Journal of Biological Inorganic Chemistry最新文献

Vimentin is a principal intermediate filament (IF) protein that is essential for maintaining cytoskeleton architecture and cellular mechanical integrity. Growing evidence is revealing that metal ions play critical roles in modulating the structure, assembly, and mechanics of vimentin IFs. Despite this, a detailed molecular-level understanding of vimentin–metal interactions and its functional consequences remains incomplete. This review summarizes the current knowledge of metal-induced effects on the structural and mechanical properties of vimentin and highlights how post-translational modifications and cytoskeletal dynamics may alter these metal–protein interactions. Advancing our understanding of the interplay between metal ions and vimentin IFs will enhance our comprehension of the complex mechanisms governing the versatile functions of vimentin and other IF proteins in health and disease.

Graphical abstract

A novel ruthenium(II) compound, cis-[Ru(phen)₂(4-bzpy)(Cl)](PF₆) (complex I), where phen = 1,10-phenanthroline and 4-bzpy = 4-benzoylpyridine, was synthesized and fully characterized using electrochemical and spectroscopic methods, and its structure was determined by single-crystal X-ray diffraction. Density functional theory (DFT) and time-dependent DFT calculations were performed to shed light on the electronic structure and nature of the vibrational and electronic transitions. The photochemical behavior of complex I in aqueous solution showed that irradiation with blue light (453 nm) promoted the release of the coordinated 4-bzpy ligand originating cis-[Ru(phen)₂(H₂O)(Cl)]⁺ ion, as identified by NMR and electronic spectroscopy. Moreover, complex I exhibited a great ability to cleave DNA molecules upon blue light irradiation, which was associated with the production of reactive oxygen species (singlet oxygen and superoxide anion). In this study, we also investigated the antimicrobial activity of complex I along with a similar compound, cis-[Ru(bpy)₂(4-bzpy)(Cl)](PF₆) (complex II), their precursors [Ru(bpy)₂Cl₂] and [Ru(phen)₂Cl₂], and the free ligand 4-bzpy. These two ruthenium complexes I and II have a common auxiliary ligand 4-bzpy, but distinct chelating ligands (phenanthroline or 2,2′-bipyridine, bpy). Notably, both complexes showed promising antibacterial activity against Gram-positive bacterial strains of Staphylococcus aureus and Staphylococcus epidermidis. However, complex I showed a superior antibacterial effect compared with complex II, supporting the important role of the phen ligand, likely providing greater lipophilicity to this compound.

Graphical Abstract

Chamomile extract (CHA) was employed in the synthesis of silver nanoparticles (AgNPs(CHA)). These nanoparticles were incorporated into a hydroxyethyl methacrylate (pHEMA) matrix during polymerization at concentrations of 1 mg/mL (pHEMA@AgNPs(CHA)_1) and 2 mg/mL (pHEMA@AgNPs(CHA)_2). The resulting materials— AgNPs(CHA), pHEMA@AgNPs(CHA)_1, and pHEMA@AgNPs(CHA)_2 —were characterized using a plethora of analytical techniques, including Refractive Index (RI), X-ray fluorescence (XRF) spectroscopy, X-ray powder diffraction (XRPD), thermogravimetric-differential thermal analysis (TG–DTA), differential scanning calorimetry (DSC), ultraviolet–visible (UV–Vis) spectroscopy, and attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy in the solid state, as well as UV–Vis spectroscopy in solution. XRPD analysis revealed a crystallite size of 8.02 nm, while the diameter of the nanoparticles, estimated using the λmax of the Surface Plasmon Resonance (SPR) spectrum, was 37 nm. The antimicrobial properties of the materials were evaluated against Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli, as well as Gram-positive bacteria, Staphylococcus epidermidis and Staphylococcus aureus. These pathogens are commonly implicated in microbial keratitis. Antimicrobial efficacy was assessed using Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), and Inhibitory Zones (IZs). The IZs for P. aeruginosa, E. coli, S. epidermidis, and S. aureus following incubation with paper discs soaked in 1 mg/mL of AgNPs(CHA) were 16.0 ± 0.6 mm, 11.1 ± 0.9 mm, 15.8 ± 1.2 mm, and 15.1 ± 0.2 mm, respectively. Bacterial viability after incubation with hydrogel discs of pHEMA@AgNPs(CHA)_1 showed reductions to 0.9 ± 0.2%, 100.0 ± 0.0%, 1.9 ± 1.0%, and 4.4 ± 1.5% for P. aeruginosa, E. coli, S. epidermidis, and S. aureus, respectively. Additionally, no toxic effects were observed on human corneal epithelial cells (HCECs). These findings suggest that pHEMA@AgNPs(CHA)_1 has potential as a promising candidate for developing non-infectious contact lenses.

Magnetic interactions between iron–sulfur (Fe/S) clusters and transition metal centers such as nickel, molybdenum, and copper play a central role in the function of key metalloenzymes. These interactions, which arise from electronic coupling, spin exchange, and spatial arrangement, directly influence redox behavior and catalytic efficiency. This review highlights three distinct complex enzymes—[NiFe] hydrogenases, mononuclear molybdenum-containing xanthine oxidase (XO) family, and [NiFe] and [MoCu] carbon monoxide dehydrogenases (CODHs)—as paradigms for understanding (Fe/S)-metal center interactions. In [NiFe] hydrogenases, (Fe/S) clusters serve as electron relays that magnetically interact with the catalytic [NiFe] active site. In XO-type enzymes, a mononuclear Mo center is functionally and magnetically coupled to nearby Fe/S clusters, modulating substrate reduction and electron transfer. Similarly, in CODHs, both [NiFe]—and [MoCu]-dependent variants exhibit strong magnetic communication between metal active sites and surrounding Fe/S clusters, crucial for CO₂/CO interconversion. Advanced spectroscopic approaches, particularly electron paramagnetic resonance (EPR) and related techniques, combined with theoretical modelling, have provided deep insights into the electronic structures and dynamic interactions within these metalloenzymes. Understanding these magnetic interactions not only sheds light on fundamental electron-transfer and enzymatic mechanisms but also guides the design of bioinspired catalysts and energy-conversion technologies.

Graphical abstract

Alterations of iron homeostasis are characteristic of malignant behavior and have been associated with poor prognosis in ovarian cancer patients. Iron-binding chelators are currently under investigation as potential cancer therapeutics because they allow manipulation of iron availability and redox chemistry. In addition, the design of prochelator systems enables the release of iron-binding chelators upon cell entry and therefore the sequestration of intracellular (rather than systemic) iron. We report the synthesis and biological evaluation of disulfide-based prochelators featuring a 2-pyridyl-hydrazone motif and resulting in a tridentate (S,N,N) donor set as found in several antiproliferative chelators (e.g., Triapine, Dp44mT, DpC, COTI-2). Upon disulfide reduction and iron(II) coordination, the chelators stabilize ferric complexes that are redox-active in neutral aqueous conditions. Symmetric prochelator (PH3-S)₂ and glucose conjugate G6PH3 have antiproliferative, pro-apoptotic effects in A2780 ovarian carcinoma cells. Both compounds sequester intracellular iron and impact the expression of the transferrin receptor TfR1 and the iron storage protein ferritin. Oxidative stress is found to be a component of the mechanism of action of these prochelators. Accordingly, the preformed iron complex FePH3 also leads to apoptosis and iron dysregulation, and its toxicity is enhanced when the antioxidant capacity of the cells is impaired. The incorporation of the 2-pyridyl-hydrazone motif in disulfide-based prochelators therefore combines iron sequestration with pro-oxidant effects that could enhance the pharmacological profile of this chelation approach for cancer applications.

Graphical Abstract

Au(I) compounds have long been associated with medicine for the treatment of various diseases, especially auranofin has been used for the treatment of rheumatoid arthritis. In addition, Au(I) based compounds also exhibit anti-cancer, anti-bacteria properties. The recent prevalence of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has aroused attention to investigate the antiviral potential of Au(I) compounds. Herein we demonstrate the pan-anti-SARS-CoV-2 activity of Au(I) metallodrugs in mammalian cells. We synthesized a panel of Au(I)-based compounds and found that these compounds could effectively inhibit the exoribonuclease and methyltransferase activities of SARS-CoV-2 nsp14/nsp10 complex, and the ATPase and DNA unwinding activities of SARS-CoV-2 nsp13 (helicase). Mechanistic studies reveal that Au(I) can not only displace the critical Zn(II) ions from nsp14/nsp10 complex and nsp13 but also changes the secondary and quaternary structure of nsp14 and perturbate the DNA unwinding of nsp13 by disrupting the ATP binding. This study illustrates a multi-target feature Au(I) compounds/drug agents for the viruses, highlighting their potential as pan-anti-SARS-CoV-2 (or relevant viruses) agents.

Graphical Abstract

Bioinorganic chemistry is a multidisciplinary field that bridges the apparent divide between inorganic chemistry and biology. The very name “bioinorganic” is an intriguing oxymoron, as “inorganic” chemistry traditionally refers to the study of the inanimate world, while the “bio” prefix refers to living systems. Bioinorganic chemistry focuses on metallic systems within biological environments, with the dual aims of better understanding these natural systems and leveraging the solutions developed through evolution to design new industrial or therapeutic applications. As a close cousin of the field of metallomics, bioinorganic chemistry shares the fundamental principles that underpin metallomics’ systemic analyses of metal-containing biomolecules. In this article, we trace the historical development of bioinorganic chemistry, highlighting its recent advancements and outlining future research challenges in this dynamic interdisciplinary area.

Graphical abstract

New organotin(IV) mono- and bis-carboxylate complexes derivatives of Bexarotene (bex), viz. R₃Sn(bex) (where R = Ph (1); Cy (2); nBu (3)), and R₂Sn(bex)₂ (where R = Et (4), tBu (5), Ph (6)) were synthesized. Compounds were fully characterized using spectroscopic techniques. The molecular structure for the Ph₃Sn(bex) (1) in crystalline form was established by single-crystal X-ray diffraction. Electrochemical properties of tin complexes and bexarotene were investigated by cyclic voltammetry. The target compounds are characterized by the high oxidation potentials in the mixture of aprotic solvents. The anti/prooxidant activity of the complexes and bexarotene in the lipid peroxidation process and in the reaction of the DNA oxidative damage was studied in vitro. Excellent cell growth inhibition against A549, HCT 116 and MCF-7 cancer cells was observed for triorganotin (IV) carboxylates with IC₅₀ values mostly under the submicromolar concentration range and there are more effective than bexarotene or cisplatin.

Graphical abstract

Metalloproteins tune the electronic properties of metal active sites through a combination of primary and secondary coordination sphere effects (PCS and SCS) to efficiently perform an array of redox chemistry, including electron transfer (ET) and catalysis. A major influence of these effects is the anisotropic spatial distribution of redox-active molecular orbitals (RAMOs), which in turn dictates redox chemistry of the metalloproteins. While much progress has been made in understanding the SCS effects on RAMOs in individual native metalloproteins, it has been difficult to experimentally examine the influence of the same SCS effects on RAMOs with different spatial distributions. Taking advantage of our recent studies of SCS effect on blue copper azurin from Pseudomonas aeruginosa (Blue CuAz) and its M121H/H46E variant that closely mimic the red copper protein (Red CuAz), in which their RAMOs are dominated by either Cu–S_π or Cu–S_σ interactions, respectively, we herein compare and contrast how the same SCS modifications impact the electronic and geometric structures of blue and red Cu center in the same protein scaffold. Specifically, we expand our understanding of unpaired electron distribution at the Cu-binding site of Red CuAz and its SCS N47S, F114P, and F114N mutations using ¹H and ¹⁴N electron–nuclear double resonance (ENDOR) spectroscopy, and then further combine these data sets with recent studies and DFT calculations to provide insight into how these mutations differentially (or similarly) impact electronic structure in Red vs. Blue CuAz. We find that electrostatics produce similar effects in both Red and Blue CuAz, where the introduction of dipole moments in the vicinity of Cu and S produces changes in spin density distribution and of the same sign and comparable magnitude. However, disruption of H-bonding with S through the F114P mutation leads to opposing effects in Red vs. Blue CuAz, which we propose arise from differences in the conformation of Cys112 sidechain adapted in the absence the stabilizing S_C112⋯H–N backbone interaction.

Graphical abstract

The interaction of metal ions with nucleic acids was studied by determining the initial binding sites of Ag⁺ ions at unmodified B-DNA by NMR spectroscopy. In particular, NMR spectra were recorded of the Dickerson-Drew dodecamer sequence in the presence of different ratios of Ag⁺ ions to DNA. The data indicate that the coordination of the first three Ag⁺ ions per duplex preferentially takes place inside the B-DNA helix rather than at other possible binding sites such as the negatively charged phosphate backbone and/or the endocyclic N7 position of purine residues. Larger DNA aggregates are formed in the presence of excess Ag⁺ ions, as indicated by the formation of a precipitate and by significant changes in the circular dichroism spectra. As shown by a titration with chloride ions, the Ag⁺ ions are only loosely bound to the nucleic acids and can be released by precipitation of AgCl.

Graphical Abstract