Journal of Inorganic Biochemistry最新文献

{"title":"Multimodal anticancer potential of newly synthesized palladium(II), platinum(II), and gold(III) complexes with 2-(Thiazol-2-yl)pyridine-4,5-dicarboxylate dimethyl ester","authors":"Tina P. Andrejević ,&nbsp;Jakob Kljun ,&nbsp;Sanja Matić ,&nbsp;Tijana Marković ,&nbsp;Žiko Milanović ,&nbsp;Kristina Milisavljević ,&nbsp;Darko P. Ašanin ,&nbsp;Suzana Popović ,&nbsp;Dejan Baskić ,&nbsp;Iztok Turel ,&nbsp;Miloš I. Djuran ,&nbsp;Biljana Đ. Glišić","doi":"10.1016/j.jinorgbio.2025.113208","DOIUrl":"10.1016/j.jinorgbio.2025.113208","url":null,"abstract":"<div><div>Novel palladium(II), platinum(II), and gold(III) complexes, [PdCl₂(py-2tz)] (<strong>1</strong>), [PtCl₂(py-2tz)] (<strong>2</strong>), and [AuCl₂(py-2tz)][AuCl₄] (<strong>3</strong>), py-2tz is 2-(Thiazol-2-yl)pyridine-4,5-dicarboxylate dimethyl ester, were synthesized and characterized using spectroscopy (¹H and ¹³C NMR, IR, and UV–Vis), mass spectrometry, density functional theory (DFT), electrochemical (cyclic voltammetry), and crystallographic methods. Single-crystal X-ray diffraction analysis revealed that all complexes are square-planar with bidentate coordination of the py-2tz ligand <em>via</em> its pyridine and thiazole nitrogen atoms to the corresponding metal ion. These complexes were further evaluated against three human cell lines, two cancer (colon, HCT-116, and cervical adenocarcinoma, HeLa) and one healthy (embryonic lung fibroblast, MRC-5), using the MTT cytotoxicity assay. The influence of these complexes on the type of cell death and cell cycle progression were examined by flow cytometry. Of all the complexes investigated, the gold(III) complex showed the most prominent cytotoxicity toward tumor cells, with reduced toxicity against MRC-5 compared to cisplatin. Furthermore, this complex induced apoptosis and autophagy in both tumor cell lines, and G2/M arrest in HCT-116 cells. The binding interactions of the complexes <strong>1</strong>–<strong>3</strong> with bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) were also investigated using fluorescence spectroscopy, complemented by molecular docking simulations.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113208"},"PeriodicalIF":3.2,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881773","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}

{"title":"Developing a novel binuclear copper complex for enhanced cellular copper uptake and cancer treatment","authors":"Haoran Liu ,&nbsp;Jingyi Zhang ,&nbsp;Yanping Li ,&nbsp;Jiamin Jin ,&nbsp;Jian Chen ,&nbsp;Juzheng Zhang","doi":"10.1016/j.jinorgbio.2025.113206","DOIUrl":"10.1016/j.jinorgbio.2025.113206","url":null,"abstract":"<div><div>Although elesclomol (Es) has been investigated as a copper ionophore in antitumor clinical trials, its therapeutic potential remains limited by suboptimal copper transport efficiency and a narrow mechanism of action. To overcome these limitations and improve the anticancer efficacy of copper ionophores, we designed and synthesized L1—a novel chelator capable of forming the binuclear copper complex C1. Our results demonstrate that C1 exhibits superior therapeutic properties compared to Elesclomol–Cu (Es<img>Cu), including enhanced cellular copper uptake in gastric cancer cells and multiple anticancer mechanisms. These mechanisms include potent induction of cuproptosis (significantly stronger than Es<img>Cu), generation of mitochondrial superoxide and intracellular reactive oxygen species, induction of autophagic lysosome accumulation, DNA damage, and activation of apoptosis. More importantly, <em>in vivo</em> studies revealed a remarkable tumor inhibition rate of 80.3 % for C1, substantially higher than that of Es<img>Cu (45 %). These findings establish C1 as a promising next-generation copper-based anticancer agent with enhanced therapeutic potential.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113206"},"PeriodicalIF":3.2,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881774","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}

{"title":"Ascorbate-enabled C-H bond amination catalyzed by myoglobin reconstituted with a trifluoromethyl-substituted Iron porphyrin","authors":"Chihiro Sonoda,&nbsp;Takashi Hayashi","doi":"10.1016/j.jinorgbio.2025.113207","DOIUrl":"10.1016/j.jinorgbio.2025.113207","url":null,"abstract":"<div><div>Nitrogen-containing organic molecules are essential structural motifs in bioactive compounds, pharmaceuticals and functional materials. Direct C-H amination via nitrene transfer provides an efficient and atom-economical route for C-N bond formation. However, most hemoprotein-based catalysts require strong reductants such as dithionite to generate the metal–nitrene intermediate. Here, we report myoglobin reconstituted with an iron complex (FePor(CF₃)₂) bearing two trifluoromethyl groups at the pyrrole β-positions of the porphyrin framework. This arrangement promotes intramolecular benzylic C-H bond amination under mild conditions using sodium <span>l</span>-ascorbate as the sole reductant. The FePor(CF₃)₂ cofactor exhibits a positively shifted Fe(III)/Fe(II) redox potential that allows efficient reduction to occur in the protein scaffold and suppresses noncatalytic substrate reduction, leading to improved chemoselectivity for secondary C-H bond amination. The H64A mutant of myoglobin reconstituted with FePor(CF₃)₂ achieved a turnover number (TON) of 133 for tertiary benzylic C-H amination. Kinetic studies revealed that the reaction rate is inversely correlated with the C-H bond dissociation energy, with a smaller negative slope in the bond dissociation energies (BDEs) plot compared to a synthetic cofactor with a negative redox potential. This suggests that there is a mechanistic shift in the rate-determining step from hydrogen atom transfer to nitrene formation. These findings highlight the potential of cofactor redox tuning to control reactivity and selectivity in artificial heme enzymes for abiological C-H bond functionalization.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113207"},"PeriodicalIF":3.2,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909877","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}

{"title":"Cyclometalated iridium complex as a PD-L1 inhibitor: Suppressing expression via COX-2 blockade","authors":"Yating Zhang ,&nbsp;Jingyue Zhao ,&nbsp;Zhengqi Shen ,&nbsp;Xiangyu Dai ,&nbsp;Peisen Wang ,&nbsp;Zhi Su ,&nbsp;Suxing Jin ,&nbsp;Xuling Xue ,&nbsp;Hong-Ke Liu","doi":"10.1016/j.jinorgbio.2025.113198","DOIUrl":"10.1016/j.jinorgbio.2025.113198","url":null,"abstract":"<div><div>Metal-based Programmed Cell Death Ligand 1 (PD-L1) inhibitors partially overcome the limitations of small-molecule inhibitors, such as ambiguous targeting and complex synthetic processes. This study explores a cyclometalated iridium(III) complex Ir-FA by incorporating bioactive natural product trans-ferulic acid (FA), which could be a promising metal-based PD-L1 inhibitor. Ir-FA demonstrated selective cytotoxicity against A549 cells while exhibiting no toxicity toward normal HLF cell line. Mechanistic studies revealed that Ir-FA induces mitochondrial dysfunction via reactive oxygen species (ROS) overproduction and membrane potential collapse. Concurrently, Ir-FA effectively suppressed the expression and activity of key inflammatory mediators, cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2). Crucially, this combined action, mitochondrial impairment and COX-2/PGE2 inhibition, resulted in the marked downregulation of intracellular PD-L1 expression, which might help suppress the tumor immune evasion. These findings highlight the potential of exploiting the synergistic effects of iridium coordination chemistry and anti-inflammatory activity to develop innovative metal-based agents targeting the Programmed Cell Death Protein 1/PD-L1 immune checkpoint pathway. This work created a transformative platform for developing multifunctional metallodrugs with synergizing chemotherapy and immune activation, holding significant value for cancer treatment.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113198"},"PeriodicalIF":3.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839080","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}

{"title":"Structural and mechanistic insights into the sulfur transfer protein SufU from Staphylococcus aureus","authors":"Emily Sabo ,&nbsp;Connor Nelson ,&nbsp;Delanie Huntoon ,&nbsp;Jing Yang ,&nbsp;Martin Kirk ,&nbsp;Simon J. George ,&nbsp;Brian Bennett ,&nbsp;Jeffrey M. Boyd ,&nbsp;Richard C. Holz","doi":"10.1016/j.jinorgbio.2025.113205","DOIUrl":"10.1016/j.jinorgbio.2025.113205","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Substitution of the active site Zn&lt;sup&gt;2+&lt;/sup&gt; ion in the sulfur transfer protein (SufU) from &lt;em&gt;Staphylococcus aureus&lt;/em&gt; (&lt;em&gt;Sa&lt;/em&gt;SufU) with a catalytically active Co&lt;sup&gt;2+&lt;/sup&gt; ion revealed a S&lt;sup&gt;−&lt;/sup&gt;➔Co&lt;sup&gt;2+&lt;/sup&gt; ligand-to-metal-charge-transfer (LMCT) band at 340 nm with an &lt;em&gt;ε&lt;/em&gt; of &lt;em&gt;∼&lt;/em&gt;&lt;span&gt;&lt;math&gt;&lt;mn&gt;2,760&lt;/mn&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;msup&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;msup&gt;&lt;mi&gt;cm&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;/math&gt;&lt;/span&gt;, as well as &lt;em&gt;d-d&lt;/em&gt; (i.e. ligand field) absorption bands at 584 nm (&lt;em&gt;ε&lt;/em&gt; = 540 &lt;span&gt;&lt;math&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;msup&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;msup&gt;&lt;mi&gt;cm&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;/math&gt;&lt;/span&gt;), 636 nm (&lt;em&gt;ε&lt;/em&gt; = 580 &lt;span&gt;&lt;math&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;msup&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;msup&gt;&lt;mi&gt;cm&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;/math&gt;&lt;/span&gt;) and 735 nm (&lt;em&gt;ε&lt;/em&gt; = 220 &lt;span&gt;&lt;math&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;msup&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;msup&gt;&lt;mi&gt;cm&lt;/mi&gt;&lt;mrow&gt;&lt;mo&gt;−&lt;/mo&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/mrow&gt;&lt;/msup&gt;&lt;/math&gt;&lt;/span&gt;). These data suggest a distorted four- or five-coordinate Co&lt;sup&gt;2+&lt;/sup&gt; center ligated by 3 Cys residues with a dissociation constant (&lt;span&gt;&lt;math&gt;&lt;msub&gt;&lt;mi&gt;K&lt;/mi&gt;&lt;mi&gt;d&lt;/mi&gt;&lt;/msub&gt;&lt;mo&gt;)&lt;/mo&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;/math&gt;&lt;/span&gt;of ∼&lt;span&gt;&lt;math&gt;&lt;mn&gt;600&lt;/mn&gt;&lt;mspace&gt;&lt;/mspace&gt;&lt;mi&gt;n&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt;M. Co K-edge absorption spectra (XAS) of Co&lt;sup&gt;2+&lt;/sup&gt;-&lt;em&gt;Sa&lt;/em&gt;SufU indicated five-coordinate Co&lt;sup&gt;2+&lt;/sup&gt;, while extended X-ray absorption fine structure (EXAFS) spectra of Co&lt;sup&gt;2+&lt;/sup&gt;-&lt;em&gt;Sa&lt;/em&gt;SufU revealed 2 N/O and 3 S ligands. EXAFS data for Zn&lt;sup&gt;2+&lt;/sup&gt;-&lt;em&gt;Sa&lt;/em&gt;SufU revealed 1 N/O and 3 S ligands consistent with the proposed Cys&lt;sub&gt;3&lt;/sub&gt;Asp coordinating residues. The fifth ligand in the Co&lt;sup&gt;2+&lt;/sup&gt;-SaSufU enzyme is either a bidentate the active site Asp ligand or an exogenous water. Upon the addition of &lt;em&gt;Sa&lt;/em&gt;SufS to either Zn&lt;sup&gt;2+&lt;/sup&gt;-&lt;em&gt;Sa&lt;/em&gt;SufU or Co&lt;sup&gt;2+&lt;/sup&gt;-&lt;em&gt;Sa&lt;/em&gt;SufU, XAS and EXAFS data suggest that one of the S ligands is displaced by an N/O atom donor. Interestingly, electronic absorption data suggest that this only occurs in the presence of Cys. EPR analysis of Co&lt;sup&gt;2+&lt;/sup&gt;&lt;em&gt;-Sa&lt;/em&gt;SufU revealed temperature- and &lt;span&gt;&lt;math&gt;&lt;msub&gt;&lt;mi&gt;B&lt;/mi&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;/msub&gt;&lt;/math&gt;&lt;/span&gt;-dependent transitions within both the &lt;span&gt;&lt;math&gt;&lt;msub&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mi&gt;s&lt;/mi&gt;&lt;/msub&gt;&lt;mo&gt;=&lt;/mo&gt;&lt;mo&gt;±&lt;/mo&gt;&lt;mfrac&gt;&lt;mn&gt;1&lt;/mn&gt;&lt;mn&gt;2&lt;/mn&gt;&lt;/mfrac&gt;&lt;/math&gt;&lt;/span&gt; and &lt;span&gt;&lt;math&gt;&lt;msub&gt;&lt;mi&gt;M&lt;/mi&gt;&lt;mi&gt;S&lt;/mi&gt;&lt;/msub&gt;&lt;mo&gt;=&lt;/mo&gt;&lt;mo&gt;±&lt;/mo&gt;&lt;mfrac&gt;&lt;mn&gt;3&lt;/mn&gt;&lt;mn&gt;2&lt;/mn&gt;&lt;/mfrac&gt;&lt;/math&gt;&lt;/span&gt; doublets of the &lt;span&gt;&lt;math&gt;&lt;mi&gt;S&lt;/mi&gt;&lt;mo&gt;=&lt;/mo&gt;&lt;mfrac&gt;&lt;mn&gt;3&lt;/mn&gt;&lt;mn&gt;2&lt;/mn&gt;&lt;/mfrac&gt;&lt;/math&gt;&lt;/span&gt; spin system that suggested either heterogeneity of the electronic structure or an unusually small zero-field splitting for Co(II). Taken together, these data provide in-solution evidence for the mechanism of S&lt;sup&gt;2−&lt;/sup&gt; transfer from &lt;em&gt;Sa&lt;/em&gt;SufS to &lt;em&gt;Sa&lt;/em","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113205"},"PeriodicalIF":3.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861648","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}

{"title":"Carbon monoxide chemistry of α-V70I Mo-nitrogenase: Evidence from EPR- and IR-monitored photolysis – or, what a difference a methyl makes","authors":"Simon J. George ,&nbsp;Aubrey D. Scott ,&nbsp;Leland B. Gee ,&nbsp;Lance C. Seefeldt ,&nbsp;Stephen P. Cramer","doi":"10.1016/j.jinorgbio.2025.113203","DOIUrl":"10.1016/j.jinorgbio.2025.113203","url":null,"abstract":"<div><div>A critical step in the global nitrogen cycle is the conversion of dinitrogen into biologically accessible ammonia. In Nature this is accomplished by the nitrogenase (N₂ase) family of enzymes. Carbon monoxide (CO) has long been known as an inhibitor of dinitrogen reduction by N₂ase, but it can also be a substrate of the enzyme, when it is catalytically reduced to hydrocarbons. Understanding the CO interactions with N₂ases are thus relevant to both dinitrogen fixation and Fischer-Tropsch-like chemistry. Here, the interaction of CO with the α-V70I variant of <em>Azotobacter vinelandii</em> MoFe N₂ase was investigated using electron paramagnetic resonance (EPR) and infrared (IR) monitored photolysis of bound CO under cryogenic conditions. This was supplemented by further analysis of stopped-flow Fourier transform IR (SF-FT-IR) data under turnover conditions. The α-V70I variant adds a single methyl group close to the FeMo-cofactor active site, and the results show that this inhibits and slows, but does not substantially chemically change, the binding of CO to the FeMo-cofactor. The EPR spectra of both the hi-CO and lo-CO states closely resemble those from the wild-type enzyme. Similarly, the SF-FT-IR spectra of CO inhibited α-V70I and wild-type enzyme are strikingly similar, showing only small shifts in band energies which allow better interpretation of the published wild-type spectra. The extra carbon does, however, impact and inhibit the photochemical release and migration of CO at cryogenic temperatures, resulting in novel CO-bound species. These include a product species, termed Lo-1*, which may involve CO photochemically migrating on the FeMo-cofactor.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113203"},"PeriodicalIF":3.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921994","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}

{"title":"The cobalamin-binding domain of cobalamin-dependent radical S-adenosylmethionine enzymes: Familiarity in unfamiliar places","authors":"Dante M. Avalos ,&nbsp;Catherine L. Drennan","doi":"10.1016/j.jinorgbio.2025.113204","DOIUrl":"10.1016/j.jinorgbio.2025.113204","url":null,"abstract":"<div><div>Cobalamin (Cbl)-dependent Radical <em>S</em>-adenosylmethionine (RS) enzymes are well known for their use of two powerful cofactors to catalyze chemically challenging reactions, such as methylations on unactivated carbons and phosphorus centers, ring contractions, ring formations, and thioether bond formations. Our repertoire of Cbl-dependent RS enzyme structures has grown since the first solved structure of the oxetanocin A biosynthetic enzyme OxsB in 2017, which has provided insight into the structural basis of catalysis. In particular, the Cbl-binding domains of these RS enzymes have been found to have interesting structural variations that seem to correlate with enzymatic function, at least for the small number of enzymes that have been characterized. In this review, we highlight the recent research about the Cbl cofactor in Cbl-dependent RS enzymes. We compare modes of Cbl binding and demonstrate a previously undetected connection between a subgroup of Cbl-dependent RS enzymes and the corrinoid iron‑sulfur protein (CFeSP) from the Wood-Ljungdahl pathway of reductive acetogenesis. Additionally, we discuss recent mechanistic findings on Cbl-dependent RS enzymes OxsB and its close homolog AlsB, which have not been recently reviewed. As Cbl-dependent RS enzymes are involved in making antiviral and antibiotic compounds, herbicides, and other molecules of value, understanding and manipulating enzyme activity has implications in both medicine and agriculture.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113204"},"PeriodicalIF":3.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881772","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}

{"title":"Polypyridyl Ru(II) tamoxifen analogues: Estrogen receptor-targeted dual photodynamic and chemotherapeutic agents","authors":"Guillermo Moreno-Alcántar ,&nbsp;Claudia Schmidt ,&nbsp;Darren Dennis Wragg ,&nbsp;Riccardo Scotti ,&nbsp;Iñigo Iribarren Aguirre ,&nbsp;Riccardo Bonsignore ,&nbsp;Angela Casini ,&nbsp;Denise Lovison","doi":"10.1016/j.jinorgbio.2025.113202","DOIUrl":"10.1016/j.jinorgbio.2025.113202","url":null,"abstract":"<div><div>The use of targeted chemotherapeutic agents and of locally active treatments such as photodynamic therapy (PDT), are strategies to tackle the side effects and enhance the effectiveness of anticancer treatments. In this context, the development of multifunctional drugs, which combine targeted chemotherapy and photosensitizing capabilities, has garnered increased attention. Herein, we introduce two polypyridyl ruthenium(II) compounds featuring tamoxifen-related ligands (<strong>RuTamOMe</strong> and <strong>RuTamOH</strong>) targeting the estrogen receptor α (ERα) and able to generate singlet oxygen via energy transfer. The compounds display enhanced phototoxicity, tested in different cell lines (A375 melanoma, MDA-MB-231 triple negative adenocarcinoma and MCF-7 ER+ breast cancer cells) and examined in terms of the ERα expression dependence. Computational studies were also performed, corroborating the suitability of the compounds to target ER, maintaining tamoxifen's affinity for the receptor binding site, and revealing a minimal influence of the stereochemical configuration of the compounds on their targeting capabilities. Altogether, our results highlight the potential of <em>hybrid</em> Ru(II) polypyridyl compounds as suitable platforms for generating targeted metallodrugs with photosensitizing capabilities.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113202"},"PeriodicalIF":3.2,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802189","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}

{"title":"Spectroscopic characterization of Mn2+-induced catalysis in cyclic GMP-AMP synthase","authors":"Karis Williamson,&nbsp;Karina Sharafutdinova,&nbsp;Micah Gaddy,&nbsp;Lucy Jolley,&nbsp;Parker Tamucci,&nbsp;Jaren Lobb,&nbsp;Eleana Parks,&nbsp;Noah Griffin,&nbsp;Molly M. Lockart","doi":"10.1016/j.jinorgbio.2025.113200","DOIUrl":"10.1016/j.jinorgbio.2025.113200","url":null,"abstract":"<div><div>Cyclic GMP-AMP synthase (cGAS) is a nucleotidyltransferase enzyme that functions as the principal cytosolic sensor of double-stranded DNA (dsDNA) in vertebrates. Upon binding dsDNA, cGAS produces the second messenger 2′3′-cyclic GMP-AMP (2′3′-cGAMP), initiating innate immune signaling. Canonical models describe activation through dsDNA-induced dimerization and recruitment of two Mg²⁺ ions into the active site. Recent studies, however, have identified Mn²⁺ as an alternative cofactor that accelerates catalysis, enhances substrate selectivity, and improves product fidelity. Interestingly, in the presence of dsDNA, Mn²⁺ acts as the preferred catalytic metal, and in its absence, it can promote dsDNA-independent synthesis of 2′3′-cGAMP. The metal-dependent divergence in activity raises key questions about the composition of the active metal cluster and the molecular basis for catalytic enhancement. Here, liquid chromatography–tandem mass spectrometry (LC-MS/MS) and electron paramagnetic resonance (EPR) spectroscopy, including electron spin echo envelope modulation (ESEEM) and electron–nuclear double resonance (ENDOR), were used to probe Mn²⁺ coordination and its interaction with substrates. Mn²⁺–cGAS generated approximately sixfold more cGAMP than Mg²⁺–cGAS with dsDNA and fourteenfold more without dsDNA, confirming enhanced catalysis and dsDNA-independent activation. CW and pulsed EPR revealed that Mn²⁺ uptake occurs during active-site assembly and that Mn²⁺ is coordinated by ATP and protein-derived ligands in the substrate-bound complex. These results provide the first spectroscopic description of Mn²⁺ coordination in cGAS and offer critical mechanistic insight into its metal-dependent activation and broader role in health and disease. Additionally, this work further defines how metal cofactors regulate innate immune signaling by cGAS.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113200"},"PeriodicalIF":3.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802165","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}

{"title":"When the wrong metal stops the cycle: Dynamics and specificity in plant copper-dependent peptide cyclases","authors":"Courtney M. Petersen,&nbsp;Winston C. Pitts,&nbsp;Shabnam Hematian","doi":"10.1016/j.jinorgbio.2025.113201","DOIUrl":"10.1016/j.jinorgbio.2025.113201","url":null,"abstract":"<div><div>Herein, we report the expression of split BURP domain peptide cyclases (BpCs), primarily CamB1 from <em>Ceanothus americanus</em>, in <em>Escherichia coli</em> using the pET22b vector without a fusion partner while retaining their disordered N-terminal region. To our knowledge, this represents the first full-length split BpC expressed and isolated without reliance on a stabilizing fusion tag (<em>e.g.</em>, maltose binding protein, MBP). Both CamB1 and ArbB2, from <em>Coffea arabica</em>, were purified and refolded from inclusion bodies, and displayed robust catalytic turnover on a minimal peptide substrate. Copper titrations revealed that catalytic assays using glutathione as the reducing agent require copper far in excess of the stoichiometric number of active sites, with activity plateauing at ∼50-fold excess, likely reflecting competition with nonspecific copper binding or solution speciation. Using ascorbic acid in place of glutathione not only restores but also increases maximal activity, requiring only near-stochiometric copper. Metal impact studies demonstrated that noncognate metals inhibit activity. Zn(II) most severely inhibited BpC function at low micromolar concentrations in enzyme-initiated assays containing Cu(II), Zn(II), and glutathione, but this effect was markedly alleviated in reducing agent-initiated assays and instead resembled the modest inhibition by Ag(I), which fully suppressed activity only near 1 mM. These results highlight how assay order influences metal competition at the active site. Given that BURP-domain proteins are implicated in plant stress responses, including tolerance to metal exposure, these findings suggest that Zn(II) and Ag(I) inhibition may represent a biochemical mechanism by which environmental metal stress modulates BpC activity.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"277 ","pages":"Article 113201"},"PeriodicalIF":3.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881775","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}