Journal of Inorganic Biochemistry最新文献_第9页

Targeting DNA mismatches with metal complexes 靶向与金属配合物不匹配的DNA

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-24 DOI: 10.1016/j.jinorgbio.2025.112977

Natália Kolozsvári, Martin R. Gill

引用次数: 0

Alternative zinc binding peptides as potential tags for recombinant protein purification 锌结合肽作为重组蛋白纯化的潜在标签

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-23 DOI: 10.1016/j.jinorgbio.2025.112981

Richmond A. Adomako, Michael B. Owusu, Airam Cordova, Laurence A. Angel

{"title":"Alternative zinc binding peptides as potential tags for recombinant protein purification","authors":"Richmond A. Adomako, Michael B. Owusu, Airam Cordova, Laurence A. Angel","doi":"10.1016/j.jinorgbio.2025.112981","DOIUrl":"10.1016/j.jinorgbio.2025.112981","url":null,"abstract":"<div><div>Efficient binding of peptides and proteins to metal-chelating resins is a cornerstone of modern biochemical purification. This study evaluates a novel heptapeptide sequence, acetyl-Aa<sub>1</sub>-Aa<sub>2</sub>-Gly<sub>3</sub>-Pro<sub>4</sub>-Aa<sub>5</sub>-His<sub>6</sub>-Cys<sub>7</sub>, where Aa<sub>1</sub> = His<sub>1</sub> or Asp<sub>1</sub>, Aa<sub>2</sub> = Cys<sub>2</sub> or Asp<sub>2</sub> and Aa<sub>5</sub> = Tyr<sub>5</sub> or Gly<sub>5</sub> for its capacity to bind zinc-chelating resin consisting of divalent zinc chelated by iminodiacetate coupled to 6 % cross-linked agarose beads. Comparisons were made against the widely utilized 7 × His tag using an internal standard method with ion mobility – mass spectrometry analyses and ultra-violet absorption analyses, which quantified the binding efficiency and selectivity of these peptides under pH 8 conditions and the elution from the zinc resin using pH 3.9 or excess imidazole. Results revealed that the heptapeptides acetyl-His<sub>1</sub>-Cys<sub>2</sub>-Gly<sub>3</sub>-Pro<sub>4</sub>-Tyr<sub>5</sub>-His<sub>6</sub>-Cys<sub>7</sub>, exhibited binding performance to the zinc chelating resin with conditions commonly used with immobilized metal affinity chromatography and efficient elution from the zinc resin at pH 3.9 or with excess imidazole, suggesting that this heptapeptide has potential as an alternative to polyhistidine tags in affinity-based purification workflows.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112981"},"PeriodicalIF":3.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501212","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}

引用次数: 0

The binding of kojic acid dimer and its Zn(II) and Cu(II) complexes at the beta-amyloid peptide: A DFT-based computational assessment 曲酸二聚体及其Zn（II）和Cu（II）配合物在β -淀粉样肽上的结合：基于dft的计算评估

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-20 DOI: 10.1016/j.jinorgbio.2025.112979

Iogann Tolbatov , Tiziano Marzo , Massimiliano Peana , Serenella Medici , Maria Antonietta Zoroddu , Diego La Mendola , Alessandro Marrone

{"title":"The binding of kojic acid dimer and its Zn(II) and Cu(II) complexes at the beta-amyloid peptide: A DFT-based computational assessment","authors":"Iogann Tolbatov , Tiziano Marzo , Massimiliano Peana , Serenella Medici , Maria Antonietta Zoroddu , Diego La Mendola , Alessandro Marrone","doi":"10.1016/j.jinorgbio.2025.112979","DOIUrl":"10.1016/j.jinorgbio.2025.112979","url":null,"abstract":"<div><div>The increasing number of people afflicted by Alzheimer's disease in the world requires a constant intensification of the efforts to seek for new agents capable of dismantling the molecular mechanisms underlying the onset and development of this neurodegenerative disorder. In this study, the binding of kojic acid dimer (KAD), and its adducts with Zn(II) and Cu(II) to the beta-amyloid peptide (Aβ) have been investigated by means of density functional theory-based computational approaches. We envisioned that the capability of KAD to inhibit the amyloid cascade may be exerted in concomitance and/or supported by the coordination of either Zn(II) or Cu(II). Thus, the structure and binding features of KAD-Zn and KAD-Cu metal complexes were computationally assessed to gain an atomistic insight of the possible Aβ inhibition. Our calculations evidenced that Zn(II), but not Cu(II), might act in concert with KAD in the binding of the Aβ peptide. Furthermore, we identified the Aβ<sub>13</sub><sub>–</sub><sub>20</sub> region as a plausible binding site for KAD and KAD-Zn complexes, emphasizing its relevance for future experimental studies.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112979"},"PeriodicalIF":3.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144471792","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}

引用次数: 0

Exploring the anticancer properties of indenyl and allyl palladates through their interaction with nucleic acids 通过与核酸的相互作用，探索芳香酸酯的抗癌特性

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-18 DOI: 10.1016/j.jinorgbio.2025.112978

Tommaso Giani , Giannantonio Tomasi , Pablo A. Nogara , Laura Orian , Fabiano Visentin , Thomas Scattolin , Tarita Biver

{"title":"Exploring the anticancer properties of indenyl and allyl palladates through their interaction with nucleic acids","authors":"Tommaso Giani , Giannantonio Tomasi , Pablo A. Nogara , Laura Orian , Fabiano Visentin , Thomas Scattolin , Tarita Biver","doi":"10.1016/j.jinorgbio.2025.112978","DOIUrl":"10.1016/j.jinorgbio.2025.112978","url":null,"abstract":"<div><div>In this work, we analyse the mechanistic features of the interaction of indenyl (<strong>1-Ind</strong>) and allyl (<strong>2-All</strong>) palladates with nucleic acids (NAs) such as DNA (natural, poly(dA)-poly(dT) and poly(dG)-poly(dC)), RNA (in double and triple helices) and non-canonical structures of DNA (G-quadruplex and i-motif). Spectrophotometric titrations under different temperature and salt content conditions, viscosimetric experiments, fluorescent intercalator displacement (FID) tests together with theoretical Density Functional Theory (DFT)/Docking calculations are used to enlighten the complicated features of the interaction. The binding occurs in the grooves of the polynucleotides and is dominated by the geometrical features of the NA. A strong affinity for RNA double helix is present, together with interesting binding signatures to G-quadruplex and i-motif. The indenyl moiety plays a role and the binding is tighter (<strong>1-Ind</strong> > <strong>2-All</strong>) for all NA systems. However, it is <strong>2-All</strong> that, interestingly, shows the more striking differences in changing from one NA to another. The formation of covalent adducts and other mechanistic features are also discussed.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112978"},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144471791","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}

引用次数: 0

Multiple catalytic functions of an engineered double mutant of myoglobin with a potential metal-binding site 具有潜在金属结合位点的肌红蛋白工程双突变体的多重催化功能

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-15 DOI: 10.1016/j.jinorgbio.2025.112976

Ai-Qun Pan , Xi-Chun Liu , Lu Yu , Shuai Tang , Shu-Qin Gao , Ying-Wu Lin

{"title":"Multiple catalytic functions of an engineered double mutant of myoglobin with a potential metal-binding site","authors":"Ai-Qun Pan , Xi-Chun Liu , Lu Yu , Shuai Tang , Shu-Qin Gao , Ying-Wu Lin","doi":"10.1016/j.jinorgbio.2025.112976","DOIUrl":"10.1016/j.jinorgbio.2025.112976","url":null,"abstract":"<div><div>Rational protein engineering has emerged as a powerful tool for creating functional enzymes, and the design of metalloenzymes with dual active sites is particularly attractive. In this study, we performed a double mutation of F46H/L49D in the helices C and D region in myoglobin (Mb). As demonstrated by X-ray crystallography, the double mutations preserved the overall Mb fold and formed a potential metal-binding site, located ∼15 Å from the heme iron, which enable the protein to bind various metal ions such as Cu<sup>2+</sup>, Mg<sup>2+</sup> and others. Moreover, the binding of Cu<sup>2+</sup>/Mg<sup>2+</sup> conferred multiple enzymatic activities to F46H/L49D Mb. The Cu<sup>2+</sup>-F46H/L49D Mb complex exhibited significant nitrite reductase and superoxide dismutase activities. Notably, the protein exhibited DNA cleavage activity in the presence of Mg<sup>2+</sup>, achieving nearly 100 % cleavage efficiency within 30 min. By demonstrating the versatility of the engineered metal-binding site in Mb, this study suggests that rational design can expand the functional repertoire of the protein. The F46H/L49D Mb mutant serves as a versatile platform for studying metal-dependent catalysis of artificial metalloenzymes with non-heme/heme dual active sites, offering potential applications in biocatalysis, medicine, and industrial catalysis.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112976"},"PeriodicalIF":3.8,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297952","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}

引用次数: 0

Cobalt complexes as modulators against amyloid-β aggregation 钴配合物作为淀粉样蛋白-β聚集的调节剂

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-12 DOI: 10.1016/j.jinorgbio.2025.112972

Jeasang Yoo , Jong-Min Suh , Gunhee Kim , Hélène Bernard , Raphaël Tripier , Dongwook Kim , Mingeun Kim , Mi Hee Lim

{"title":"Cobalt complexes as modulators against amyloid-β aggregation","authors":"Jeasang Yoo , Jong-Min Suh , Gunhee Kim , Hélène Bernard , Raphaël Tripier , Dongwook Kim , Mingeun Kim , Mi Hee Lim","doi":"10.1016/j.jinorgbio.2025.112972","DOIUrl":"10.1016/j.jinorgbio.2025.112972","url":null,"abstract":"<div><div>The progressive aggregation of amyloid-β (Aβ) peptides is central to the development of Alzheimer's disease, contributing to memory loss, cognitive decline, and neuronal degeneration. Transition metal complexes, owing to their tunable oxidation states and diverse coordination geometries, have been explored as chemical modulators to disrupt the aggregation pathways of Aβ peptides. Their biological applications, however, are often constrained by inherent toxicity and potential metal release. Herein, we report the selection and preparation of cobalt complexes with macrocyclic 1,4,8,11-tetraazacyclotetradecane (<strong>Cyclam</strong>) and 1,8-dimethyl-1,4,8,11-tetraazacyclotetradecane (<strong>DMC</strong>) ligands, [Co(<strong>Cyclam</strong>)(NO<sub>3</sub>)](NO<sub>3</sub>), [Co(<strong>Cyclam</strong>)(Cl)<sub>2</sub>]Cl, [Co(<strong>DMC</strong>)(H<sub>2</sub>O)<sub>2</sub>](NO<sub>3</sub>)<sub>2</sub>, and [Co(<strong>DMC</strong>)(Cl)<sub>2</sub>]Cl, adopting either <em>trans</em>-III or <em>cis</em>-V geometry as relatively stable chemical reagents for controlling the assembly and toxicity profiles of Aβ peptides. Our mechanistic investigations reveal that these cobalt complexes can form adducts with Aβ peptides and, subsequently, redirect their aggregation pathway away from the canonical on-pathway process towards the formation of amorphous clusters and shorter fibrils. Furthermore, cobalt complexes mitigate Aβ-induced toxicity with minimal intrinsic toxicity in living cells. Overall, our study illustrates a guidance for selecting metal complexes as chemical modulators against Aβ amyloidogenesis by integrating the characteristics of both metal centers and ligand scaffolds.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112972"},"PeriodicalIF":3.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297951","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}

引用次数: 0

DNA cleavage and antitumoral activity of zinc(II) and iron(III) complexes with a new phenol-based ligand containing uncoordinated thioether moieties 含不配位硫醚基团的新型酚基配体对锌（II）和铁（III）的DNA切割和抗肿瘤活性的影响

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-10 DOI: 10.1016/j.jinorgbio.2025.112974

Daniele C. Durigon , Rafaella B. Marinho , Laura G. Magnabosco , Tetsade C.B. Piermartiri , Lucas Göbel , Carla I. Tasca , Fernando R. Xavier , Cláudia B. Nedel , Adailton J. Bortoluzzi , Hernán Terenzi , Rosely A. Peralta

{"title":"DNA cleavage and antitumoral activity of zinc(II) and iron(III) complexes with a new phenol-based ligand containing uncoordinated thioether moieties","authors":"Daniele C. Durigon , Rafaella B. Marinho , Laura G. Magnabosco , Tetsade C.B. Piermartiri , Lucas Göbel , Carla I. Tasca , Fernando R. Xavier , Cláudia B. Nedel , Adailton J. Bortoluzzi , Hernán Terenzi , Rosely A. Peralta","doi":"10.1016/j.jinorgbio.2025.112974","DOIUrl":"10.1016/j.jinorgbio.2025.112974","url":null,"abstract":"<div><div>In this study, a novel ligand: 2-((bis(2-(phenylthio)ethyl)amino)methyl)-6-((bis(pyridin-2-ylmethyl)amino)methyl)-4-methylphenol (<strong>HL</strong>) was prepared and subsequently used to synthesize the complexes [Zn(L)(OAc)]ClO<sub>4</sub> (<strong>1</strong>) and [Fe<sub>2</sub>(L)(μ-OAc)(μ-O)](ClO<sub>4</sub>)<sub>2</sub> (<strong>2</strong>). The metal complexes were comprehensively characterized using different techniques such as IR, Mass Spectrometry, UV–Vis, elemental analysis and X-ray analysis. The crystal structures show that compound <strong>1</strong> is a mononuclear pentacoordinate zinc(II) complex, while compound <strong>2</strong> is a dinuclear hexacoordinate iron(III) compound, with the metal centers connected by μ-oxo and μ-acetato bridges. In both cases, the phenol-based ligand features thioether substituents as pendant arms. We have evaluated the binding of the new complexes to DNA and also their capacity to cleave it. Both complexes have excellent antitumor activity against an astrocytic tumor derived from a primary human GBM1 cell line.</div></div><div><h3>Synopsis</h3><div>The paper reports synthesis and characterization of two new complexes [Zn(L)(OAc)]ClO<sub>4</sub> (<strong>1</strong>) and [Fe<sub>2</sub>(L)(μ-OAc)(μ-O)](ClO<sub>4</sub>)<sub>2</sub> (<strong>2</strong>). Complex <strong>1</strong> exhibits better activity than <strong>2</strong> at lower concentrations and with a faster rate of action, showing a preference for the minor groove. The cytotoxicity studies demonstrated a reduction in cell viability when exposed to the complexes, with GBM and C6 cells.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112974"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144291491","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}

引用次数: 0

Mutation of an active site-adjacent residue in VIM indirectly dictates interactions with and blunts inhibition by D-captopril VIM中活性位点邻近残基的突变间接决定了与d -卡托普利的相互作用并减弱了d -卡托普利的抑制作用

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-10 DOI: 10.1016/j.jinorgbio.2025.112975

Surendra Bikram Silwal , Bode Wamsley , Zongyao Wang , Benjamin W. Gung , Jay C. Nix , Richard C. Page

{"title":"Mutation of an active site-adjacent residue in VIM indirectly dictates interactions with and blunts inhibition by D-captopril","authors":"Surendra Bikram Silwal , Bode Wamsley , Zongyao Wang , Benjamin W. Gung , Jay C. Nix , Richard C. Page","doi":"10.1016/j.jinorgbio.2025.112975","DOIUrl":"10.1016/j.jinorgbio.2025.112975","url":null,"abstract":"<div><div>Activity assays and X-ray crystallographic studies were undertaken to elucidate the inhibitory mechanism of captopril stereoisomers on Verona integron-encoded metallo-β-lactamases, specifically VIM-20, VIM-31, and VIM-15. All three VIM-2-like variants (VIM-20, VIM-31, and VIM-15) and VIM-2 expressed in <em>Escherichia coli</em> exhibited catalytic activity with comparable steady-state kinetic parameters. Among the tested thiol drugs (L- and D-captopril, D,L-thiorphan, and 2,3-dimercaprol), IC<sub>50</sub> analyses indicated that D-captopril and 2,3-dimercaprol were more potent inhibitors against the VIM enzymes examined in this study. Notably, the IC<sub>50</sub> value of D-captopril against VIM-31 was an exception, closely resembling that of L-captopril. To elucidate this exceptional inhibitory potency of D-captopril and its binding mode in the active site of VIM-31, high-resolution crystal structures of VIM-20, VIM-31, and VIM-15 in complex with both L- and D-captopril are reported. These findings will help evaluate whether the identified potent inhibitor D-captopril could be further developed as a pan inhibitor targeting the VIM-family enzymes.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112975"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263124","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}

引用次数: 0

NMR insights into the behavior of bis-His motifs toward copper ions: A study using mono-N-methylated histidines 核磁共振洞察双- his基序对铜离子的行为：使用单n -甲基化组氨酸的研究

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-09 DOI: 10.1016/j.jinorgbio.2025.112973

Arian Kola , Nicolas Quéméré , Charlène Gadais , Daniela Valensin

{"title":"NMR insights into the behavior of bis-His motifs toward copper ions: A study using mono-N-methylated histidines","authors":"Arian Kola , Nicolas Quéméré , Charlène Gadais , Daniela Valensin","doi":"10.1016/j.jinorgbio.2025.112973","DOIUrl":"10.1016/j.jinorgbio.2025.112973","url":null,"abstract":"<div><div>The bis-histidine (bis-His) motif, formed by two adjacent histidines, plays a central role in metal coordination within biological systems. Its versatility stems from the imidazole ring of histidine, which offers two distinct nitrogen donors (Nδ/Nπ and Nε/Nτ). This motif contributes to enzymatic activity, redox processes, and metal homeostasis in proteins and peptides. To investigate its coordination properties, we developed a four-point comparative model based on the Aβ<sub>12–16</sub> pentapeptide, introducing selective mono-<em>N</em>-methylation of histidine residues. This strategy enabled a detailed NMR-based characterization of the bis-His motif in the presence of Cu (II) and Cu (I). For Cu(II), distinct paramagnetic relaxation effects were observed depending on the methylation site, reflecting differences in metal–ligand coordination sphere. Similarly, variations in chemical shift induced by Ag(I), used as a probe for Cu(I), confirmed differential interactions with the imidazole nitrogens. The His-His pair was found to act as a structurally flexible binding site able to accommodate both copper oxidation state. Our findings highlight a clear preference for Nπ coordination, with specific patterns of interaction depending on the oxidation state and histidine modification. Reactivity studies in the presence of the endogenous antioxidant glutathione (GSH) further confirmed the role of histidine coordination within the bis-His motif in Cu(II)/Cu(I) redox cycling. Notably, the redox behavior was influenced by the specific imidazole nitrogen involved in metal coordination, with distinct reactivity patterns observed depending on whether the Nπ or Nτ nitrogen was engaged.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112973"},"PeriodicalIF":3.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297950","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}

引用次数: 0

A molecular basis of Ferredoxin Reductase (FdxR) mutations that result in mitochondriopathies 铁氧还蛋白还原酶（FdxR）突变导致线粒体疾病的分子基础

IF 3.8 2区化学

Journal of Inorganic Biochemistry Pub Date : 2025-06-04 DOI: 10.1016/j.jinorgbio.2025.112969

Amit Kumar, Janie E. McGlohon, D. Fernando Estrada

{"title":"A molecular basis of Ferredoxin Reductase (FdxR) mutations that result in mitochondriopathies","authors":"Amit Kumar, Janie E. McGlohon, D. Fernando Estrada","doi":"10.1016/j.jinorgbio.2025.112969","DOIUrl":"10.1016/j.jinorgbio.2025.112969","url":null,"abstract":"<div><div>Inherited mutations in the Ferredoxin Reductase (FdxR) gene can result in a spectrum of disorders that include auditory and optic neural atrophies as well as adrenal insufficiency. FdxR (also referred to as Adrenodoxin Reductase) is a flavoprotein located in the inner mitochondrial membrane. It is responsible for mediating electron transfer from NADPH to either Fdx1 (Adrenodoxin), which is the sole reductant for all seven mitochondrial cytochromes P450, or to the related ferredoxin Fdx2, which is a component in the Fe<img>S cluster biogenesis pathway. In most cases, the mechanistic causes that underpin FdxR-related neuropathies and steroid imbalances remain unknown. In this study, we investigate three clinically relevant variants of FdxR (R211Q, R275C, and R355Q) that exhibit classic FdxR-related disease phenotypes and are widely distributed in the protein. We use a combination of biophysical and biochemical techniques to evaluate both the FdxR:Fdx1 complex and the FdxR:Fdx2 complex since these redox complexes represent an important branch point in FdxR function. Two key findings from this study are that i) all three mutants alter the recognition of Fdx1 and Fdx2, despite R275C and R355Q being located distally from the expected site of interaction, and ii) R275C and R355Q disrupt the functional complex with Fdx1, but not with Fdx2. These findings are supplemented with 2D NMR data of each mutant FdxR complex. In summary, this work implicates protein instability and degradation as the proximal cause of FdxR-related disease, with a secondary cause being the disruption of cytochrome P450-mediated metabolism in mitochondria.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"271 ","pages":"Article 112969"},"PeriodicalIF":3.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222038","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}

引用次数: 0