“…With the increase of metal ion concentration, two intense bands emerge at l B 240 and 280 nm with molar absorption coefficients (Table 1) similar to those previously reported for HgS 3 type complexes. 36,37,80 Absorbances increase linearly up to 1 : 1 Hg(II)-peptide ratios, which reflects the formation of a single mononuclear complex, where Hg(II) is very likely coordinated by the three cysteine thiolates of the peptides. In the presence of Hg(II) in excess, a decrease of the absorbances at the selected wavelength values can be observed, indicating that the mononuclear complex transforms into polymetallic species with Hg(II) ions coordinated by only two cysteine thiolate residues.…”
Section: Hg(ii) Complexesmentioning
confidence: 98%
“…34,35 Using a different strategy, tripodal pseudopeptide ligands were designed with cysteine or D-penicillamine (D-Pen) moieties grafted onto a nitrilotriacetic acid scaffold. 36,37 These constructs were able to stabilize the HgS 3 coordination mode in a broad pH-range, starting even at pH B 5.5 with one of the D-Pen ligands. 36 Interestingly, the behaviour of the same ligands in binding Cu(I) was less straightforward.…”
Section: Introductionmentioning
confidence: 99%
“…36,37 These constructs were able to stabilize the HgS 3 coordination mode in a broad pH-range, starting even at pH B 5.5 with one of the D-Pen ligands. 36 Interestingly, the behaviour of the same ligands in binding Cu(I) was less straightforward. Depending on the bulkiness and hydrophobicity of the arms attached to the tripodal template, the formation of mononuclear and (Cu 2 Lig) x type complexes with (Cu 2 S 3 ) x cores was observed with high stabilities.…”
The essential Cu(i) and the toxic Hg(ii) ions possess similar coordination properties, and therefore, similar cysteine rich proteins participate in the control of their intracellular concentration. In this work we present the metal binding properties of linear and cyclic model peptides incorporating the three-cysteine motifs, CxCxxC or CxCxC, found in metallothioneins. Cu(i) binding to the series of peptides at physiological pH revealed to be rather complicated, with the formation of mixtures of polymetallic species. In contrast, the Hg(ii) complexes display well-defined structures with spectroscopic features characteristic for a HgS2 and HgS3 coordination mode at pH = 2.0 and 7.4, respectively. Stability data reflect a ca. 20 orders of magnitude larger affinity of the peptides for Hg(ii) (log βpH7.4HgP ≈ 41) than for Cu(i) (log βpH7.4CuP ≈ 18). The different behaviour with the two metal ions demonstrates that the use of Hg(ii) as a probe for Cu(i), coordinated by thiolate ligands in water, may not always be fully appropriate.
“…With the increase of metal ion concentration, two intense bands emerge at l B 240 and 280 nm with molar absorption coefficients (Table 1) similar to those previously reported for HgS 3 type complexes. 36,37,80 Absorbances increase linearly up to 1 : 1 Hg(II)-peptide ratios, which reflects the formation of a single mononuclear complex, where Hg(II) is very likely coordinated by the three cysteine thiolates of the peptides. In the presence of Hg(II) in excess, a decrease of the absorbances at the selected wavelength values can be observed, indicating that the mononuclear complex transforms into polymetallic species with Hg(II) ions coordinated by only two cysteine thiolate residues.…”
Section: Hg(ii) Complexesmentioning
confidence: 98%
“…34,35 Using a different strategy, tripodal pseudopeptide ligands were designed with cysteine or D-penicillamine (D-Pen) moieties grafted onto a nitrilotriacetic acid scaffold. 36,37 These constructs were able to stabilize the HgS 3 coordination mode in a broad pH-range, starting even at pH B 5.5 with one of the D-Pen ligands. 36 Interestingly, the behaviour of the same ligands in binding Cu(I) was less straightforward.…”
Section: Introductionmentioning
confidence: 99%
“…36,37 These constructs were able to stabilize the HgS 3 coordination mode in a broad pH-range, starting even at pH B 5.5 with one of the D-Pen ligands. 36 Interestingly, the behaviour of the same ligands in binding Cu(I) was less straightforward. Depending on the bulkiness and hydrophobicity of the arms attached to the tripodal template, the formation of mononuclear and (Cu 2 Lig) x type complexes with (Cu 2 S 3 ) x cores was observed with high stabilities.…”
The essential Cu(i) and the toxic Hg(ii) ions possess similar coordination properties, and therefore, similar cysteine rich proteins participate in the control of their intracellular concentration. In this work we present the metal binding properties of linear and cyclic model peptides incorporating the three-cysteine motifs, CxCxxC or CxCxC, found in metallothioneins. Cu(i) binding to the series of peptides at physiological pH revealed to be rather complicated, with the formation of mixtures of polymetallic species. In contrast, the Hg(ii) complexes display well-defined structures with spectroscopic features characteristic for a HgS2 and HgS3 coordination mode at pH = 2.0 and 7.4, respectively. Stability data reflect a ca. 20 orders of magnitude larger affinity of the peptides for Hg(ii) (log βpH7.4HgP ≈ 41) than for Cu(i) (log βpH7.4CuP ≈ 18). The different behaviour with the two metal ions demonstrates that the use of Hg(ii) as a probe for Cu(i), coordinated by thiolate ligands in water, may not always be fully appropriate.
“…30,31 Another approach consists in assembling the three sulfur donors in pseudopeptides derived from tripodal chemical scaffolds such as nitrilotriacetic acid to make the sulfur-donors converge to the metal center. [32][33][34][35] In this paper, we describe the synthesis and complexation properties of the peptide P 3C , shown…”
Mercury(II) is an unphysiological soft ion with high binding affinity for thiolate ligands. Its toxicity lies in the interactions with low molecular weight thiols including glutathione and cysteine-containing proteins that disrupt the thiol balance and alter vital functions. However, mercury can also be detoxified via interactions with Hg(II)-responsive regulatory proteins such as MerR, which coordinates Hg(II) with three cysteine residues in a trigonal planar fashion (HgS coordination). The model cyclodecapeptide P, c(GCTCSGCSRP) was designed to promote Hg(II) chelation in a HgS coordination environment through the parallel orientation of three cysteine side chains. The binding motif is derived from the dicysteine P cyclodecapeptide validated previously as a model for d metal transporters containing the binding sequence CxxC. The formation of the mononuclear HgP complex with a HgS coordination is demonstrated using electrospray ionization mass spectrometry, UV absorption, and Hg NMR. Hg L-edge extended X-ray absorption fine structure (EXAFS) spectroscopy indicates that the Hg(II) coordination environment is T-shaped with two short Hg-S distances at 2.45 Å and one longer distance at 2.60 Å. The solution structure of the HgP complex was refined based on H-H NMR constraints and EXAFS results. The cyclic peptide scaffold has a rectangular shape with the three binding cysteine side chains pointing toward Hg(II). The HgPH complex has a p K of 4.3, indicating that the HgS coordination mode is stable over a large range of pH. This low p K value suggests that the preorientation of the three cysteine groups is particularly well-achieved for Hg(II) trithiolate coordination in P.
“…The nitrilotriacetic (NTA) scaffold is a perfect candidate to anchor three amino acids that can be grafted to the three acidic functions with peptide amide bonds. Moreover, bioinspired pseudopeptides built up on the NTA template and extended with three sulfur amino acids such as cysteines[25] d -penicillamine[26] or methionine,[27] have proven their capacity to tightly bind Cu i in trigonal planar coordination sites, Cu i S 3 , with three sulfur donors in the first sphere. Therefore the novel ligand L (Scheme 1), based on a similar design with His is expected to make the N-donors of the three amino acids converge to the metal center.…”
The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for Cu and Cu are described. L efficiently complex Cu in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, Cu is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the Cu complex to oxidation by oxygen and the Cu complex reduction by ascorbate. The affinities of L for Cu and Cu at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease.
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