Similarities between <i>N</i>-Acetylcysteine and Glutathione in Binding to Lead(II) Ions

Sisombath, Natalie S.; Jalilehvand, Farideh

doi:10.1021/acs.chemrestox.5b00323

Cited by 21 publications

(14 citation statements)

References 73 publications

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“…This difference allows for the distinction of Pb(II)S 3 from Pb(II)S 2 O sites. A similar trend is observed in the UV/VIS spectroscopy of small molecule Pb(II) complexes containing inorganic thiolate ligands [22, 151, 152]. The spectroscopic fingerprints for Pb(II) bound to a series of small biomolecules (L-Cys, L-Pen, NAC and GSH) in alkaline aqueous solutions established that the environment of the metal center depends on ligand-to-metal ratios, concentrations, and the pH of the solution [22, 151, 152].…”

Section: Lead Chemistry With Designed Proteinssupporting

confidence: 74%

10. Lead(II) Binding in Natural and Artificial Proteins

Cangelosi¹,

Ruckthong²,

Pecoraro³

2017

Lead – Its Effects on Environment and Health

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This article describes recent attempts to understand the biological chemistry of lead using a synthetic biology approach. Lead binds to a variety of different biomolecules ranging from enzymes and regulatory and signaling proteins to bone matrix. We have focused on the interactions of this element in thiolate-rich sites that are found in metalloregulatory proteins such as Pbr, Znt, and CadC and in enzymes such as δ-aminolevulinic acid dehydratase (ALAD). In these proteins, Pb(II) is often found as a homoleptic and hemidirectic Pb(II)(SR)3− complex. Using first principles of biophysics, we have developed relatively short peptides that can associate into three-stranded coiled coils (3SCCs), in which a cysteine group is incorporated into the hydrophobic core to generate a (cysteine)3 binding site. We describe how lead may be sequestered into these sites, the characteristic spectral features may be observed for such systems and we provide crystallographic insight on metal binding. The Pb(II)(SR)3− that is revealed within these α-helical assemblies forms a trigonal pyramidal structure (having an endo orientation) with distinct conformations than are also found in natural proteins (having an exo conformation). This structural insight, combined with 207Pb NMR spectroscopy, suggests that while Pb(II) prefers hemidirected Pb(II)(SR)3− scaffolds regardless of the protein fold, the way this is achieved within α-helical systems is different than in β-sheet or loop regions of proteins. These interactions between metal coordination preference and protein structural preference undoubtedly are exploited in natural systems to allow for protein conformation changes that define function. Thus, using a design approach that separates the numerous factors that lead to stable natural proteins allows us to extract fundamental concepts on how metals behave in biological systems.

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Section: Lead Chemistry With Designed Proteinssupporting

confidence: 74%

10. Lead(II) Binding in Natural and Artificial Proteins

Cangelosi¹,

Ruckthong²,

Pecoraro³

2017

Lead – Its Effects on Environment and Health

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“…We previously assigned the peaks for 0.1 M alkaline solutions of these ligands (calibrated relative to the CH 3 OH signal at 49.15 ppm). 27−29 The sets of doublets observed for solid d -penicillamine can be attributed to polymorphs, that is, two nonequivalent molecules in the crystal asymmetric unit, 30,31 although only the structure of crystalline racemic dl -penicillamine is known. 32 Similarly, the crystal structure has been reported for dihydrated Rh 2 (AcO) 4 , 33 but not for anhydrous Rh 2 (AcO) 4 .…”

Section: Resultsmentioning

confidence: 99%

Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh₂(CH₃COO)₄ with Cysteine and Its Derivatives

2017

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We have combined results from several spectroscopic techniques to investigate the aerobic reactions of Rh 2 (AcO) 4 (AcO – = CH 3 COO – ) with l -cysteine (H 2 Cys) and its derivatives d -penicillamine (3,3′-dimethylcysteine, H 2 Pen), with steric hindrance at the thiol group, and N -acetyl- l -cysteine (H 2 NAC), with its amino group blocked. Previous investigations have shown that antitumor active dirhodium(II) carboxylates may irreversibly inhibit enzymes containing a thiol group at or near their active sites. Also, cysteine, the only thiol-containing proteinogenic amino acid, interacts in vivo with this class of antitumor compounds, but structural information on the products of such reactions is lacking. In the present study, the reactions of Rh 2 (AcO) 4 and H 2 L were carried out in aqueous solutions at the pH of mixing (acidic) and at physiological pH, using the different mole ratios 1:2, 1:4, and 1:6, which resulted in the same products in increasing yields. Electrospray ionization mass spectrometry (ESI-MS) indicates formation of dimeric [Rh III 2 Pen 4 ] 2– or oligomeric {Rh III 2 L 4 } n (L = Cys, NAC) complexes with bridging thiolate groups. Analyses of Rh K edge extended X-ray absorption fine structure (EXAFS) data reveal 3–4 Rh–S and 2–3 Rh–(N/O) bonds around six-coordinated Rh(III) ions at mean distances of 2.33 ± 0.02 and 2.09 ± 0.02 Å, respectively. In the N -acetyl- l -cysteine compound, the Rh III ···Rh III distance 3.10 ± 0.02 Å obtained from the EXAFS spectrum supports trithiolate bridges between the Rh(III) ions, as was also found when using glutathione as ligand. In the cysteine and penicillamine complexes, double thiolate bridges join the Rh(III) ions, with the nonbridging Cys 2– and Pen 2– ligands in tridentate chelating (S,N,O) mode, which is consistent with the Δδ C = 7.3–8.4 ppm shift of the COO – signal in their carbon-13 cross polarization magic angle spinning (CPMAS) NMR spectra. For the penicillamine complex, the 2475.6 eV peak in its S K edge X-ray absorption near edge structure (XANES) spectrum shows partial oxidation, probably caused by peroxide generated from reduction of dissolved O 2 , of thiolato to sulfenato (S=O) groups, which were also identified by ESI-MS for all three {Rh III 2 L 4 } ...

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“…These solutions are dominated by PbS 2 NO and PbS 3 species, respectively. 26, 47 In the next step the DATFIT program in the EXAFSPAK suite was used to estimate the relative amounts of such PbS 2 N(N/O) and PbS 3 coordinated species in the Pb(II) cysteine solutions A* – F*. This was achieved by fitting the k 3 -weighted EXAFS spectra of solutions A* – F* to a linear combination of EXAFS oscillations for the above lead(II) penicillamine / N -acetylcysteine solutions; however, a clear oscillatory residual was observed.…”

Section: Resultsmentioning

confidence: 99%

Lead(II) Complex Formation with l-Cysteine in Aqueous Solution

et al. 2015

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The lead(II) complexes formed with the multidentate chelator L-cysteine (H2Cys) in alkaline aqueous solution were studied using 207Pb, 13C and 1H NMR, Pb LIII-edge X-ray absorption and UV-vis. spectroscopic techniques, complemented by electro-spray ion mass spectrometry (ESI-MS). The H2Cys/Pb(II) mole ratios were varied from 2.1 to 10.0 for two sets of solutions with CPb(II) = 0.01 and 0.1 M, respectively, prepared at pH values (9.1 – 10.4) for which precipitates of Pb(II)-cysteine dissolved. At low H2Cys/Pb(II) mole ratios (2.1 – 3.0) a mixture of the dithiolate [Pb(S,N-Cys)2]2− and [Pb(S,N,O-Cys)(S-HCys)]− complexes with the average Pb-(N/O) and Pb-S distances 2.42 ± 0.04 Å and 2.64 ± 0.04 Å, respectively, was found to dominate. At high concentration of free cysteinate (> 0.7 M) a significant amount converts to the trithiolate [Pb(S,N-Cys)(S-HCys)2]2−, including a minor amount of a PbS3 coordinated [Pb(S-HCys)3]− complex. The coordination mode was evaluated by fitting linear combinations of EXAFS oscillations to the experimental spectra, and by the 207Pb NMR signals in the chemical shift range δPb = 2006 – 2507 ppm, which became increasingly deshielded with increasing free cysteinate concentration. One-pulse magic angle spinning (MAS) 207Pb NMR spectra of crystalline Pb(aet)2 (Haet = 2-aminoethanethiol or cysteamine) with PbS2N2 coordination were measured for comparison (δiso = 2105 ppm). The UV-vis. spectra displayed absorption maxima at 298 – 300 nm (S− → PbII charge transfer) for the dithiolate PbS2N(N/O) species; with increasing ligand excess a shoulder appeared at ∼ 330 nm for the trithiolate PbS3N and PbS3 (minor) complexes. The results provide spectroscopic fingerprints for structural models for Pb(II) coordination modes to proteins and enzymes.

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Similarities between N-Acetylcysteine and Glutathione in Binding to Lead(II) Ions

Cited by 21 publications

References 73 publications

10. Lead(II) Binding in Natural and Artificial Proteins

10. Lead(II) Binding in Natural and Artificial Proteins

Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh₂(CH₃COO)₄ with Cysteine and Its Derivatives

Lead(II) Complex Formation with l-Cysteine in Aqueous Solution

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Similarities between N-Acetylcysteine and Glutathione in Binding to Lead(II) Ions

Cited by 21 publications

References 73 publications

10. Lead(II) Binding in Natural and Artificial Proteins

10. Lead(II) Binding in Natural and Artificial Proteins

Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh2(CH3COO)4 with Cysteine and Its Derivatives

Lead(II) Complex Formation with l-Cysteine in Aqueous Solution

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Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh₂(CH₃COO)₄ with Cysteine and Its Derivatives