0000000000182178
AUTHOR
Henryk Kozlowski
Binding ability of N-Para-amino-phenylsulfonyl derivatives of amino acids. Potentiometric and spectroscopic studies of Cu(II) complexes
Abstract N-Para-amino-phenylsulfonyl derivatives of amino acids are very effective ligands for Cu(II) ions. Potentiometric and spectroscopic results have shown that Cu(II) ions are able to deprotonate and bind to sulfonamide nitrogen below pH 5 to form stable mono- and bis-[N − , COO − ] chelates. The basicity of sulfonamide nitrogen is lower than peptide amide nitrogen and no distinct anchoring site is necessary to promote the amide nitrogen deprotonation.
Impact of α,β-dehydroamino acid residues on the binding abilities of di-, tri- and tetra-peptides
Insertion of a dehydroamino acid residue into a sequence of di-, tri- or tetra-peptide changed considerably the binding abilities of peptide ligands towards copper(II) ions. Potentiometric and spectroscopic (EPR, UV-VIS and CD) data have shown that the amide nitrogen of the dehydroamino acid residue is more effective in co-ordination than its parent analogue. In the case of the bulky ΔPhe residue also the (Z–E) isomerisation has a critical impact on the co-ordination equilibria in the system studied.
Increased LH and FSH release from the anterior pituitary of ovariectomized rat, in vivo, by copper-, nickel-, and zinc-LHRH complexes.
Abstract The effect of Cu 2+ , Ni 2+ , Zn 2+ and their complexes with LHRH on the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) was estimated in in vivo experiments with the use of the method proposed by Ramirez and McCann. Ovariectomized, estradiol, and progesterone pretreated rats were injected intraveneously either with LHRH alone, a metal ion alone, a mixture of metal and hormone, or a metal-LHRH complex. A metal alone or a mixture of it with LHRH did not affect gonadotropin release at all or no more than LHRH alone. However, the complex of Cu 2+ with LHRH brought about a high release of LH and even higher release of FSH. This indicates that copper complex i…
Uncapping the N-terminus of a ubiquitous His-tag peptide enhances its Cu2+ binding affinity
Metal complexes with an N-terminally free and N-terminally acetylated polyhistidine region of Echis ocellatus venom, with an interesting His-rich motif present in numerous metal binding proteins from all kingdoms of life (DHDHDHHHHHHPGSSV-NH2 and Ac-DHDHDHHHHHHPGSSV-NH2) show the role of the free amino group in the thermodynamic enhancement of Cu2+, Ni2+ and Zn2+ binding. In the studied sequences, Cu2+ can be coordinated by different sets of imidazole rings, and a 3–10 helix is detected in close proximity of Cu2+ binding sites. The complexes are more stable than those with a typical His6-tag, despite a similar copper(II) coordination mode in both cases.
N-p-Amino- and N-p-nitro-phenylsulfonyl derivatives of dipeptides, a new family of ligands for copper(II). Potentiometric and spectroscopic studies
The co-ordination ability of four dipeptide analogues substituted on the N-terminal amino group with p-nitrophenylsulfonyl (nps-Ala-Ala and nps-Ala-His) and p-aminophenylsulfonyl (aps-Ala-Ala and aps-Ala-His) groups was studied by potentiometric and spectroscopic (UV/VIS absorption, CD and EPR) techniques. The N-terminal sulfonyl substituent drastically changes the acidity of the sulfonamide proton making nitrogen very efficient in binding to CuII. The sulfonamide nitrogen having pK between 9 and 11 does not need any anchoring binding group to form complexes with CuII. The para substituent on the phenyl ring (amino or nitro) influences very strongly the acidity of the sulfonamide proton. Th…
Pneumococcal HxxHxH triad – Copper(II) interactions – How important is the ‘x’?
Abstract PhtA, a Streptococcus pneumoniae polyhistidine triad protein, which contributes to virulence by interacting with components of the immune system, by being involved in adherence of bacteria and in Zn(II) uptake, contains five copies of the HxxHxH sequence. Since this motif is also present in numerous Cu(II) binding proteins, we decided to focus on the bioinorganic chemistry of copper(II) with three of such PhtA repeats, in order to understand which of the PhtA triads binds Cu(II) with the highest affinity and explain if Cu(II) would be able to outcompete Zn(II) from its native binding site under physiological metal concentrations.
Co-ordination of copper(II) ions by prolyl-α,β-dehydroamino acids: comparative studies and general considerations
Potentiometric and spectroscopic measurements and theoretical calculations have revealed that α,β-dehydroamino acid residues have a considerable effect on the co-ordination ability of an adjacent amide nitrogen towards Cu2+ ions. Also the side chain of such residues affects the stability constants and, in some cases, the binding mode of short peptides containing α,β-dehydroamino acid residues. The theoretical calculations showed that all dehydroamino acids except α,β-dehydroalanine tend to bend a peptide chain towards a turn conformation. This has a very strong impact on the co-ordination ability of a dehydropeptide ligand.
Metal Complexes of Two Specific Regions of ZnuA, a Periplasmic Zinc(II) Transporter from Escherichia coli
The crystal structure of ZnZnuA from Escherichia coli reveals two metal binding sites. (i) The primary binding site, His143, is located close the His-rich loop (residues 116-138) and plays a significant role in Zn(II) acquisition. (ii) The secondary binding site involves His224. In this work, we focus on understanding the interactions of two metal ions, Zn(II) and Cu(II), with two regions of ZnuA, which are possible anchoring sites for Zn(II): Ac-115MKSIHGDDDDHDHAEKSDEDHHHGDFNMHLW145-NH2 (primary metal binding site) and Ac-223GHFTVNPEIQPGAQRLHE240-NH2 (secondary metal binding site). The histidine-rich loop (residues 116-138) has a role in the capture of zinc(II), which is then further deliv…
Unusual binding ability of α,β-dehydrodipeptides towards metal ions
Abstract Ni II , Zn II and Co II complexes of α,β-dehydro-dipeptides (containing Gly, Leu, Ala, Val or Phe residues) were studied by potentiometric and spectroscopic methods. Deprotonation and coordination of amide nitrogens occurred in all cases around the physiological pH range. The dipeptides with composition of Xaa-Δ-Ala formed octahedral species, while Gly-Δ-Xaa (Xaa = Leu or Phe) formed square planar bis complexes with Ni II .
Pneumococcal histidine triads – involved not only in Zn2+, but also Ni2+ binding?
Polyhistidine triad proteins, which participate in Zn2+ uptake in Streptococcus pneumoniae, contain multiple copies of the HxxHxH (histidine triad motif) sequence. We focus on three such motifs from one of the most common and well-conserved polyhistidine triad proteins, PhtA, in order to understand their bioinorganic chemistry; particular focus is given to (i) understanding which of the PhtA triads binds Zn2+ with the highest affinity (and why) and (ii) explaining whether Ni2+ (also crucial for bacterial survival and virulence) could potentially outcompete Zn2+ at its native binding site. There is no significant difference in the stability of zinc(II) complexes with the three studied protei…
Ovulation-inducing activity of luliberin (LHRH) complexed by copper(II), nickel(II), and zinc(II) ions.
We have shown that the complexation of luteinizing hormone releasing hormone, luliberin (LHRH), a hypothalamic neurohormone, by Cu(II), Ni(II), and Zn(II) may affect its basic, ovulation-inducing potency in the dose responsive manner. Some explanation of the obtained results are offered here.
Metal specificity of the Ni(II) and Zn(II) binding sites of the N-terminal and G-domain of E. coli HypB
HypB is one of the chaperones required for proper nickel insertion into [NiFe]-hydrogenase. Escherichia coli HypB has two potential Ni(II) and Zn(II) binding sites—the N-terminal one and the so-called GTPase one. The metal-loaded HypB–SlyD metallochaperone complex activates nickel release from the N-terminal HypB site. In this work, we focus on the metal selectivity of the two HypB metal binding sites and show that (i) the N-terminal region binds Zn(II) and Ni(II) ions with higher affinity than the G-domain and (ii) the lower affinity G domain binds Zn(II) more effectively than Ni(II). In addition, the high affinity N-terminal domain, both in water and membrane mimicking SDS solution, has a…
Cyclic Analogs of Desferrioxamine E Siderophore for 68Ga Nuclear Imaging: Coordination Chemistry and Biological Activity in Staphylococcus aureus
As multidrug-resistant bacteria are an emerging problem and threat to humanity, novel strategies for treatment and diagnostics are actively sought. We aim to utilize siderophores, iron-specific strong chelating agents produced by microbes, as gallium ion carriers for diagnosis, applying that Fe(III) can be successfully replaced by Ga(III) without losing biological properties of the investigated complex, which allows molecular imaging by positron emission tomography (PET). Here, we report synthesis, full solution chemistry, thermodynamic characterization, and the preliminary biological evaluation of biomimetic derivatives (FOX) of desferrioxamine E (FOXE) siderophore, radiolabeled with 68Ga …
General Aspects of Metal Ions as Signaling Agents in Health and Disease
This review focuses on the current knowledge on the involvement of metal ions in signaling processes within the cell, in both physiological and pathological conditions. The first section is devoted to the recent discoveries on magnesium and calcium-dependent signal transduction—the most recognized signaling agents among metals. The following sections then describe signaling pathways where zinc, copper, and iron play a key role. There are many systems in which changes in intra- and extra-cellular zinc and copper concentrations have been linked to important downstream events, especially in nervous signal transduction. Iron signaling is mostly related with its homeostasis. However, it is also …
Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif
A diphenylalanine motif in peptides plays a crucial role in supramolecular systems. The current work represents a novel strategy in which a diphenylalanine motif in the central domain of neuropeptides conserves the specific Zn2+ binding site and prevents "hopping" of the Zn2+ ion between alternative metal binding sites. Alternative metal binding sites may also include carboxylic atoms in the terminal domains of a peptide. Therefore, one needs to design a peptide in which the metal will not bind the carboxylic groups in the terminal domains. Herein, we propose that engineering and designing peptides with a diphenylalanine motif in the central domain may yield excellent metal chelators.