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EPR spectroscopic characterisation of native Cu^II-binding sites in human serum albumin.

ABSTRACT: Human serum albumin (HSA) is the most abundant plasma protein, which functions to transport a large range of ligands within the circulation. These interactions have important implications for human health and disease. The primary binding site for Cu^II ions on HSA is known to be the so-called amino-terminal Cu^II and Ni^II binding (ATCUN) motif. However, the number and identity of secondary binding sites is currently not understood. In this study, we harnessed a suite of contemporary electron paramagnetic resonance (EPR) spectroscopy methods to investigate recombinantly produced constructs of HSA bearing single-histidine knockouts, with the aim to characterise its endogenous Cu^II ion binding sites.

SUBMITTER: Ackermann K

PROVIDER: S-EPMC11320662 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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EPR spectroscopic characterisation of native CuII-binding sites in human serum albumin.

Ackermann Katrin K Wu Dongmei D Stewart Alan J AJ Bode Bela E BE

Dalton transactions (Cambridge, England : 2003) 20240813 32

Human serum albumin (HSA) is the most abundant plasma protein, which functions to transport a large range of ligands within the circulation. These interactions have important implications for human health and disease. The primary binding site for CuII ions on HSA is known to be the so-called amino-terminal CuII and NiII binding (ATCUN) motif. However, the number and identity of secondary binding sites is currently not understood. In this study, we harnessed a sui ...[more]

PMID: 39072685

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Project description:We report a complex with a rare Cu(II)-O-Cu(II) structural motif that is stable at room temperature, which allows its in-depth characterization by a variety of spectroscopic methods. Interest in such compounds is fueled by the recent discovery that a Cu(II)-O-Cu(II) species on the surface of Cu-ZSM-5 is capable of oxidizing methane to methanol, and this in turn ties into mechanistic discussions on the methane oxidation at the dicopper site within the particulate methane monooxygenase. For the synthesis of our Cu2O complex we have developed a novel, neutral ligand system, FurNeu, exhibiting two N-(N',N'-dimethylaminoethyl)(2-pyridylmethyl)amino binding pockets connected by a dibenzofuran spacer. The reaction of FurNeu with CuCl yielded [FurNeu](Cu2(μ-Cl))(CuCl2), 1, demonstrating the geometric potential of the ligand to stabilize Cu-X-Cu moieties. A Cu(I) precursor with weakly coordinating anions was chosen in the next step, namely [Cu(NCCH3)4]OTf, which led to the formation of [FurNeu](Cu(NCCH3))2(OTf)2, 3. Treatment of 3 with O2 or PhIO led to identical green solutions, whose UV-vis spectra were markedly different from the one displayed by [FurNeu](Cu)2(OTf)4, 4, prepared independently from FurNeu and Cu(OTf)2. Further investigations including PhIO consumption experiments, NMR and UV-vis spectroscopy, HR-ESI mass spectrometry, and protonation studies led to the identification of the green product as [FurNeu](Cu2(μ-O))(OTf)2, 5. DOSY NMR spectroscopy confirmed its monomeric character. Over longer periods of time 5 decomposes to give [Cu(picoloyl)2], formed through an oxidative N-dealkylation reaction followed by further oxidation of the ligand. Due to its slow decomposition reaction, all attempts to crystallize 5 failed. However, its structure in solution could be determined by EXAFS analysis in combination with DFT calculations, which revealed a Cu-O-Cu angle that amounts to 105.17°. Moreover, TDDFT calculations helped to rationalize the UV-vis absorptions of 5. The reactivity of complex 5 with 2,4-di-tert-butylphenol, DTBP, was also investigated; the initially formed biphenol product, TBBP, was found to further react in the presence of excessive O2 to yield 2,4,7,9-tetra-tert-butyloxepino[2,3-b]benzofuran, TBOBF, via an intermediate diphenoquinone. It turned out that 5, or its precursor 3, can even be employed as a catalyst for the oxidation of DTBP to TBBP or for the oxidation of TBBP to TBOBF.

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EPR spectroscopic characterisation of native Cu^II-binding sites in human serum albumin.

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EPR spectroscopic characterisation of native Cu<sup>II</sup>-binding sites in human serum albumin.

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Dataset Information

EPR spectroscopic characterisation of native CuII-binding sites in human serum albumin.

Publications

EPR spectroscopic characterisation of native Cu&lt;sup&gt;II&lt;/sup&gt;-binding sites in human serum albumin.

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EPR spectroscopic characterisation of native Cu^II-binding sites in human serum albumin.

EPR spectroscopic characterisation of native Cu<sup>II</sup>-binding sites in human serum albumin.