Pub Date : 2024-12-19DOI: 10.1016/j.jinorgbio.2024.112814
Barry Arkles , David Segarnick , Leandro C. Clementino , Keith H. Pannell , Andrew P. Thomas
Crown ethers have been shown to have physiological effects ascribed to their ionophoric properties. However, high levels of toxicity precluded interest in their evaluation as therapeutic agents. We prepared new silacrown analogs of crown ethers. These initial studies focused on examples of large ring silacrown ethers having at least fourteen ring atoms with at least one lipophilic or hydrophobic substituent on the ring and/or on the silicon atom. The synthesis of silacrown ethers, ionophoric behavior, toxicity studies, and preliminary pharmacodynamic studies in cardiac myocyte cell lines are presented and compared to their carbon analogs. We report the effects of these compounds in HL-1 cells, an atrial muscle cell line with plasma membrane and sarcoplasmic reticulum Ca2+ channels that give rise to spontaneous Ca2+ transients driven by action potentials. Dicyclohexano-18-crown-6 and the silacrown equivalent dimethylsila-17-cyclohexanocrown-6 were both found to rapidly inhibit the Ca2+ transients after acute treatment, and these effects were reversed when extracellular KCl was increased to cause plasma membrane depolarization. The data suggest that the silacrowns can mimic the effects of crown ethers with similar ring sizes, and this appears to be due to their effects on membrane potential and suppression of action potential firing.
{"title":"Silacrown ethers as ion transport modifiers and preliminary observations of cardiovascular cell line response","authors":"Barry Arkles , David Segarnick , Leandro C. Clementino , Keith H. Pannell , Andrew P. Thomas","doi":"10.1016/j.jinorgbio.2024.112814","DOIUrl":"10.1016/j.jinorgbio.2024.112814","url":null,"abstract":"<div><div>Crown ethers have been shown to have physiological effects ascribed to their ionophoric properties. However, high levels of toxicity precluded interest in their evaluation as therapeutic agents. We prepared new silacrown analogs of crown ethers. These initial studies focused on examples of large ring silacrown ethers having at least fourteen ring atoms with at least one lipophilic or hydrophobic substituent on the ring and/or on the silicon atom. The synthesis of silacrown ethers, ionophoric behavior, toxicity studies, and preliminary pharmacodynamic studies in cardiac myocyte cell lines are presented and compared to their carbon analogs. We report the effects of these compounds in HL-1 cells, an atrial muscle cell line with plasma membrane and sarcoplasmic reticulum Ca<sup>2+</sup> channels that give rise to spontaneous Ca<sup>2+</sup> transients driven by action potentials. Dicyclohexano-18-crown-6 and the silacrown equivalent dimethylsila-17-cyclohexanocrown-6 were both found to rapidly inhibit the Ca<sup>2+</sup> transients after acute treatment, and these effects were reversed when extracellular KCl was increased to cause plasma membrane depolarization. The data suggest that the silacrowns can mimic the effects of crown ethers with similar ring sizes, and this appears to be due to their effects on membrane potential and suppression of action potential firing.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"265 ","pages":"Article 112814"},"PeriodicalIF":3.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, has a dismal 5-year survival rate, making palliative chemotherapy the only treatment option. Targeted therapy has limited efficacy in PDAC, underscoring the need for novel therapeutic approaches. The inducible stress-response protein, haem oxygenase-1 (HMOX1), has been implicated in treatment failure in PDAC.
Copper coordination complexes have shown promise as anticancer agents against various cancers, and are associated with apoptotic cell death. The different ligands to which copper is complexed, determine the specificity and efficacy of each complex.
Three different classes of copper complexes were evaluated for anti-cancer activity against AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines. A copper-phenanthroline-theophylline complex (CuPhTh2), a copper-8-aminoquinoline-naphthyl complex (Cu8AqN), and two copper-aromatic-isoindoline complexes (CuAIsI) were effective inhibitors of cell proliferation with clinically relevant IC50 values below 5 μM. The copper complexes caused reactive oxygen species (ROS) formation, promoted annexin-V binding, disrupted the mitochondrial membrane potential (MMP) and activated caspase-9 and caspase-3/7, confirming apoptotic cell death.
Expression of nuclear HMOX1 was increased in both cell lines, with the CuPhTh2 complex being the most active. Inhibition of HMOX1 activity significantly decreased the IC50 values of these copper complexes suggesting that HMOX1 inhibition may alter treatment outcomes in PDAC.
{"title":"Copper complexes induce haem oxygenase-1 (HMOX1) and cause apoptotic cell death in pancreatic cancer cells","authors":"Zakeeya Jhetam , Carla Martins-Furness , Cathy Slabber , Orde Q. Munro , Marietha Nel , Leonie Harmse","doi":"10.1016/j.jinorgbio.2024.112815","DOIUrl":"10.1016/j.jinorgbio.2024.112815","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, has a dismal 5-year survival rate, making palliative chemotherapy the only treatment option. Targeted therapy has limited efficacy in PDAC, underscoring the need for novel therapeutic approaches. The inducible stress-response protein, haem oxygenase-1 (HMOX1), has been implicated in treatment failure in PDAC.</div><div>Copper coordination complexes have shown promise as anticancer agents against various cancers, and are associated with apoptotic cell death. The different ligands to which copper is complexed, determine the specificity and efficacy of each complex.</div><div>Three different classes of copper complexes were evaluated for anti-cancer activity against AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines. A copper-phenanthroline-theophylline complex (CuPhTh<sub>2</sub>), a copper-8-aminoquinoline-naphthyl complex (Cu8AqN), and two copper-aromatic-isoindoline complexes (CuAIsI) were effective inhibitors of cell proliferation with clinically relevant IC<sub>50</sub> values below 5 μM. The copper complexes caused reactive oxygen species (ROS) formation, promoted annexin-V binding, disrupted the mitochondrial membrane potential (MMP) and activated caspase-9 and caspase-3/7, confirming apoptotic cell death.</div><div>Expression of nuclear HMOX1 was increased in both cell lines, with the CuPhTh<sub>2</sub> complex being the most active. Inhibition of HMOX1 activity significantly decreased the IC<sub>50</sub> values of these copper complexes suggesting that HMOX1 inhibition may alter treatment outcomes in PDAC.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112815"},"PeriodicalIF":3.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-15DOI: 10.1016/j.jinorgbio.2024.112813
Boglárka Tűz , Isabel Correia , Paulo N. Martinho
Due to their diverse chemical properties and high ability to interact with biological molecules and cellular processes, transition metal-based compounds have emerged as promising candidates for cancer therapy. Iron complexes are among them, however, there is a gap in the comprehensive analysis of heterometallic iron complexes in the anticancer field. This review aims to fill this gap by summarizing recent progress in the study of Fe(II) and Fe(III) heterobimetallic complexes for anticancer applications and to gather important insights and future perspectives, with special emphasis on their theranostic capabilities. Works published between 2014 and 2024 were considered in this critical survey, that covers a range of complex types, including ferrocene in bimetallic complexes with Pt, Pd, Au, Ag, Ru, Rh, Ir, Cu, Re, Sn and Co; organometallic Fe-complexes with Ru and Ag; photoactive metal complexes with Pt and Co; and magnetic resonance imaging contrast agents with Gd and Mn. Studies conducted to determine the modes of action are highlighted and suggest the involvement of the metal species in reactive oxygen species generation within cells, the impact on apoptosis and cell cycle arrest, and many others. By pursuing interdisciplinary research, innovative theranostic platforms with enhanced efficacy, specificity, and clinical relevance can be developed for cancer management.
{"title":"A critical analysis of the potential of iron heterobimetallic complexes in anticancer research","authors":"Boglárka Tűz , Isabel Correia , Paulo N. Martinho","doi":"10.1016/j.jinorgbio.2024.112813","DOIUrl":"10.1016/j.jinorgbio.2024.112813","url":null,"abstract":"<div><div>Due to their diverse chemical properties and high ability to interact with biological molecules and cellular processes, transition metal-based compounds have emerged as promising candidates for cancer therapy. Iron complexes are among them, however, there is a gap in the comprehensive analysis of heterometallic iron complexes in the anticancer field. This review aims to fill this gap by summarizing recent progress in the study of Fe(II) and Fe(III) heterobimetallic complexes for anticancer applications and to gather important insights and future perspectives, with special emphasis on their theranostic capabilities. Works published between 2014 and 2024 were considered in this critical survey, that covers a range of complex types, including ferrocene in bimetallic complexes with Pt, Pd, Au, Ag, Ru, Rh, Ir, Cu, Re, Sn and Co; organometallic Fe-complexes with Ru and Ag; photoactive metal complexes with Pt and Co; and magnetic resonance imaging contrast agents with Gd and Mn. Studies conducted to determine the modes of action are highlighted and suggest the involvement of the metal species in reactive oxygen species generation within cells, the impact on apoptosis and cell cycle arrest, and many others. By pursuing interdisciplinary research, innovative theranostic platforms with enhanced efficacy, specificity, and clinical relevance can be developed for cancer management.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112813"},"PeriodicalIF":3.8,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.jinorgbio.2024.112812
Gerda T. Gátszegi , Tatsiana V. Petrasheuskaya , Nóra V. May , Bálint Hajdu , Gabriella Spengler , Felix Bacher , Sergiu Shova , Vladimir B. Arion , Éva A. Enyedy
Schiff bases derived from aminoguanidine are extensively investigated for their structural versatility. The tridentate 2-formylpyridine guanylhydrazones act as analogues of 2-formyl or 2-acetylpyridine thiosemicarbazones, where the thioamide unit is replaced by the guanidyl group. Six derivatives of 2-formylpyridine guanylhydrazone were synthesized and their proton dissociation and complex formation processes with Cu(II), Fe(II) and Fe(III) ions were studied using pH-potentiometry, UV–visible, NMR and electron paramagnetic resonance spectroscopic methods. The ligands have substituents such as amine, morpholine, N-methyl-piperazine at different positions of the pyridine ring. The influence of the different structural elements on the solution chemical properties and cytotoxicity has been disclosed. The solid state structure of four ligands was determined by X-ray crystallography. The ligands bind to Cu(II) in a tridentate fashion via an (N,N,N) donor set, forming mono-ligand complexes. However, for ligands with heterocyclic morpholine and piperazine nitrogen atoms in coordination position a tetradentate binding was observed. Despite the additional coordinating donor atom, the stability of these Cu(II) complexes showed little or no increase. The Cu(II), Fe(II) and Fe(III) complexes of the studied 2-formylpyridine guanylhydrazones exhibited significantly lower stability compared to their corresponding 2-formyl or 2-acetylpyridine thiosemicarbazone analogues. The ligands underwent slow partial hydrolysis (and oxidation) in the presence of Cu(II) ions, leading to the formation of new ligands through the reorganization of structural components around the metal ion. Additionally, the studied Cu(II) complexes demonstrated a great propensity for reduction by glutathione. All these features contributed to the finding that these 2-formylpyridine guanylhydrazones and their Cu(II) complexes did not display measurable cytotoxic activity.
{"title":"Solution equilibrium and redox properties of metal complexes with 2-formylpyridine guanylhydrazone derivatives: Effect of morpholine and piperazine substitutions","authors":"Gerda T. Gátszegi , Tatsiana V. Petrasheuskaya , Nóra V. May , Bálint Hajdu , Gabriella Spengler , Felix Bacher , Sergiu Shova , Vladimir B. Arion , Éva A. Enyedy","doi":"10.1016/j.jinorgbio.2024.112812","DOIUrl":"10.1016/j.jinorgbio.2024.112812","url":null,"abstract":"<div><div>Schiff bases derived from aminoguanidine are extensively investigated for their structural versatility. The tridentate 2-formylpyridine guanylhydrazones act as analogues of 2-formyl or 2-acetylpyridine thiosemicarbazones, where the thioamide unit is replaced by the guanidyl group. Six derivatives of 2-formylpyridine guanylhydrazone were synthesized and their proton dissociation and complex formation processes with Cu(II), Fe(II) and Fe(III) ions were studied using pH-potentiometry, UV–visible, NMR and electron paramagnetic resonance spectroscopic methods. The ligands have substituents such as amine, morpholine, <em>N</em>-methyl-piperazine at different positions of the pyridine ring. The influence of the different structural elements on the solution chemical properties and cytotoxicity has been disclosed. The solid state structure of four ligands was determined by X-ray crystallography. The ligands bind to Cu(II) in a tridentate fashion via an (N,N,N) donor set, forming mono-ligand complexes. However, for ligands with heterocyclic morpholine and piperazine nitrogen atoms in coordination position a tetradentate binding was observed. Despite the additional coordinating donor atom, the stability of these Cu(II) complexes showed little or no increase. The Cu(II), Fe(II) and Fe(III) complexes of the studied 2-formylpyridine guanylhydrazones exhibited significantly lower stability compared to their corresponding 2-formyl or 2-acetylpyridine thiosemicarbazone analogues. The ligands underwent slow partial hydrolysis (and oxidation) in the presence of Cu(II) ions, leading to the formation of new ligands through the reorganization of structural components around the metal ion. Additionally, the studied Cu(II) complexes demonstrated a great propensity for reduction by glutathione. All these features contributed to the finding that these 2-formylpyridine guanylhydrazones and their Cu(II) complexes did not display measurable cytotoxic activity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112812"},"PeriodicalIF":3.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.jinorgbio.2024.112811
Yuyin Du , Toshiyuki Kowada , EunHye Sung , Rong Liu , Andrei Soloviev , Toshitaka Matsui , Shin Mizukami
Lysosomal labile Zn2+ levels have been unclear. By targeting a small-molecule fluorescent Zn2+ probe, ZnDA-3H, to lysosomes via VAMP7-Halo, the lysosomal labile Zn2+ concentration was determined to be 1.9 nM in HeLa cells. Furthermore, ZnDA-3H enabled direct visualization of the Zn2+ efflux from the lysosomes to cytosol upon TRPMLs activation.
{"title":"Quantification of lysosomal labile Zn2+ and monitoring of Zn2+ efflux using a small-molecule–protein hybrid fluorescent probe","authors":"Yuyin Du , Toshiyuki Kowada , EunHye Sung , Rong Liu , Andrei Soloviev , Toshitaka Matsui , Shin Mizukami","doi":"10.1016/j.jinorgbio.2024.112811","DOIUrl":"10.1016/j.jinorgbio.2024.112811","url":null,"abstract":"<div><div>Lysosomal labile Zn<sup>2+</sup> levels have been unclear. By targeting a small-molecule fluorescent Zn<sup>2+</sup> probe, ZnDA-3H, to lysosomes via VAMP7-Halo, the lysosomal labile Zn<sup>2+</sup> concentration was determined to be 1.9 nM in HeLa cells. Furthermore, ZnDA-3H enabled direct visualization of the Zn<sup>2+</sup> efflux from the lysosomes to cytosol upon TRPMLs activation.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112811"},"PeriodicalIF":3.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.jinorgbio.2024.112809
Tarali Devi , Stefan Mebs , Dibya Jyoti Barman , Amanda Opis-Basilio , Michael Haumann , Kallol Ray
This study deals with the unprecedented reactivity of a [(cyclam)MnII(OTf)2] (3-cis; OTf = CF3SO3−) with O2, which, depending on the presence or absence of a hydrogen atom donor like 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H), selectively generates di-μ-oxo Mn(III)Mn(IV) (1) or MnIV2 (2) complexes, respectively. Both dimers have been characterized by different techniques including single-crystal X-ray diffraction, X-ray absorption spectroscopy, and electron paramagnetic resonance. Oxygenation reactions carried out with labeled 18O2 and Resonance Raman spectroscopy unambiguously show that the oxygen atoms present in the MnIVMnIII dimer originate from O2. Experimental evidences are provided for a novel method of dioxygen activation involving three Mn ions or two Mn ions and TEMPO-H to generate the bis(μ-oxo)dimanganese(IV) or bis(μ-oxo) dimanganese(III, IV) cores, respectively.
{"title":"Reinvestigation of the mechanism of dioxygen activation at a MnII(cyclam) center","authors":"Tarali Devi , Stefan Mebs , Dibya Jyoti Barman , Amanda Opis-Basilio , Michael Haumann , Kallol Ray","doi":"10.1016/j.jinorgbio.2024.112809","DOIUrl":"10.1016/j.jinorgbio.2024.112809","url":null,"abstract":"<div><div>This study deals with the unprecedented reactivity of a [(cyclam)Mn<sup>II</sup>(OTf)<sub>2</sub>] (<strong>3</strong>-<em>cis</em>; OTf = CF<sub>3</sub>SO<sub>3<sup>−</sup></sub>) with O<sub>2</sub>, which, depending on the presence or absence of a hydrogen atom donor like 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H), selectively generates di-<em>μ</em>-oxo Mn(III)Mn(IV) (<strong>1</strong>) or Mn<sup>IV</sup><sub>2</sub> (<strong>2</strong>) complexes, respectively. Both dimers have been characterized by different techniques including single-crystal X-ray diffraction, X-ray absorption spectroscopy, and electron paramagnetic resonance. Oxygenation reactions carried out with labeled <sup>18</sup>O<sub>2</sub> and Resonance Raman spectroscopy unambiguously show that the oxygen atoms present in the Mn<sup>IV</sup>Mn<sup>III</sup> dimer originate from O<sub>2</sub>. Experimental evidences are provided for a novel method of dioxygen activation involving three Mn ions or two Mn ions and TEMPO-H to generate the bis(<em>μ</em>-oxo)dimanganese(IV) or bis(<em>μ</em>-oxo) dimanganese(III, IV) cores, respectively.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112809"},"PeriodicalIF":3.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.jinorgbio.2024.112810
Luigi F. Di Costanzo , Gianmattia Sgueglia , Carla Orlando , Maurizio Polentarutti , Linda Leone , Salvatore La Gatta , Maria De Fenza , Luca De Gioia , Angela Lombardi , Federica Arrigoni , Marco Chino
The design of protein-metal complexes is rapidly advancing, with applications spanning catalysis, sensing, and bioremediation. We report a comprehensive investigation of METPsc1, a Miniaturized Electron Transfer Protein, in complex with cadmium. This study elucidates the impact of metal coordination on protein folding and structural dynamics across temperatures from 100 K to 300 K. Our findings reveal that METPsc1, composed of two similar halves stabilized by intramolecular hydrogen bonds, exhibits a unique “clothespin-like” recoil mechanism. This allows it to adapt to metal ions of varying radii, mirroring the flexibility observed in natural rubredoxins. High-resolution crystallography and molecular dynamics simulations unveil concerted backbone motions and subtle temperature-dependent shifts in side-chain conformations, particularly for residues involved in crystal packing. Notably, CdS bond lengths increase with temperature, correlating with anisotropic motions of the sulfur atoms involved in second-shell hydrogen bonding. This suggests a dynamic role of protein matrix upon redox cycling. These insights into METPsc1 highlight its potential for catalysis and contribute to the designing of artificial metalloproteins with functional plasticity.
{"title":"Structural insights into temperature-dependent dynamics of METPsc1, a miniaturized electron-transfer protein","authors":"Luigi F. Di Costanzo , Gianmattia Sgueglia , Carla Orlando , Maurizio Polentarutti , Linda Leone , Salvatore La Gatta , Maria De Fenza , Luca De Gioia , Angela Lombardi , Federica Arrigoni , Marco Chino","doi":"10.1016/j.jinorgbio.2024.112810","DOIUrl":"10.1016/j.jinorgbio.2024.112810","url":null,"abstract":"<div><div>The design of protein-metal complexes is rapidly advancing, with applications spanning catalysis, sensing, and bioremediation. We report a comprehensive investigation of METPsc1, a Miniaturized Electron Transfer Protein, in complex with cadmium. This study elucidates the impact of metal coordination on protein folding and structural dynamics across temperatures from 100 K to 300 K. Our findings reveal that METPsc1, composed of two similar halves stabilized by intramolecular hydrogen bonds, exhibits a unique “clothespin-like” recoil mechanism. This allows it to adapt to metal ions of varying radii, mirroring the flexibility observed in natural rubredoxins. High-resolution crystallography and molecular dynamics simulations unveil concerted backbone motions and subtle temperature-dependent shifts in side-chain conformations, particularly for residues involved in crystal packing. Notably, Cd<img>S bond lengths increase with temperature, correlating with anisotropic motions of the sulfur atoms involved in second-shell hydrogen bonding. This suggests a dynamic role of protein matrix upon redox cycling. These insights into METPsc1 highlight its potential for catalysis and contribute to the designing of artificial metalloproteins with functional plasticity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112810"},"PeriodicalIF":3.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.jinorgbio.2024.112808
Yajie Niu , Shuanghui Tang , Jiongbang Li , Chunxia Huang , Yan Yang , Lin Zhou , Yunjun Liu , Xiandong Zeng
In this study, [Ir(ppy)2(DMHBT)](PF6) (ppy = deprotonated 1-phenylpyridine, DMHBT = 10,12-dimethylpteridino[6,7-f][1,10]phenanthroline-11,13-(10,12H)-dione, 8a), [Ir(bzq)2(DMHBT)](PF6) (bzq = deprotonated benzo[h]quinoline, 8b) and [Ir(piq)2(DMHBT)](PF6) (piq = deprotonated 1-phenylisoquinoline, 8c) were synthesized and characterized by HRMS, 13C NMR and 1H NMR. In vitro cytotoxicity experiments showed that 8a, 8b, 8c show moderate cytotoxicity against B16 cells, while the cytotoxicity of the complexes 8a, 8b and 8c toward B16 cells was greatly improved upon light irradiation, which can be used as photosensitizers to exert anticancer efficacy in photodynamic therapy (PDT). After being taken up by cells, 8a, 8b, 8c were localized in the mitochondria, resulting in a large amount of Ca2+ in-flux, a burst release of ROS, a sustained opening of mitochondrial permeability transition pore, and a decrease of the mitochondrial membrane potential, which led to mitochondrial dysfunction and further activation of caspase 3 and Bcl-2 family proteins to induce apoptosis. Overloaded ROS reacted with polyunsaturated fatty acids on the cell membrane, and initiated lipid peroxidation, inhibited the xc−-system-glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant defense system, and upregulated the expression of the damage-associated molecules, HMGB1, CRT, and HSP70. The presence of Fer-1 was effective on increasing the cell survival, which demonstrates that the complexes possess the potential to induce ferroptosis and immunogenic cell death. In addition, 8a, 8b and 8c induced autophagy by inhibiting the AKT/PI3K/mTOR signaling pathway, downregulating p62 and promoting Beclin-1 expression upon light irradiation.
{"title":"Induction of ferroptosis of iridium(III) complexes localizing at the mitochondria and lysosome by photodynamic therapy","authors":"Yajie Niu , Shuanghui Tang , Jiongbang Li , Chunxia Huang , Yan Yang , Lin Zhou , Yunjun Liu , Xiandong Zeng","doi":"10.1016/j.jinorgbio.2024.112808","DOIUrl":"10.1016/j.jinorgbio.2024.112808","url":null,"abstract":"<div><div>In this study, [Ir(ppy)<sub>2</sub>(DMHBT)](PF<sub>6</sub>) (ppy = deprotonated 1-phenylpyridine, DMHBT = 10,12-dimethylpteridino[6,7-f][1,10]phenanthroline-11,13-(10,12H)-dione, 8a), [Ir(bzq)<sub>2</sub>(DMHBT)](PF<sub>6</sub>) (bzq = deprotonated benzo[<em>h</em>]quinoline, 8b) and [Ir(piq)<sub>2</sub>(DMHBT)](PF<sub>6</sub>) (piq = deprotonated 1-phenylisoquinoline, 8c) were synthesized and characterized by HRMS, <sup>13</sup>C NMR and <sup>1</sup>H NMR. In vitro cytotoxicity experiments showed that 8a, 8b, 8c show moderate cytotoxicity against B16 cells, while the cytotoxicity of the complexes 8a, 8b and 8c toward B16 cells was greatly improved upon light irradiation, which can be used as photosensitizers to exert anticancer efficacy in photodynamic therapy (PDT). After being taken up by cells, 8a, 8b, 8c were localized in the mitochondria, resulting in a large amount of Ca<sup>2+</sup> in-flux, a burst release of ROS, a sustained opening of mitochondrial permeability transition pore, and a decrease of the mitochondrial membrane potential, which led to mitochondrial dysfunction and further activation of caspase 3 and Bcl-2 family proteins to induce apoptosis. Overloaded ROS reacted with polyunsaturated fatty acids on the cell membrane, and initiated lipid peroxidation, inhibited the x<sub>c</sub><sup>−</sup>-system-glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant defense system, and upregulated the expression of the damage-associated molecules, HMGB1, CRT, and HSP70. The presence of Fer-1 was effective on increasing the cell survival, which demonstrates that the complexes possess the potential to induce ferroptosis and immunogenic cell death. In addition, 8a, 8b and 8c induced autophagy by inhibiting the AKT/PI3K/mTOR signaling pathway, downregulating p62 and promoting Beclin-1 expression upon light irradiation.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112808"},"PeriodicalIF":3.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.jinorgbio.2024.112802
Marek Štekláč , Michal Malček , Peter Gajdoš , Simona Vevericová , Milan Čertík , Marián Valko , Vlasta Brezová , Miriama Malček Šimunková
Acacetin (AC) is a natural polyphenol from the group of flavonoids. It is well established that the behavior of flavonoids depends on the presence of redox-active substances; therefore, we aim to investigate their biological activity following the interaction with Cu(II) ion. Our study demonstrates that AC can effectively bind Cu(II) ions, as confirmed by UV–Vis and EPR spectroscopy as well as DFT calculations. AC appears as a potent scavenger against the model ABTS radical cation by itself, but this ability is significantly limited upon Cu(II) coordination. The possible mild synergistic effect of AC in the presence of vitamin C and glutathione was also shown by the ABTS•+ test. In contrast, an inhibitory effect was observed in the presence of Cu(II) ions. The equimolar addition of AC to the model Fenton-like system containing Cu(II) did not have a noticeable effect on the concentration of hydroxyl radicals produced, but in its excess the formation of •OH decreased, as proved by EPR spin trapping. Absorption titrations and gel electrophoresis revealed effective binding to calf thymus (CT)-DNA with a stronger interaction for the Cu(II)-AC complex. The detailed mode of binding to biomolecules was described using molecular docking and molecular dynamics. Obtained results indicate that the double helix of DNA unwinds after interaction with the Cu(II)-AC complex. Fluorescence spectroscopy, employing human serum albumin (HSA), suggested a potential transport capacity for both AC and its Cu(II) complex.
{"title":"Antioxidant effect, DNA-binding, and transport of the flavonoid acacetin influenced by the presence of redox-active Cu(II) ion: Spectroscopic and in silico study","authors":"Marek Štekláč , Michal Malček , Peter Gajdoš , Simona Vevericová , Milan Čertík , Marián Valko , Vlasta Brezová , Miriama Malček Šimunková","doi":"10.1016/j.jinorgbio.2024.112802","DOIUrl":"10.1016/j.jinorgbio.2024.112802","url":null,"abstract":"<div><div>Acacetin (AC) is a natural polyphenol from the group of flavonoids. It is well established that the behavior of flavonoids depends on the presence of redox-active substances; therefore, we aim to investigate their biological activity following the interaction with Cu(II) ion. Our study demonstrates that AC can effectively bind Cu(II) ions, as confirmed by UV–Vis and EPR spectroscopy as well as DFT calculations. AC appears as a potent scavenger against the model ABTS radical cation by itself, but this ability is significantly limited upon Cu(II) coordination. The possible mild synergistic effect of AC in the presence of vitamin C and glutathione was also shown by the ABTS<sup>•+</sup> test. In contrast, an inhibitory effect was observed in the presence of Cu(II) ions. The equimolar addition of AC to the model Fenton-like system containing Cu(II) did not have a noticeable effect on the concentration of hydroxyl radicals produced, but in its excess the formation of <sup>•</sup>OH decreased, as proved by EPR spin trapping. Absorption titrations and gel electrophoresis revealed effective binding to calf thymus (CT)-DNA with a stronger interaction for the Cu(II)-AC complex. The detailed mode of binding to biomolecules was described using molecular docking and molecular dynamics. Obtained results indicate that the double helix of DNA unwinds after interaction with the Cu(II)-AC complex. Fluorescence spectroscopy, employing human serum albumin (HSA), suggested a potential transport capacity for both AC and its Cu(II) complex.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112802"},"PeriodicalIF":3.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The catalytic mechanisms of enzymes can be phylogenetically mapped corresponding to their catalytic structures. This mapping effectively elucidates the diversity of enzyme catalytic mechanisms and the emergence of new enzymatic activities within enzyme superfamilies. The haloacid dehalogenase (HAD) superfamily serves as an exemplary model system for comprehending the co-evolution of catalytic structures and mechanisms. This study delves into the mechanism underlying the functional divergence of β-phosphoglucomutase (β-PGM) from the phosphatase branch of the HAD superfamily, employing a chemical perspective. Through the construction and calculation of three models of varying scales using the Density Functional Theory method with B3LYP function, we aim to investigate the chemical mechanism driving this functional divergence of β-PGM from the HAD family. The computational results indicate that residues His20 and Lys76 in the second shell stabilize substrates and enhance the acid-base catalytic ability of Asp10. Additionally, residues Arg49, Ser116 and Asn118 facilitate substrate binding by engaging in close hydrogen bonding interactions with the substrates. Through cooperative action, these residues enable β-PGM to function as an efficient phosphoglucomutase. Through computational modeling and a chemical perspective, we unravel the mechanisms enabling β-PGM to convert β-d-glucose 1-phosphate to β-d-glucose 6-phosphate. Finally, based on the analysis of the evolutionary tree, we discussed and summarized the evolutionary relationships among different forms of metal cores of hydrolases.
{"title":"Unraveling the mechanism: How does β-phosphoglucomutase from the haloacid dehalogenase superfamily catalyze the interconversion of β-d-glucose 1-phosphate and β-d-glucose 6-phosphate? A chemical perspective","authors":"Hao Zhang , Mingming Zhang , Kangning Zhu , Yulan Feng , Ling Yang , Wanjian Ding","doi":"10.1016/j.jinorgbio.2024.112794","DOIUrl":"10.1016/j.jinorgbio.2024.112794","url":null,"abstract":"<div><div>The catalytic mechanisms of enzymes can be phylogenetically mapped corresponding to their catalytic structures. This mapping effectively elucidates the diversity of enzyme catalytic mechanisms and the emergence of new enzymatic activities within enzyme superfamilies. The haloacid dehalogenase (HAD) superfamily serves as an exemplary model system for comprehending the co-evolution of catalytic structures and mechanisms. This study delves into the mechanism underlying the functional divergence of <em>β</em>-phosphoglucomutase (<em>β</em>-PGM) from the phosphatase branch of the HAD superfamily, employing a chemical perspective. Through the construction and calculation of three models of varying scales using the Density Functional Theory method with B3LYP function, we aim to investigate the chemical mechanism driving this functional divergence of <em>β</em>-PGM from the HAD family. The computational results indicate that residues His20 and Lys76 in the second shell stabilize substrates and enhance the acid-base catalytic ability of Asp10. Additionally, residues Arg49, Ser116 and Asn118 facilitate substrate binding by engaging in close hydrogen bonding interactions with the substrates. Through cooperative action, these residues enable <em>β</em>-PGM to function as an efficient phosphoglucomutase. Through computational modeling and a chemical perspective, we unravel the mechanisms enabling <em>β</em>-PGM to convert <em>β</em>-<span>d</span>-glucose 1-phosphate to <em>β</em>-<span>d</span>-glucose 6-phosphate. Finally, based on the analysis of the evolutionary tree, we discussed and summarized the evolutionary relationships among different forms of metal cores of hydrolases.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"264 ","pages":"Article 112794"},"PeriodicalIF":3.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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