A fémionok lehetséges szerepe az idegrendszeri betegségek kifejlődésében és lefolyásában. A hisztidintartalmú peptidek átmenetifém-ionokkal való komplexképződési folyamatai = Metal based neurodegeneration. Transition metal ion complexes of oligopeptides containing histidine

1. Kistagszámú hisztidintartalmú-peptidek átmenetifémionokkal alkotott törzs- és vegyes fémkomplexei: A hisztidin nitrogén donoratomok az elsődleges fémkötőhelyek. Ezek koordinációjával makrokelátok képződhetnek, illetve önálló fémmegkötőhelyek lehetnek, ezért kétmagvú komplexeket képeznek, és vegyes fémkomplexek kialakulására is lehetőség van. 2. A prion fehérje peptidfragmenseinek Cu(II)-, Ni(II)-törzskomplexei és Cu(II)/Ni(II) vegyes fémkomplexei: A vizsgált fragmensek általában annyi fémion megkötésére képesek, ahány hisztidint tartalmaznak. Amíg a Cu(II)-ionok számára a 111-es, a Ni(II)-ionok számára a 96-os hisztidin a preferált kötőhely. 3. A ß-amiloid Ni(II) törzs-, illetve Ni(II)/Cu(II) és Ni(II)/Cu(II)/Zn(II) vegyes fémkomplexei: A Ni(II)-ionok esetén is az N-terminális részen történő kötődés preferált. Sem a Zn(II)-, sem a Ni(II)-ionok nem képesek kiszorítani a Cu(II)-iont a ß-amiloid peptid fémion-megkötőhelyeiről, azonban mindkét fémion képes megváltoztatni a Cu(II)-ionok eloszlását a különböző fémion-kötőhelyek között. 4. Amilin fragmensek Cu(II)-ionokkal való kölcsönhatása: Bár a patkány amilin 17-29 fragmense nem tartalmaz a fémion koordinálódását elősegítő oldalláncokat, a fiziológiás pH-tartományban egy ekvivalens fémion megkötésére képes. Az aszparagin amidcsoportja is elsődleges fémionkötőhely lehet, koordinálódásával indukálhatja a peptidvázbeli amidnitrogének deprotonálódását. | 1. Transition and mixed metal complexes of short histidine containing peptides: Histidyl residues are the primary metal binding sites resulting in the formation of macrochelates or they can act as independent metal binding sites, providing a good chance for the formation of dinuclear and various mixed metal complexes. 2. Cu(II), Ni(II) and mixed metal complexes of the peptide fragments of human prion protein: Usually all fragments are able to bind as many Cu(II) ions as the number of histidyl residues. His111 and His96 were assigned as the preferred binding sites of Cu(II) and Ni(II), respectively. 3. Ni(II) complexes and Ni(II)/Cu(II) and Ni(II)/Cu(II)/Zn(II) mixed metal complexes of amiloid-ß: Ni(II) ions also prefer the coordination at the N-terminus. Neither zinc(II) nor Ni(II) can, however, substitute Cu(II) in the mixed metal complexes of amiloid-ß, but both metal ions are able to alter the distribution of Cu(II) ions among the various binding sites. 4. Copper(II) complexes of amylin fragments: Although rat amylin(17-29) does not contain any strongly coordinating side chain residues but it can bind one equivalent of copper(II) ions under physiological conditions. The amide group of asparagine can also be primary metal binding site, its coordination may induce the deprotonation of the amide functions of the peptide backbone

Az imidazolgyűrű biológiai szerepének modellezése bisz(imidazolil) és hisztidin-analóg származékok átmenetifém komplexeinek vizsgálatával = Modelling of the biological role of imidazole residues in the metal complexes of bis(imidazolyl) compounds and histidine analogues

A vizsgálataink célja a Cu,Zn-szuperoxid-diszmutáz (SOD) enzim Cu(II)- és Zn(II)-kötőhelyének tanulmányozása volt. A vizsgálatok három fő területen folytak. a) A bisz(imidazolil)csoportot tartalmazó aminosav- és peptidszármazékok átmenetifém komplexeinek vizsgálata azt mutatja, hogy a koordinálódó oldalláncot nem tartalmazó dipeptidszármazékok, illetve a hisztidint tartalmazó aminosavszármazék Cu(II) komplexe lehet potenciális modellje a SOD enzimnek. A bisz(imidazolil)csoport erős fémmegkötő tulajdonsága révén jelentősen megváltoztatja a peptidek koordinációs sajátságait. Ez a csoport képes horgonycsoportként elősegíteni az amidnitrogének deprotonálódását és koordinálódását Cu(II), Ni(II), és néhány esetben a Zn(II), VO(IV)-ionok esetén is. A potenciális donorcsoportok nagy száma változatos szerkezetű ligandum-, illetve imidazolhidas többmagvú izomer komplexek képződését eredményezi. b) A két- vagy több hisztidint és/vagy aszparaginsavat tartalmazó oligopeptidek a SOD enzim aktív centruma kötőhelyének megfelelő aminosavszekvenciát tartalmazzák. A hisztidinek kötödése ugyanahhoz a fémionhoz nagymértékben megnöveli az ML komplexek stabilitását. Az ML komplexek stabilitása a HisXaaHisYaaHis szekvenciát tartalmazó peptidek esetén a legnagyobb. c) A hisztidinnel analóg aminosav- és peptidszármazékok esetén az aromás gyűrű hatása az aminosav-, illetve peptidszerű koordinációra az imidazol > piridin ~ triazolil > tiazolil ~ tienil sorrendben csökken. | The main aim of our research was the study of Cu(II) and Zn(II) binding site of Cu,Zn superoxide dismutase. Our studies were performed in three fields: a) The studies on transition metal complexes of amino acid and peptide derivatives of bis(imidazolyl) group revealed that the copper(II) complex of dipeptides containing non-coordinating side chains and the histidine containing amino acid derivatives potentially mimic the SOD enzyme. Due to the strong metal binding ability of bis(imidazolyl) group it influences significantly the coordination behaviour of peptides. This group as an anchor is able to promote the deprotonation and coordination of amide nitrogens in the Cu(II), Ni(II) and in some cases in Zn(II) and VO(IV) complexes. The presence of numerous donor groups in the ligands, however, results in the formation of various isomeric dinuclear complexes with ligand- or imidazole bridges. b) The studied ligands containing two or more histidines and/or aspartic acids correspond to the amino acid sequence of active site of SOD enzyme. The binding of histidine side chains to the same metal ions significantly enhances the stability of ML complexes. The highest stability of ML complexes was detected in the case of peptide containing HisXaaHisYaaHis sequence. c) For histidine analogue amino acids and peptides the heteroaromatic rings influences the amino acid or peptide like coordination mode in the order imidazole > pyridine ~ triazolyl > thiazolyl ~thienyl rings

Copper(II), nickel(II) and zinc(II) complexes of hexapeptides containing separate aspartyl and histidyl residues

Copper(II), nickel(II) and zinc(II) complexes of two N-terminally free and C-terminally blocked hexapeptides, NH2-ADAAAH-NH2 and NH2-AADAAH-NH2, containing separate aspartyl and histidyl residues have been studied by potentiometric, UV-Vis, CD and ESR spectroscopic methods. The amino termini were found as the primary anchoring sites of both ligands for the complexation with all three metal ions. The β-carboxylate function of the second or third aspartyl residue enhances the thermodynamic stability of the copper(II) and nickel(II) complexes and shifts the deprotonation of the subsequent amide functions into a more alkaline pH range. In the case of NH2-AADAAH-NH2 the imidazole-N donor of the histidyl residue does not have a significant contribution to the overall stability of the mononuclear complexes. The side chain imidazole, however, can be an independent metal binding site resulting in the formation of dinuclear or even mixed metal complexes. The stabilizing role of the histidyl residue is much more pronounced in the complexes of the NH2-ADAAAH-NH2 peptide. In this case a tridentately (NH2,N-,β-COO-)-coordinated species is formed and its stability is significantly enhanced by the macrochelation of the side chain imidazole. The presence of two anchoring sites (terminal amino and side chain imidazole) in one molecule enhances the stability of the corresponding zinc(II) complexes, too, but the amide nitrogens are not involved in metal binding in this case

Copper(II) interaction with the Human Prion 103-112 fragment - Coordination and oxidation

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Complex formation processes and metal ion catalyzed oxidation of model peptides related to the metal binding site of the human prion protein

Interaction of copper(II) and nickel(II) ions with the Ac-PHAAAGTHSMKHM-NH2 tridecapeptide containing the His85, His96 and His111 binding sites of human prion protein has been studied by various techniques. pH-potentiometry, UV-Vis and circular dichroism spectroscopy were applied to study the stoichiometry, stability and structure of the copper(II) and nickel(II) complexes, while HPLC-MS and MS/MS were used for identifying the products of copper(II) catalyzed oxidation. The copper binding ability of shorter fragments, namely the nonapeptide Ac-PHAAAGTHS-NH2 and pentapeptide Ac-PHAAA-NH2 have also been studied. The tridecapeptide is able to bind three equivalent of copper(II) ion, since the histidine residues behave as independent metal binding sites. Nevertheless, the metal binding ability of histidine residue mimicking the octarepeat domain (His85) is decreased, while the other parts of the peptide mimicking the histidines outside the octarepeat domain bind the copper ions in comparable concentration. On the other hand, this peptide is able to coordinate only two equivalents of nickel ion on the domains outside the octarepeat region. Furthermore the His96 binding site is more effective for the nickel ions. Both histidine and methionine residues are sensitive for oxidation, the oxidation of these residues are proved, and in the case of the histidine residues follows the order His96 >His85 >> His111

Potentiometric and spectroscopic studies on the copper(ii) complexes of rat amylin fragments. The anchoring ability of specific non-coordinating side chains.

Copper(ii) complexes of peptides modelling the sequence of the 17-22 residues of rat amylin have been studied by potentiometric, UV-Vis, CD and ESR spectroscopic methods. The peptides were synthesized in N-terminally free forms, NH2-VRSSNN-NH2, NH2-VRSSAA-NH2, NH2-VRAANN-NH2, NH2-VRSS-NH2, NH2-SSNN-NH2, NH2-SSNA-NH2 and NH2-AANN-NH2, providing a possibility for the comparison of the metal binding abilities of the amino terminus and the -SSNN- domain. The amino terminus was the primary ligating site in all cases and the formation of only mononuclear complexes was obtained for the tetrapeptides. The thermodynamic stability of the (NH2, N-, N-) coordinated complexes was, however, enhanced by the asparaginyl moiety in the case of NH2-SSNN-NH2, NH2-SSNA-NH2 and NH2-AANN-NH2. Among the hexapeptides the formation of dinuclear complexes was characteristic for NH2-VRSSNN-NH2 demonstrating the anchoring ability of the -SSNN- (SerSerAsnAsn) domain. The complexes of the heptapeptide NH2-GGHSSNN-NH2 were also studied and the data supported the above mentioned anchoring ability of the -SSNN- site

Thermodynamic and Structural Characterization of the Copper(II) Complexes of Peptides Containing Both Histidyl and Aspartyl Residues

Terminally protected pentapeptides with 2 histidines (Ac-HHVGD-NH2 and Ac-HVGDH-NH2) and the terminally free peptides containing both internal aspartyl and C-terminal histidyl residues (FDAH and VIDAH) have been synthesized, and copper(II) complexes studied by potentiometric, UV-Vis, CD, and EPR spectroscopic techniques in solution. Both thermodynamic and spectroscopic data reveal that side chain donor atoms of aspartyl and histidyl residues have a significant contribution to the metal binding affinity of peptide molecules. In the case of terminally protected peptides, the role of the imidazole-N donor functions is reflected in the enhanced stability of the 3N and 4N coordinated copper(II) complexes. The amino and β-carboxylate groups of FDAH and VIDAH create a very effective metal binding site with the (NH2, N−, β-COO−) and (NH2, N−, N−, β-COO−) coordination modes including the N-termini, while the histidine sites are available for the formation of the (Nim, N−, N−) binding mode resulting in the preference of dinuclear complex formation

Potentiometric and spectroscopic studies on the copper(II) complexes of rat amylin fragments. The anchoring ability of specific non-coordinating side chains

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Nickel(II), zinc(II) and cadmium(II) complexes of hexapeptides containing separate histidyl and cysteinyl binding sites

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Az átmenetifémionok peptidekkel alkotott komplexei. A fémion-fehérje kölcsönhatás modellezése. = Transition metal complexes of peptides. Models of the metal ion protein interactions.

1. Multihisztidin peptidek réz(II)- és cink(II)komplexei: A hisztidin nitrogén donoratomok a peptidek elsődleges fémkötőhelyei. Ezek koordinációjával makrokelátok képződhetnek, amelyek stabilitása a hisztidinek számától és távolságától függ. A karboxilcsoportok jelenléte a cink(II)komplexek stabilitását növeli. A réz(II)ionok az amidcsoport deprotonálódását is indukálhatják, ami többmagvú komplexek képződéséhez vezet. A megkötött rézionok száma megegyezik a hisztidinek számával. 2. A prion protein peptid fragmenseinek fémkomplexei: Az oktarepeaten kívüli hisztidinek is stabilis rézkötőhelyek. A HuPrP(84-114) fragmensre kapott eredmények szerint a kötési helyek stabilitási sora: His111 > His96 >> His85. Egyéb átmenetifémek komplexeit is tanulmányoztuk, amelyek stabilitási sora a következő: Pd(II) > Cu(II) > Ni(II) > Zn(II) > Cd(II) ~ Co(II) > Mn(II). 3. Az amyloid-? peptid réz(II)komplexei: Az A?(1-16) peptidnek kiugróan nagy rézionaffinitása van. A terminális aminocsoport az elsődleges fémkötőhely, amit a hisztidinek koordinációja követ. Egy A?(1-16) molekula 4 réziont képes megkötni. Az egy- két- és három-magvú komplexeknek koordinációs izomerjei lehetnek, de a terminális aminocsoport és a szomszédos amidnitrogének koordinációja preferált. | 1. Copper(II) and zinc(II) complexes of multihistidine peptides: Histidyl residues are the primary metal binding sites resulting in the formation of macrochelates. The stabilities of macrochelates are influenced by the number and location of histidyl residues. The stability of zinc(II) complexes is enhanced by the presence of carboxylate functions. Formation of polynuclear complexes has also been detected and their nuclearities correspond to the number of histidyl sites. 2. Metal binding affinity of prion peptide fragments: Histidyl residues outside the octarerepat domain are effective copper binding sites. The results obtained for the copper(II) complexes of HuPrP(84-114) revealed the following stability order: His111 > His96 >> His85. Complex formation with several other transition elements has also been studied and their stability order: Pd(II) > Cu(II) > Ni(II) > Zn(II) > Cd(II) ~ Co(II) > Mn(II). 3. Copper(II) complexes of amyloid-? peptide fragments: A?(1-16) has an outstanding affinity towards the complexation with copper. The terminal amino group is the primary metal binding site, followed by the coordination of histidyl residues. One molecule of A?(1-16) can bind as much as four copper(II) ions. Various coordination isomers of the mono-, di- and tri-nuclear complexes can exist with a preference for the coordination via the terminal amino and subsequent amide groups