ISBN: 978-83-60043-10-3 - eurobic9

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Eurobic9, 2-6 September, 2008, Wrocław, Poland SL12. N-terminal, Histidine-containing Metal Binding Sites in Proteins: Lessons from Model Studies T. Gajda a , A. Jancsó a , A. Kolozsi a , A. Battistoni b , Z. Paksi a a Dept. of Inorganic and Analytical Chemistry, University of Szeged, Hungary, b Dept. of Biology, University of Rome Tor Vergata, Roma, Italy e-mail: gajda@chem.u-szeged.hu Recent biochemical studies pointed out the presence of relatively short, histidine-containing sequences with strong metal binding ability, being independent from the other parts of the biomolecule, in a great number of proteins and enzymes. According to the various biological studies, the metal ion coordination to these sites determines or substantially contributes to the function of the given protein/enzyme, i.e. they have catalytic, structural or some alternative functions, promoting the biological role of these biomolecules. The N-terminal fragments of proteins often have no stable preorganized structures, therefore their metal binding and functional properties can be assessed by studying oligopeptides with identical sequences. Here we report three examples related to the above mentioned three different functions of N-terminal fragments. During the last decade several nickel-containing SOD enzymes (Ni-SOD) have been isolated from aerobic soil bacteria, with no apparent similarity to other SODs. Their crystal structure [1] indicates, that the metal ions are bound to the N-terminal six amino acids in both the oxidized and reduced enzyme, thus the well conserved Nterminal sequence 1 HCDXPC– (X=G or L) provides practically all critical interactions for metal ion binding and catalysis. This offers a unique possibility for structural and functional modelling of these enzymes, since the metal binding sites in metalloenzymes are generally well separated in the amino acid sequences, therefore the structure of the active centres is almost impossible to mimic by small peptides. The solution chemical study of the nickel(II)–HCDLPCG-NH2 (L 1 ) system indicated the formation of the square planar NiH–1L 1 species above pH 6, with {NH2, N – , S – , S – } donor set, being identical with the active site of the reduced enzyme. This species possesses high SOD-like activity, in contrast to the majority of nickel(II) complexes. Cu, Zn-SOD enzymes of some Gram-negative bacteria are characterized by a His-rich N-terminal extension with strong metal binding ability. The N-terminal sequence of the Cu, Zn-SOD from H. ducreyi has been suggested to play a chaperoning role during the uptake of active-site copper, promoting the bacterial survival [2]. We have undertaken equilibrium and solution structural study in the copper(II)- and zinc(II)- NH2-HGDHMHNHDTK- OH (L 2 ) systems, in order to support this assumption and to investigate the possibility of similar function in zinc uptake [3]. L 2 possesses extraordinary metal ion sequestering capacity in the neutral pH, provided only by side chain donors, which approaches to the metal-trafficking proteins. The picomolar affinity for copper(II) supports the proposed chaperoning role of the N-terminal His-rich region, while the nanomolar zinc(II) binding affinity may suggest similar role in the zinc(II) uptake, too. Interestingly, the complex CuHL 2 has significant SOD-like activity, suggesting multifunctional role of the N-terminal His-rich domain. Endostatin, a fragment of collagen XVIII, is a special inhibitor of endothelial cell proliferation and migration, and possesses marked anticancer properties without any side effects. Recently it was shown that the anticancer activity of the N-terminal 25 amino acids and the protein itself are equivalent [4], which is of crucial importance for future therapeutic usage. The presence of zinc(II), which is likely to have structural role, is necessary to exert the anticancer effect in both cases, but details on the metal ion interaction of the N-terminal fragment is not known. Here we report solution chemical investigation of the zinc(II) and copper(II) complexes of HSHRDFQPVLHL–NH2 (L 3 ) peptide, which is identical with the first twelve amino acids of human endostatine, and contains all possible metal binding sites of the N-terminal fragment. In presence of zinc(II) the ZnL complex is formed in the neutral pH range with {NH2, 3Nim} coordination, creating huge macrochelates. Due to the presence of an ATCUN motif, L 3 also binds copper(II) very efficiently. This finding may have biological importance, since copper(II) is also deeply involved in angiogenesis. The presentation will discuss some properties of the metallopeptides which uncovered some subtle details on the functioning of the corresponding metalloproteins. Acknowledgement: This work was supported by the Hungarian Scientific Research Found (NI61786, K63606). References: [1] J. Wuerges, J.-W. Lee, Y.-I. Yim, H.-S. Yim, K.D. Carugo, Proc. Natl. Acad. Sci. USA, <strong>10</strong>1, 8569 (2004). [2] P. D'Angelo, F. Pacello, G. Mancini, O.Proux, J.L. Hazemann, A. Desideri, A. Battistoni, Biochemistry, 44, 13144 (2005). [3] Z. Paksi, A. Jancsó, F. Pacello, N. Nagy, A. Battistoni, T. Gajda, J. Inorg. Biochem., in press (2008). [4] R. M. Tjin Tham Sjin, R. Satchi-Fainaro, A. E. Birsner, V.M. S. Ramanujam, J. Folkman, K. Javaherian, Cancer Res., 65, 3656-3663 (2005). _____________________________________________________________________ 64
Eurobic9, 2-6 September, 2008, Wrocław, Poland SL13. Antitumour Activity of Transition Metal Complexes with Hydrazone Ligands D. Sladić Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade. Serbia e-mail: dsladic@chem.bg.ac.yu Research on coordination compounds as antitumor agents has been an important part of bioinorganic and medicinal chemistry since the discovery of the antiproliferative activity of cisplatin. In this talk results of antitumor activity investigation in vitro of chelate complexes of d-metals (Zn, Cd, Cu, Ni, Pd, Pt, Co, Fe) with hydrazone type ligands, namely hydrazones, hydrazide-hydrazones, thiosemicarbazones and selenosemicarbazones will be presented. For some of the most active complexes results of investigations of cell cycle perturbations, apoptotic assays and gelatin zymography in relation to invasion and metastasis of tumor cells will be discussed. Acknowledgement: The research presented in this lecture was supported by the Ministry of Science of the Republic of Serbia (Grant no. 142026). _____________________________________________________________________ 65
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ISBN: 978-83-60043-10-3 - eurobic9

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