Pub Date : 2023-01-19DOI: 10.1007/s00775-022-01982-z
Gizem Celebi Torabfam, Güleser K. Demir, Durmuş Demir
Guanine-rich quadruplex DNA (G-quadruplex) is of interest both in cell biology and nanotechnology. Its biological functions necessitate a G-quadruplex to be stabilized against escape of the monovalent metal cations. The potassium ion (({{varvec{K}}}^{+})) is particularly important as it experiences a potential energy barrier while it enters and exits the G-quadruplex systems which are normally found in human telomere. In the present work, we analyzed the time it takes for the ({{varvec{K}}}^{+}) cations to get in and out of the G-quadruplex. Our time estimate is based on entropic tunneling time—a time formula which gave biologically relevant results for DNA point mutation by proton tunneling. The potential energy barrier experienced by ({{varvec{K}}}^{+}) ions is determined from a quantum mechanical simulation study, Schrodinger equation is solved using MATLAB, and the computed eigenfunctions and eigenenergies are used in the entropic tunneling time formula to compute the time delay and charge accumulation rate during the tunneling of ({{varvec{K}}}^{+}) in G-quadruplex. The computations have shown that ion tunneling takes picosecond times. In addition, average ({{varvec{K}}}^{+}) accumulation rate is found to be in the picoampere range. Our results show that time delay during the ({{varvec{K}}}^{+}) ion tunneling is in the ballpark of the conformational transition times in biological systems, and it could be an important parameter for understanding its biological role in human DNA as well as for the possible applications in biotechnology. To our knowledge, for the first time in the literature, time delay during the ion tunneling from and into G-quadruplexes is computed.
{"title":"Quantum tunneling time delay investigation of ({{varvec{K}}}^{+}) ion in human telomeric G-quadruplex systems","authors":"Gizem Celebi Torabfam, Güleser K. Demir, Durmuş Demir","doi":"10.1007/s00775-022-01982-z","DOIUrl":"10.1007/s00775-022-01982-z","url":null,"abstract":"<div><p>Guanine-rich quadruplex DNA (G-quadruplex) is of interest both in cell biology and nanotechnology. Its biological functions necessitate a G-quadruplex to be stabilized against escape of the monovalent metal cations. The potassium ion (<span>({{varvec{K}}}^{+})</span>) is particularly important as it experiences a potential energy barrier while it enters and exits the G-quadruplex systems which are normally found in human telomere. In the present work, we analyzed the time it takes for the <span>({{varvec{K}}}^{+})</span> cations to get in and out of the G-quadruplex. Our time estimate is based on entropic tunneling time—a time formula which gave biologically relevant results for DNA point mutation by proton tunneling. The potential energy barrier experienced by <span>({{varvec{K}}}^{+})</span> ions is determined from a quantum mechanical simulation study, Schrodinger equation is solved using MATLAB, and the computed eigenfunctions and eigenenergies are used in the entropic tunneling time formula to compute the time delay and charge accumulation rate during the tunneling of <span>({{varvec{K}}}^{+})</span> in G-quadruplex. The computations have shown that ion tunneling takes picosecond times. In addition, average <span>({{varvec{K}}}^{+})</span> accumulation rate is found to be in the picoampere range. Our results show that time delay during the <span>({{varvec{K}}}^{+})</span> ion tunneling is in the ballpark of the conformational transition times in biological systems, and it could be an important parameter for understanding its biological role in human DNA as well as for the possible applications in biotechnology. To our knowledge, for the first time in the literature, time delay during the ion tunneling from and into G-quadruplexes is computed.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01982-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4754152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A facile and dual fluorescent chemosensor (named 7-IDF) based on a phenylalanine derivative with an indole group was designed and synthesized. 7-IDF can selectively and sensitively detect Zn2+ via obvious fluorescence enhancement in an aqueous solution. Remarkably, the 7-IDF-Zn complex with blue luminescence has higher selectivity toward cysteine (Cys) and histidine (His) than for other amino acids. Intriguingly, 7-IDF can also be used as an excellent probe to detect Zn2+ in real water samples. Moreover, 7-IDF and 7-IDF-Zn possess excellent biocompatibility and cell permeability, and 7-IDF can consecutively detect Zn2+ and Cys/His in Hela cells through fluorescence imaging experiments. This study suggests that the phenylalanine-based chemosensor possesses great potential applications for the sequential detection of Zn2+ and Cys/His in biosystems.
{"title":"A fluorescent probe based on a phenylalanine derivative is capable of sequential detection of Zn2+ and Cys/His","authors":"Qiu-Yu Yu, Chuan-Wan Wei, Xiao-Juan Wang, Shu-Qin Gao, Xin-Yi Tong, Ying-Wu Lin","doi":"10.1007/s00775-022-01984-x","DOIUrl":"10.1007/s00775-022-01984-x","url":null,"abstract":"<div><p>A facile and dual fluorescent chemosensor (named 7-IDF) based on a phenylalanine derivative with an indole group was designed and synthesized. 7-IDF can selectively and sensitively detect Zn<sup>2+</sup> via obvious fluorescence enhancement in an aqueous solution. Remarkably, the 7-IDF-Zn complex with blue luminescence has higher selectivity toward cysteine (Cys) and histidine (His) than for other amino acids. Intriguingly, 7-IDF can also be used as an excellent probe to detect Zn<sup>2+</sup> in real water samples. Moreover, 7-IDF and 7-IDF-Zn possess excellent biocompatibility and cell permeability, and 7-IDF can consecutively detect Zn<sup>2+</sup> and Cys/His in Hela cells through fluorescence imaging experiments. This study suggests that the phenylalanine-based chemosensor possesses great potential applications for the sequential detection of Zn<sup>2+</sup> and Cys/His in biosystems.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01984-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5012930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-17DOI: 10.1007/s00775-022-01972-1
Melissa Jansing, Steffen Mielenbrink, Hannah Rosenbach, Sabine Metzger, Ingrid Span
Iron–sulfur clusters are ubiquitous cofactors required for fundamental biological processes. Structural and spectroscopic analysis of Fe–S proteins is often limited by low cluster occupancy in recombinantly produced proteins. In this work, we report a systematic comparison of different maturation strategies for three well-established [4Fe–4S] proteins. Aconitase B, HMBPP reductase (IspH), and quinolinate synthase (NadA) were used as model proteins as they have previously been characterized. The protein production strategies include expression of the gene of interest in BL21(DE3) cells, maturation of the apo protein using chemical or semi-enzymatic reconstitution, co-expression with two different plasmids containing the iron–sulfur cluster (isc) or sulfur formation (suf) operon, a cell strain lacking IscR, the transcriptional regulator of the ISC machinery, and an engineered “SufFeScient” derivative of BL21(DE3). Our results show that co-expression of a Fe–S biogenesis pathway influences the protein yield and the cluster content of the proteins. The presence of the Fe–S cluster is contributing to correct folding and structural stability of the proteins. In vivo maturation reduces the formation of Fe–S aggregates, which occur frequently when performing chemical reconstitution. Furthermore, we show that the in vivo strategies can be extended to the radical SAM protein ThnB, which was previously only maturated by chemical reconstitution. Our results shed light on the differences of in vitro and in vivo Fe–S cluster maturation and points out the pitfalls of chemical reconstitution.
{"title":"Maturation strategy influences expression levels and cofactor occupancy in Fe–S proteins","authors":"Melissa Jansing, Steffen Mielenbrink, Hannah Rosenbach, Sabine Metzger, Ingrid Span","doi":"10.1007/s00775-022-01972-1","DOIUrl":"10.1007/s00775-022-01972-1","url":null,"abstract":"<div><p>Iron–sulfur clusters are ubiquitous cofactors required for fundamental biological processes. Structural and spectroscopic analysis of Fe–S proteins is often limited by low cluster occupancy in recombinantly produced proteins. In this work, we report a systematic comparison of different maturation strategies for three well-established [4Fe–4S] proteins. Aconitase B, HMBPP reductase (IspH), and quinolinate synthase (NadA) were used as model proteins as they have previously been characterized. The protein production strategies include expression of the gene of interest in BL21(DE3) cells, maturation of the apo protein using chemical or semi-enzymatic reconstitution, co-expression with two different plasmids containing the iron–sulfur cluster (<i>isc</i>) or sulfur formation (<i>suf</i>) operon, a cell strain lacking IscR, the transcriptional regulator of the ISC machinery, and an engineered “SufFeScient” derivative of BL21(DE3). Our results show that co-expression of a Fe–S biogenesis pathway influences the protein yield and the cluster content of the proteins. The presence of the Fe–S cluster is contributing to correct folding and structural stability of the proteins. In vivo maturation reduces the formation of Fe–S aggregates, which occur frequently when performing chemical reconstitution. Furthermore, we show that the in vivo strategies can be extended to the radical SAM protein ThnB, which was previously only maturated by chemical reconstitution. Our results shed light on the differences of in vitro and in vivo Fe–S cluster maturation and points out the pitfalls of chemical reconstitution.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01972-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4674622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-13DOI: 10.1007/s00775-022-01975-y
Shaik Waseem Vali, Paul A. Lindahl
Hereditary hemochromatosis is an iron-overload disease most often arising from a mutation in the Homeostatic Fe regulator (HFE)?gene. HFE organs become overloaded with iron which causes damage. Iron-overload is commonly detected by NMR imaging, but the spectroscopic technique is insensitive to diamagnetic iron. Here, we used M?ssbauer spectroscopy to examine the iron content of liver, spleen, kidney, heart, and brain of 57Fe-enriched HFE(?/?) mice of ages 3–52 wk. Overall, the iron contents of all investigated HFE organs were similar to the same healthy organ but from an older mouse. Livers and spleens were majorly overloaded, followed by kidneys. Excess iron was generally present as ferritin. Iron–sulfur clusters and low-spin FeII hemes (combined into the central quadrupole doublet) and nonheme high-spin FeII species were also observed. Spectra of young and middle-aged HFE kidneys were dominated by the central quadrupole doublet and were largely devoid of ferritin. Collecting and comparing?spectra at 5 and 60?K allowed the presence of hemosiderin, a decomposition product of ferritin, to be quantified, and it also allowed the diamagnetic central doublet to be distinguished from ferritin. Hemosiderin was observed in spleens and livers from HFE mice, and in spleens from controls, but only when iron concentrations exceeded 2–3?mM. Even in those cases, hemosiderin represented only 10–20% of the iron in the sample. NMR imaging can identify iron-overload under non-invasive room-temperature conditions, but M?ssbauer spectroscopy of 57Fe-enriched mice can detect all forms of iron and perhaps allow the process of iron-overloading to be probed in greater detail.
{"title":"Low-temperature Mössbauer spectroscopy of organs from 57Fe-enriched HFE(−/−) hemochromatosis mice: an iron-dependent threshold for generating hemosiderin","authors":"Shaik Waseem Vali, Paul A. Lindahl","doi":"10.1007/s00775-022-01975-y","DOIUrl":"10.1007/s00775-022-01975-y","url":null,"abstract":"<div><p>Hereditary hemochromatosis is an iron-overload disease most often arising from a mutation in the Homeostatic Fe regulator (HFE)?gene. HFE organs become overloaded with iron which causes damage. Iron-overload is commonly detected by NMR imaging, but the spectroscopic technique is insensitive to diamagnetic iron. Here, we used M?ssbauer spectroscopy to examine the iron content of liver, spleen, kidney, heart, and brain of <sup>57</sup>Fe-enriched HFE<sup>(?/?)</sup> mice of ages 3–52 wk. Overall, the iron contents of all investigated HFE organs were similar to the same healthy organ <i>but from an older mouse</i>. Livers and spleens were majorly overloaded, followed by kidneys. Excess iron was generally present as ferritin. Iron–sulfur clusters and low-spin Fe<sup>II</sup> hemes (combined into the central quadrupole doublet) and nonheme high-spin Fe<sup>II</sup> species were also observed. Spectra of young and middle-aged HFE kidneys were dominated by the central quadrupole doublet and were largely devoid of ferritin. Collecting and comparing?spectra at 5 and 60?K allowed the presence of hemosiderin, a decomposition product of ferritin, to be quantified, and it also allowed the diamagnetic central doublet to be distinguished from ferritin. Hemosiderin was observed in spleens and livers from HFE mice, and in spleens from controls, but only when iron concentrations exceeded 2–3?mM. Even in those cases, hemosiderin represented only 10–20% of the iron in the sample. NMR imaging can identify iron-overload under non-invasive room-temperature conditions, but M?ssbauer spectroscopy of <sup>57</sup>Fe-enriched mice can detect all forms of iron and perhaps allow the process of iron-overloading to be probed in greater detail.</p><h3>Graphical Abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01975-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4531397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-09DOI: 10.1007/s00775-022-01977-w
Pooja Pandey, Kimaya Meher, Berness Falcao, Manu Lopus, V. L. Sirisha
Several microbial pathogens are capable of forming biofilms. These microbial communities pose a serious challenge to the healthcare sector as they are quite difficult to combat. Given the challenges associated with the antibiotic-based management of biofilms, the research focus has now been shifted towards finding alternate treatment strategies that can replace or complement the antibacterial properties of antibiotics. The field of nanotechnology offers several novel and revolutionary approaches to eradicate biofilm-forming microbes. In this study, we evaluated the antibacterial and antibiofilm efficacy of in-house synthesized, tryptone-stabilized silver nanoparticles (Ts-AgNPs) against the superbug Serratia marcescens. The nanoparticles were of spherical morphology with an average hydrodynamic diameter of 170?nm and considerable colloidal stability with a Zeta potential of ??24?±?6.15?mV. Ts-AgNPs showed strong antibacterial activities with a minimum inhibitory concentration (MIC50) of 2.5?μg/mL and minimum bactericidal concentration (MBC) of 12.5?μg/mL against S. marcescens. The nanoparticles altered the cell surface hydrophobicity and inhibited biofilm formation. The Ts-AgNPs were also effective in distorting pre-existing biofilms by degrading the extracellular DNA (eDNA) component of the extracellular polymeric substance (EPS) layer. Furthermore, reduction in quorum-sensing (QS)-induced virulence factors produced by S. marcescens indicated that Ts-AgNPs attenuated the QS pathway. Together, these findings suggest that Ts-AgNPs are an important anti-planktonic and antibiofilm agent that can be explored for both the prevention and treatment of infections caused by S. marcescens.
{"title":"Tryptone-stabilized silver nanoparticles’ potential to mitigate planktonic and biofilm growth forms of Serratia marcescens","authors":"Pooja Pandey, Kimaya Meher, Berness Falcao, Manu Lopus, V. L. Sirisha","doi":"10.1007/s00775-022-01977-w","DOIUrl":"10.1007/s00775-022-01977-w","url":null,"abstract":"<div><p>Several microbial pathogens are capable of forming biofilms. These microbial communities pose a serious challenge to the healthcare sector as they are quite difficult to combat. Given the challenges associated with the antibiotic-based management of biofilms, the research focus has now been shifted towards finding alternate treatment strategies that can replace or complement the antibacterial properties of antibiotics. The field of nanotechnology offers several novel and revolutionary approaches to eradicate biofilm-forming microbes. In this study, we evaluated the antibacterial and antibiofilm efficacy of in-house synthesized, tryptone-stabilized silver nanoparticles (Ts-AgNPs) against the superbug <i>Serratia marcescens</i>. The nanoparticles were of spherical morphology with an average hydrodynamic diameter of 170?nm and considerable colloidal stability with a Zeta potential of ??24?±?6.15?mV. Ts-AgNPs showed strong antibacterial activities with a minimum inhibitory concentration (MIC<sub>50</sub>) of 2.5?μg/mL and minimum bactericidal concentration (MBC) of 12.5?μg/mL against <i>S. marcescens</i>. The nanoparticles altered the cell surface hydrophobicity and inhibited biofilm formation. The Ts-AgNPs were also effective in distorting pre-existing biofilms by degrading the extracellular DNA (eDNA) component of the extracellular polymeric substance (EPS) layer. Furthermore, reduction in quorum-sensing (QS)-induced virulence factors produced by <i>S. marcescens</i> indicated that Ts-AgNPs attenuated the QS pathway. Together, these findings suggest that Ts-AgNPs are an important anti-planktonic and antibiofilm agent that can be explored for both the prevention and treatment of infections caused by <i>S. marcescens</i>.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01977-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4378404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-09DOI: 10.1007/s00775-022-01979-8
Megan O’Shaughnessy, Jasmine Hurley, Shane C. Dillon, Celine Herra, Pauraic McCarron, Malachy McCann, Michael Devereux, Orla Howe
Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of metal complexes (metal?=?Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dianionic dicarboxylate ligands, along with their simple metal salt and dicarboxylic acid precursors, against common AMR pathogens were investigated. Overall, the highest level of antibacterial activity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylic acid precursors. The chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. Whole-genome sequencing (WGS) was carried out on the reference Pseudomonas aeruginosa strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties with the aim of elucidating their mechanism of action. Various mutations were detected in the mutant P. aeruginosa genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda and warrants further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR infections.
{"title":"Antibacterial activity of metal–phenanthroline complexes against multidrug-resistant Irish clinical isolates: a whole genome sequencing approach","authors":"Megan O’Shaughnessy, Jasmine Hurley, Shane C. Dillon, Celine Herra, Pauraic McCarron, Malachy McCann, Michael Devereux, Orla Howe","doi":"10.1007/s00775-022-01979-8","DOIUrl":"10.1007/s00775-022-01979-8","url":null,"abstract":"<div><p>Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of metal complexes (metal?=?Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dianionic dicarboxylate ligands, along with their simple metal salt and dicarboxylic acid precursors, against common AMR pathogens were investigated. Overall, the highest level of antibacterial activity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylic acid precursors. The chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. Whole-genome sequencing (WGS) was carried out on the reference <i>Pseudomonas aeruginosa</i> strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties with the aim of elucidating their mechanism of action. Various mutations were detected in the mutant <i>P. aeruginosa</i> genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda and warrants further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR infections.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01979-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4380661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-09DOI: 10.1007/s00775-022-01974-z
Daniel Oliveira Silva Martins, Rafael Aparecido Carvalho Souza, Marjorie Caroline Liberato Cavalcanti Freire, Nathalya Cristina de Moraes Roso Mesquita, Igor Andrade Santos, Débora Moraes de Oliveira, Nilson Nicolau Junior, Raphael Enoque Ferraz de Paiva, Mark Harris, Carolina Gonçalves Oliveira, Glaucius Oliva, Ana Carolina Gomes Jardim
Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [CoIII(L1)2]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication). Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV-nanoluciferase in the presence of the compound, showing that [CoIII(L1)2]Cl inhibited CHIKV infection with the selective index of 3.26. [CoIII(L1)2]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [CoIII(L1)2]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [CoIII(L1)2]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [CoIII(L1)2]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects.
{"title":"Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4","authors":"Daniel Oliveira Silva Martins, Rafael Aparecido Carvalho Souza, Marjorie Caroline Liberato Cavalcanti Freire, Nathalya Cristina de Moraes Roso Mesquita, Igor Andrade Santos, Débora Moraes de Oliveira, Nilson Nicolau Junior, Raphael Enoque Ferraz de Paiva, Mark Harris, Carolina Gonçalves Oliveira, Glaucius Oliva, Ana Carolina Gomes Jardim","doi":"10.1007/s00775-022-01974-z","DOIUrl":"10.1007/s00775-022-01974-z","url":null,"abstract":"<div><p>Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication)<i>.</i> Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV-<i>nanoluciferase</i> in the presence of the compound, showing that [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl inhibited CHIKV infection with the selective index of 3.26. [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [Co<sup>III</sup>(L<sup>1</sup>)<sub>2</sub>]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01974-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4683685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-07DOI: 10.1007/s00775-022-01969-w
Jack Silver, Golzar al-Jaff, Jehad A. Taies, Michael T. Wilson, Daniel den Engelsen, George R. Fern, Terry G. Ireland
The visible and M?ssbauer spectra of [Fe(II)(Por)L2] and [Fe(II)(Por)L(CO)] complexes (where Por?=?protoporphyrin IX (PPIX) or tetra(p-sulfophenyl)porphyrin (TPPS) and L?=?an aliphatic or aromatic nitrogenous base) are reported and discussed. The results are compared to those of previously reported [Fe(II)(Por)L(CO)] complexes (where Por?=?PPIX, TPPS, PMXPP, TPP, OMTBP and OEP; L?=?a nitrogenous aromatic ligand) and HbCO (where Hb?=?haemoglobin) and MyCO (where My?=?myoglobin). A new approach, to extracting information from the M?ssbauer parameters has been developed by plotting those of the [Fe(II)(Por)L2] complexes against those of [Fe(II)(Por)L(CO)] complexes for the same ligands, has yielded a series of trend lines that show a significant dependence on both the nature of the porphyrin and also of the nitrogenous ligand. Different trend lines were found for aromatic nitrogenous ligands to aliphatic nitrogenous ligands showing that the porphyrins could donate different amounts of charge to the Fe(II) cations as the L ligand changed, and hence, they display electron sink properties. From the plots, it was shown that haemoglobin and myoglobin both bind CO very strongly compared to the model complexes studied herein. Using the reported structural and M?ssbauer data for the [Fe(II)(Por)L2] and [Fe(II)(Por)L(CO)] complexes, it proved possible and instructive to plot the M?ssbauer parameters against a number of the bond lengths around the Fe(II) cations. The interpretation of the resulting trend lines both supported and facilitated the extension of our findings enabling further understanding of the geometry of the bonding in CO haemoglobin and CO myoglobin.
{"title":"Studies on the binding of CO to low-spin [Fe(II)(Por)L2] complexes: an aid to understanding the binding of CO to haemoglobin and myoglobin","authors":"Jack Silver, Golzar al-Jaff, Jehad A. Taies, Michael T. Wilson, Daniel den Engelsen, George R. Fern, Terry G. Ireland","doi":"10.1007/s00775-022-01969-w","DOIUrl":"10.1007/s00775-022-01969-w","url":null,"abstract":"<div><p>The visible and M?ssbauer spectra of [Fe(II)(Por)L<sub>2</sub>] and [Fe(II)(Por)L(CO)] complexes (where Por?=?protoporphyrin IX (PPIX) or tetra(<i>p</i>-sulfophenyl)porphyrin (TPPS) and L?=?an aliphatic or aromatic nitrogenous base) are reported and discussed. The results are compared to those of previously reported [Fe(II)(Por)L(CO)] complexes (where Por?=?PPIX, TPPS, PMXPP, TPP, OMTBP and OEP; L?=?a nitrogenous aromatic ligand) and HbCO (where Hb?=?haemoglobin) and MyCO (where My?=?myoglobin). A new approach, to extracting information from the M?ssbauer parameters has been developed by plotting those of the [Fe(II)(Por)L<sub>2</sub>] complexes against those of [Fe(II)(Por)L(CO)] complexes for the same ligands, has yielded a series of trend lines that show a significant dependence on both the nature of the porphyrin and also of the nitrogenous ligand. Different trend lines were found for aromatic nitrogenous ligands to aliphatic nitrogenous ligands showing that the porphyrins could donate different amounts of charge to the Fe(II) cations as the L ligand changed, and hence, they display electron sink properties. From the plots, it was shown that haemoglobin and myoglobin both bind CO very strongly compared to the model complexes studied herein. Using the reported structural and M?ssbauer data for the [Fe(II)(Por)L<sub>2</sub>] and [Fe(II)(Por)L(CO)] complexes, it proved possible and instructive to plot the M?ssbauer parameters against a number of the bond lengths around the Fe(II) cations. The interpretation of the resulting trend lines both supported and facilitated the extension of our findings enabling further understanding of the geometry of the bonding in CO haemoglobin and CO myoglobin.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><img></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00775-022-01969-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4613358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-07DOI: 10.1007/s00775-022-01980-1
Andrew T. Stoltzfus, Courtney J. Campbell, Madison M. Worth, Kellie Hom, Timothy L. Stemmler, Sarah L. J. Michel
Tristetraprolin (TTP) is a nonclassical CCCH zinc finger (ZF) that plays a crucial role in regulating inflammation. TTP regulates cytokine mRNAs by specific binding of its two conserved ZF domains (CysX8CysX5CysX3His) to adenylate-uridylate-rich sequences (AREs) at the 3?-untranslated region, leading to degradation of the RNA. Dysregulation of TTP in animal models has demonstrated several cytokine-related syndromes, including chronic inflammation and autoimmune disorders. Exposure to Pb(II), a prevalent environmental toxin, is known to contribute to similar pathologies, in part by disruption of and/or competition with cysteine-rich metalloproteins. TTP’s role during stress as a ubiquitous translational regulator of cell signaling (and dysfunction), which may underpin various phenotypes of Pb(II) toxicity, highlights the importance of understanding the interaction between TTP and Pb(II). The impact of Pb(II) binding on TTP’s fold and RNA-binding function was analyzed via UV–Vis spectroscopy, circular dichroism, X-ray absorption spectroscopy, nuclear magnetic resonance spectroscopy, and fluorescence anisotropy. A construct containing the two ZF domains of TTP (TTP-2D) bound to Pb(II) with nanomolar affinity and exhibited a different geometry and fold in comparison to Zn2-TTP-2D. Despite the altered secondary structure, Pb(II)-substituted TTP-2D bound a canonical ARE sequence more selectively than Zn2-TTP-2D. Taken together, these data suggest that Pb(II) may interfere with proper TTP regulation and hinder the cell’s ability to respond to inflammation.
{"title":"Pb(II) coordination to the nonclassical zinc finger tristetraprolin: retained function with an altered fold","authors":"Andrew T. Stoltzfus, Courtney J. Campbell, Madison M. Worth, Kellie Hom, Timothy L. Stemmler, Sarah L. J. Michel","doi":"10.1007/s00775-022-01980-1","DOIUrl":"10.1007/s00775-022-01980-1","url":null,"abstract":"<p>Tristetraprolin (TTP) is a nonclassical CCCH zinc finger (ZF) that plays a crucial role in regulating inflammation. TTP regulates cytokine mRNAs by specific binding of its two conserved ZF domains (CysX<sub>8</sub>CysX<sub>5</sub>CysX<sub>3</sub>His) to adenylate-uridylate-rich sequences (AREs) at the 3?-untranslated region, leading to degradation of the RNA. Dysregulation of TTP in animal models has demonstrated several cytokine-related syndromes, including chronic inflammation and autoimmune disorders. Exposure to Pb(II), a prevalent environmental toxin, is known to contribute to similar pathologies, in part by disruption of and/or competition with cysteine-rich metalloproteins. TTP’s role during stress as a ubiquitous translational regulator of cell signaling (and dysfunction), which may underpin various phenotypes of Pb(II) toxicity, highlights the importance of understanding the interaction between TTP and Pb(II). The impact of Pb(II) binding on TTP’s fold and RNA-binding function was analyzed via UV–Vis spectroscopy, circular dichroism, X-ray absorption spectroscopy, nuclear magnetic resonance spectroscopy, and fluorescence anisotropy. A construct containing the two ZF domains of TTP (TTP-2D) bound to Pb(II) with nanomolar affinity and exhibited a different geometry and fold in comparison to Zn<sub>2</sub>-TTP-2D. Despite the altered secondary structure, Pb(II)-substituted TTP-2D bound a canonical ARE sequence more selectively than Zn<sub>2</sub>-TTP-2D. Taken together, these data suggest that Pb(II) may interfere with proper TTP regulation and hinder the cell’s ability to respond to inflammation.</p>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4287691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-06DOI: 10.1007/s00775-022-01985-w
Hajime Hirao, Songyan Xia, Shuyang Liu
There are different views in the literature regarding how to interpret the observed spectral features of the ferrous–CO complexes in cytochrome P450 enzymes (P450s). In this work, we applied density functional theory (DFT) and time-dependent DFT (TDDFT) calculations at the B3LYP-D3BJ/def2-TZVP level with a CPCM correction to the ferrous–CO models of P450s as well as of proteins that contain a histidine-ligated heme. Our results support the notion derived from a previously reported iterative extended Hückel calculation that the involvement of the sulfur lone-pair orbital (S(nz)) of the axial cysteine ligand in the electronic excitations gives rise to a spectral anomaly. The Q and the shorter-wavelength Soret (B′) peaks are primarily due to the electronic transitions from the a2u- and S(nz)-type molecular orbitals (MOs), generated via an orbital interaction of fragment orbitals, to the near-degenerate eg-type π* MOs, respectively. The transitions from the a1u-type MO to the eg-type MOs contribute most to the longer wavelength Soret (B) peaks. Both a2u- and S(nz)-type MOs contribute to the B peaks, but the contribution of the latter is greater. When the axial ligand is histidine, the Q and Soret peaks originate essentially from the excitations from the a2u- and a1u-type MOs to the eg-type MOs. The transitions from the b2u-type MOs to the eg-type MOs play the most significant role in the N peaks of such ferrous–CO complexes. Here, the b2u-type MOs have a large contribution from the imidazole π orbital.
{"title":"Spectral features of the ferrous–CO complex in cytochrome P450: a revisit using TDDFT calculations","authors":"Hajime Hirao, Songyan Xia, Shuyang Liu","doi":"10.1007/s00775-022-01985-w","DOIUrl":"10.1007/s00775-022-01985-w","url":null,"abstract":"<div><p>There are different views in the literature regarding how to interpret the observed spectral features of the ferrous–CO complexes in cytochrome P450 enzymes (P450s). In this work, we applied density functional theory (DFT) and time-dependent DFT (TDDFT) calculations at the B3LYP-D3BJ/def2-TZVP level with a CPCM correction to the ferrous–CO models of P450s as well as of proteins that contain a histidine-ligated heme. Our results support the notion derived from a previously reported iterative extended Hückel calculation that the involvement of the sulfur lone-pair orbital (S(n<sub>z</sub>)) of the axial cysteine ligand in the electronic excitations gives rise to a spectral anomaly. The Q and the shorter-wavelength Soret (B′) peaks are primarily due to the electronic transitions from the a<sub>2u</sub>- and S(n<sub>z</sub>)-type molecular orbitals (MOs), generated via an orbital interaction of fragment orbitals, to the near-degenerate e<sub>g</sub>-type π* MOs, respectively. The transitions from the a<sub>1u</sub>-type MO to the e<sub>g</sub>-type MOs contribute most to the longer wavelength Soret (B) peaks. Both a<sub>2u</sub>- and S(n<sub>z</sub>)-type MOs contribute to the B peaks, but the contribution of the latter is greater. When the axial ligand is histidine, the Q and Soret peaks originate essentially from the excitations from the a<sub>2u</sub>- and a<sub>1u</sub>-type MOs to the e<sub>g</sub>-type MOs. The transitions from the b<sub>2u</sub>-type MOs to the e<sub>g</sub>-type MOs play the most significant role in the N peaks of such ferrous–CO complexes. Here, the b<sub>2u</sub>-type MOs have a large contribution from the imidazole π orbital.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":603,"journal":{"name":"JBIC Journal of Biological Inorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"4244929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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