancements were interpreted by the Solomon-Bloembergen-Morgan theory, allowing us to calculate copper-proton distances that were used to build a model of the complex by molecular mechanics and dynamics calculations.

Structural characterization and antimicrobial activity of the Zn(II) complex with P113 (demegen), a derivative of histatin 5.

Zinc binding to P113 (or demegen), a 12 amino acid (AKRHHGYKRKFH-NH(2)) fragment of histatin 5, was investigated by means of NMR and CD techniques, yielding delineation of the metal binding site and the 3D structure of the complex in water and in DMSO as well. The three His imidazole and the N-terminus nitrogens were found to act as the zinc coordinating atoms. A comparison with the previously reported Cu(II)-P113 complex disclosed that the two structures were rather diverse, in spite of an identical donor set.

fac-{Ru(CO)(3)}(2+) selectively targets the histidine residues of the beta-amyloid peptide 1-28. Implications for new Alzheimer's disease treatments based on ruthenium complexes.

The reaction of the ruthenium(II) complex fac-[Ru(CO)(3)Cl(2)(N(1)-thz)] (I hereafter; thz = 1,3-thiazole) with human beta-amyloid peptide 1-28 (Abeta(28)) and the resulting {Ru(CO)(3)}(2+) peptide adduct was investigated by a variety of biophysical methods. (1)H NMR titrations highlighted a selective interaction of {Ru(CO)(3)}(2+) with Abeta(28) histidine residues; circular dichroism revealed the occurrence of a substantial conformational rearrangement of Abeta(28); electrospray ionization mass spectrometry (ESI-MS) suggested a prevalent 1:1 metal/peptide stoichiometry and disclosed the nature of peptide-bound metallic fragments. Notably, very similar ESI-MS results were obtained when I was reacted with Abeta(42).

Cu(II) ion interaction with teicoplanin-vancomycin's analog.

Teicoplanin, a member of the "last chance" antibiotic family has a similar structure and the same mechanism of action as parent drug vancomycin, which is proved to be an effective binder of Cu(II) ions. However, the potentiometric and spectroscopic studies (UV-visible, CD, NMR) have shown that the modification of the N-terminal structure of the peptide backbone in teicoplanin affects considerably the binding ability towards Cu(II) ions. While vancomycin forms almost instantly the stable 3N complex species involving the N-terminal and two amide nitrogen donors, in case of teicoplanin only two nitrogen donors derived from the N-terminal amino group and adjacent peptide bond are coordinated to Cu(II) ion within the whole pH range studied.

Copper binding to chicken and human prion protein amylodogenic regions: differences and similarities revealed by Ni2+ as a diamagnetic probe.

Both human (h) and chicken (Ch) prion proteins (PrP) bind copper ions within the so called "tandem repeat" N-terminal region. Outside this region, hPrP possesses two additional copper binding sites, localized at His-96 and His-111 in the so called "amylodogenic" or neurotoxic region (residues 91-126). Also ChPrP possesses a similar region (ChPrP(105-140)) containing two His (His-110 and His-124) and an identical hydrophobic tail of 15 amino acids rich in Ala and Gly.

Heteronuclear and homonuclear Cu2+ and Zn2+ complexes with multihistidine peptides based on zebrafish prion-like protein.

The homeostasis of metal ions, especially copper and zinc, is a major factor that may influence the prion diseases and the biological function of prion protein (PrP). The His-rich regions are basic sites for metal binding and antioxidant activity of the PrP structures. Animal prion-like proteins contain also His-rich domains, and their coordination chemistry may provide better insight into the chemistry and biology of PrP structures and related diseases.

Structural features of the Zn(2+) complex with the single repeat region of "prion related protein" (PrP-rel-2) of zebrafish zPrP63-70 fragment.

The interaction between Zn(2+) and the single repeat of PrP-rel-2 of zebrafish at physiological pH was investigated by NMR spectroscopy; the chemical shift mapping and the proton-proton distances were used to obtain the structural model of the Zn(2+) complex.

[(1)H] magnetic resonance spectroscopy of urine: diagnosis of a guanidinoacetate methyl transferase deficiency case.

For the first time, the use of urine [(1)H] magnetic resonance spectroscopy has allowed the detection of 1 case of guanidinoacetate methyl transferase in a database sample of 1500 pediatric patients with a diagnosis of central nervous system impairment of unknown origin. The urine [(1)H] magnetic resonance spectroscopy of a 9-year-old child, having severe epilepsy and nonprogressive mental and motor retardation with no apparent cause, revealed a possible guanidinoacetic acid increase. The definitive assignment of guanidinoacetic acid was checked by addition of pure substance to the urine sample and by measuring [(1)H]-[(1)H] correlation spectroscopy.

Copper(II) coordination outside the tandem repeat region of an unstructured domain of chicken prion protein.

Combined potentiometric, calorimetric and spectroscopic methods were used to investigate the Cu(2+) binding ability and coordination behaviour of some peptide fragments related to the neurotoxic region of chicken Prion Protein. The systems studied were the following protein fragments: chPrP(106-114), chPrP(119-126), chPrP(108-127), chPrP(105-127) and chPrP(105-133).The complex formation always starts around pH 4 with the coordination of an imidazole nitrogen, followed by the deprotonation and binding of amide nitrogens from the peptidic backbone.

Guanidinoacetate methyltransferase (GAMT) deficiency diagnosed by proton NMR spectroscopy of body fluids.

In patients with guanidinoacetate methyltransferase (GAMT) deficiency several parameters may point towards the diagnosis of GAMT deficiency. These include the low levels of creatine and creatinine in urine, the high concentration of guanidinoacetic acid (GAA) in urine and the low levels of creatine and creatinine in the cerebrospinal fluid (CSF). In this study, body fluids from 10 GAMT deficient patients were analysed using (1)H NMR spectroscopy.

Molecular dynamics study of the Cu2+ binding-induced "structuring" of the N-terminal domain of human prion protein.

In this work, we report molecular dynamics simulations on a fragment of the human prion protein spanning residues 31-120, with copper(II) bound to the repeat region in several ways corresponding to the known intra- and inter-repeat coordination modes, or to the metal site located at His111. The results of this study point to a different structuring tendency of the protein fragment depending on copper binding mode, with the highest degree of structuring in the case of intrarepeat Cu(II) coordination corresponding to high copper concentration.

Structural characterization of the intra- and inter-repeat copper binding modes within the N-terminal region of "prion related protein" (PrP-rel-2) of zebrafish.

The unique biology of prion proteins (PrPs) allied with the public-health risks posed by prion zoonoses, such as various animal neurodegenerations, has focused much attention on the molecular basis of the controls cross-species and on the similarities between PrPs from different species. Given the common feature of PrPs as Cu(2+) binding proteins, it appears relevant to compare the impact of Cu(2+) on the stability constants and structures of "physiological" complexes. After having comprehensively delineated the interaction of Cu(2+) with mammalian and avian PrPs, the stabilities and molecular structures of species generated by Cu(2+) interacting with the irregular repeated domain derived from Danio rerio zebrafish PrP-rel-2 were investigated.

Binding of Ni2+ and Cu2+ ions to peptides with a Cys-His motif.

Waglerin I is a 22 amino acid snake venom toxin. Its three fragments (GGKPDLRPCHP-NH2, PCHYIPRPKPR-NH2, PCHPPCHYIPR-NH2), due to the presence of two Cys and His residues, are potentially very attractive ligands for transition metal ions. The main aim of this work was to establish the impact of these two adjacent residues on Ni2+ ion binding, especially because this kind of motif is very common in nature, and the study of low molecular weight models could be helpful in understanding larger systems.