Pub Date : 2024-07-23DOI: 10.3389/fchbi.2024.1425501
Yvett Sosa, Bhav Kapur, Jessica Hurtak, Laura J. Kingsley, Hao Wu, Stefanie Gruber, Herbert Nar, Saad Khattabi, Jesus Seco Moral, Maria Fátima Lucas, Caterina Martin, Nikola Lončar, Frederic Buono, Noah Pefaur, Andrew E. Nixon, Jinhua J. Song
Introduction: Biocatalysis, particularly through engineered enzymes, presents a cost-effective, efficient, and eco-friendly approach to compound synthesis. We sought to identify ketoreductases capable of synthesizing optically pure alcohols or ketones, essential chiral building blocks for active pharmaceutical ingredients.Methods: Using BioMatchMaker®, an in silico high-throughput platform that allows the identification of wild-type enzyme sequences for a desired chemical transformation, we identified a bacterial SDR ketoreductase from Thermus caliditerrae, Tcalid SDR, that demonstrates favorable reaction efficiency and desired enantiomeric excess.Results: Here we present two crystal structures of the Tcalid SDR in an apo-form at 1.9 Å and NADP-complexed form at 1.7 Å resolution (9FE6 and 9FEB, respectively). This enzyme forms a homotetramer with each subunit containing an N-terminal Rossmann-fold domain. We use computational analysis combined with site-directed mutagenesis and enzymatic characterization to define the substrate-binding pocket. Furthermore, the enzyme retained favorable reactivity and selectivity after incubation at elevated temperature.Conclusion: The enantioselectivity combined with the thermostability of Tcalid SDR makes this enzyme an attractive engineering starting point for biocatalysis applications.
简介：生物催化，特别是通过工程酶，为化合物合成提供了一种经济、高效和环保的方法。我们试图找出能够合成光学纯醇或酮的酮还原酶，它们是活性药物成分的重要手性构件：方法：利用 BioMatchMaker®（一种可为所需化学转化鉴定野生型酶序列的硅学高通量平台），我们鉴定出了一种来自 Thermus caliditerrae 的细菌 SDR 酮还原酶 Tcalid SDR，它具有良好的反应效率和所需的对映体过量：在此，我们展示了 Tcalid SDR 的两种晶体结构，一种是 1.9 Å 分辨率的无对映体形式，另一种是 1.7 Å 分辨率的 NADP 复合物形式（分别为 9FE6 和 9FEB）。这种酶形成一个同源四聚体，每个亚基都含有一个 N 端罗斯曼折叠结构域。我们利用计算分析结合定点突变和酶学特性鉴定了底物结合口袋。此外，该酶在高温培养后仍保持良好的反应性和选择性：结论：Tcalid SDR 的对映体选择性和恒温性使这种酶成为生物催化应用的一个有吸引力的工程起点。
{"title":"In silico enzyme screening identifies an SDR ketoreductase from Thermus caliditerrae as an attractive biocatalyst and promising candidate for protein engineering","authors":"Yvett Sosa, Bhav Kapur, Jessica Hurtak, Laura J. Kingsley, Hao Wu, Stefanie Gruber, Herbert Nar, Saad Khattabi, Jesus Seco Moral, Maria Fátima Lucas, Caterina Martin, Nikola Lončar, Frederic Buono, Noah Pefaur, Andrew E. Nixon, Jinhua J. Song","doi":"10.3389/fchbi.2024.1425501","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1425501","url":null,"abstract":"Introduction: Biocatalysis, particularly through engineered enzymes, presents a cost-effective, efficient, and eco-friendly approach to compound synthesis. We sought to identify ketoreductases capable of synthesizing optically pure alcohols or ketones, essential chiral building blocks for active pharmaceutical ingredients.Methods: Using BioMatchMaker®, an in silico high-throughput platform that allows the identification of wild-type enzyme sequences for a desired chemical transformation, we identified a bacterial SDR ketoreductase from Thermus caliditerrae, Tcalid SDR, that demonstrates favorable reaction efficiency and desired enantiomeric excess.Results: Here we present two crystal structures of the Tcalid SDR in an apo-form at 1.9 Å and NADP-complexed form at 1.7 Å resolution (9FE6 and 9FEB, respectively). This enzyme forms a homotetramer with each subunit containing an N-terminal Rossmann-fold domain. We use computational analysis combined with site-directed mutagenesis and enzymatic characterization to define the substrate-binding pocket. Furthermore, the enzyme retained favorable reactivity and selectivity after incubation at elevated temperature.Conclusion: The enantioselectivity combined with the thermostability of Tcalid SDR makes this enzyme an attractive engineering starting point for biocatalysis applications.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"143 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141810967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.3389/fchbi.2024.1408621
R. Janssens, R. van Haperen, Michael van der Reijden, Alex Maas, Jingsong Wang, Frank Grosveld, D. Drabek
Mesothelin (MSLN) is an attractive target for anticancer therapeutics and bioimaging reagents that utilize antibodies. This study was aimed at developing a novel human anti-MSLN single-domain antibody that exclusively binds to the membrane-attached MSLN using transgenic mice generating human heavy-chain-only antibodies (HCAbs) and exploring the resulting HCAbs as imaging tools.We introduced a doxycycline-inducible human MSLN gene in genetically modified mice expressing human HCAbs. This new method of non-invasive immunization by antigen induction results in MSLN antigen production in its native conformation on the cell surface. Screening of 2,000 HCAbs from the resulting immune library yielded numerous binders, from which we chose 19G6 as the lead antibody. This antibody was 111Indium radiolabeled and tested in a xenotransplantation tumor model with OVCAR-3 cells.The 19G6 antibody shows nanomolar affinity toward membrane-bound MSLN and does not recognize soluble MSLN. The human MSLN-positive tumors were visualized in an in vivo mouse model. The non-labeled antibody prevented binding when provided in excess, showing tumor specificity.19G6 with a human Fc is a promising tumor-cell tracer in vivo. This HCAb can also be engineered into a smaller and shorter-lived tracer (only the VH domain) or combined with other target-binding domains to form multispecific modalities for tumor immunotherapy.
{"title":"Generation and preclinical evaluation of a human heavy-chain-only antibody recognizing the membrane-bound tumor-associated antigen mesothelin","authors":"R. Janssens, R. van Haperen, Michael van der Reijden, Alex Maas, Jingsong Wang, Frank Grosveld, D. Drabek","doi":"10.3389/fchbi.2024.1408621","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1408621","url":null,"abstract":"Mesothelin (MSLN) is an attractive target for anticancer therapeutics and bioimaging reagents that utilize antibodies. This study was aimed at developing a novel human anti-MSLN single-domain antibody that exclusively binds to the membrane-attached MSLN using transgenic mice generating human heavy-chain-only antibodies (HCAbs) and exploring the resulting HCAbs as imaging tools.We introduced a doxycycline-inducible human MSLN gene in genetically modified mice expressing human HCAbs. This new method of non-invasive immunization by antigen induction results in MSLN antigen production in its native conformation on the cell surface. Screening of 2,000 HCAbs from the resulting immune library yielded numerous binders, from which we chose 19G6 as the lead antibody. This antibody was 111Indium radiolabeled and tested in a xenotransplantation tumor model with OVCAR-3 cells.The 19G6 antibody shows nanomolar affinity toward membrane-bound MSLN and does not recognize soluble MSLN. The human MSLN-positive tumors were visualized in an in vivo mouse model. The non-labeled antibody prevented binding when provided in excess, showing tumor specificity.19G6 with a human Fc is a promising tumor-cell tracer in vivo. This HCAb can also be engineered into a smaller and shorter-lived tracer (only the VH domain) or combined with other target-binding domains to form multispecific modalities for tumor immunotherapy.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"20 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141817417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-12DOI: 10.3389/fchbi.2024.1428646
Nigel G. J. Richards, James H. Naismith
Remarkable progress has been made to elucidate the structural and mechanistic enzymology of the biosynthetic pathways that give rise to naturally occurring C-nucleosides. These compounds are generally cytotoxic and exhibit interesting antiviral, antibiotic and anti-parasitic activity. Here we review current knowledge concerning formycin biosynthesis and highlight deficiencies in our understanding of key chemical transformations in the pathway.
在阐明产生天然 C 核苷的生物合成途径的结构和机理酶学方面取得了显著进展。这些化合物通常具有细胞毒性，并表现出有趣的抗病毒、抗生素和抗寄生虫活性。在此，我们回顾了目前有关甲氨霉素生物合成的知识，并强调了我们对该途径中关键化学转化的认识存在的不足。
{"title":"The chemistry of Formycin biosynthesis","authors":"Nigel G. J. Richards, James H. Naismith","doi":"10.3389/fchbi.2024.1428646","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1428646","url":null,"abstract":"Remarkable progress has been made to elucidate the structural and mechanistic enzymology of the biosynthetic pathways that give rise to naturally occurring C-nucleosides. These compounds are generally cytotoxic and exhibit interesting antiviral, antibiotic and anti-parasitic activity. Here we review current knowledge concerning formycin biosynthesis and highlight deficiencies in our understanding of key chemical transformations in the pathway.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"52 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141654701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.3389/fchbi.2024.1431412
Hui Xu, Jessica R. Kenneson, Laura E. Minton, Douglas C. Goodwin
Many novel structural features impart a robust catalase activity to KatG that is absent from all other members of its superfamily. The conformationally dynamic “Arg switch” and oxidizable “proximal Trp” have both figured prominently in investigations of KatG structure and mechanism, but the full scope of their contributions to catalysis remains unclear. The switch (R418) appears to regulate active-site intramolecular electron transfer. The proximal Trp (W321) is a conspicuous site of radical formation, but W321•+ does not appear to participate directly in the KatG catalase cycle. To explore the extent to which these residues may cooperate in KatG’s catalase activity, we generated R418N and W321F/R418N KatG and compared their catalytic and spectroscopic properties to wt KatG. R418N KatG showed pH-independent susceptibility to H2O2-based inactivation, whereas wt KatG only showed this response under conditions where the Arg switch would be oriented away from the active site (i.e., low pH). Peroxidatic electron donors (PxEDs) prevented inactivation of wt and R418N KatG regardless of pH; however, protection of R418N KatG activity by this mechanism produced at least ten-fold greater extents of PxED oxidation. Elimination of the proximal Trp in addition to the Arg switch (i.e., W321F/R418N KatG) resulted in a near complete inability to sustain H2O2 degradation. Remarkably, W321F KatG showed resistance to H2O2-dependent inactivation indistinguishable from wt at pH 7 (i.e., when the Arg switch is oriented toward the active site) but sensitivity to H2O2-dependent inactivation indistinguishable from W321F/R418N KatG at pH 5 (i.e., when the Arg switch is oriented away from the active site). These data suggest loss of the Arg switch (either by mutagenesis or conformationally due to environmental pH) results in a KatG that is substantially compromised in the sustained degradation of H2O2. This can be overcome provided that KatG retains its ability to utilize the proximal Trp as a site of protein-based oxidation and has a PxED available to repair protein oxidation events. However, if both the Arg switch and the proximal Trp are absent, rapid H2O2-dependent inactivation is observed, and PxEDs are unable to effectively intervene to preserve KatG’s catalase activity.
{"title":"A switch and a failsafe: KatG’s mechanism for preservation of catalase activity using a conformationally dynamic Arg and an active-site Trp","authors":"Hui Xu, Jessica R. Kenneson, Laura E. Minton, Douglas C. Goodwin","doi":"10.3389/fchbi.2024.1431412","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1431412","url":null,"abstract":"Many novel structural features impart a robust catalase activity to KatG that is absent from all other members of its superfamily. The conformationally dynamic “Arg switch” and oxidizable “proximal Trp” have both figured prominently in investigations of KatG structure and mechanism, but the full scope of their contributions to catalysis remains unclear. The switch (R418) appears to regulate active-site intramolecular electron transfer. The proximal Trp (W321) is a conspicuous site of radical formation, but W321•+ does not appear to participate directly in the KatG catalase cycle. To explore the extent to which these residues may cooperate in KatG’s catalase activity, we generated R418N and W321F/R418N KatG and compared their catalytic and spectroscopic properties to wt KatG. R418N KatG showed pH-independent susceptibility to H2O2-based inactivation, whereas wt KatG only showed this response under conditions where the Arg switch would be oriented away from the active site (i.e., low pH). Peroxidatic electron donors (PxEDs) prevented inactivation of wt and R418N KatG regardless of pH; however, protection of R418N KatG activity by this mechanism produced at least ten-fold greater extents of PxED oxidation. Elimination of the proximal Trp in addition to the Arg switch (i.e., W321F/R418N KatG) resulted in a near complete inability to sustain H2O2 degradation. Remarkably, W321F KatG showed resistance to H2O2-dependent inactivation indistinguishable from wt at pH 7 (i.e., when the Arg switch is oriented toward the active site) but sensitivity to H2O2-dependent inactivation indistinguishable from W321F/R418N KatG at pH 5 (i.e., when the Arg switch is oriented away from the active site). These data suggest loss of the Arg switch (either by mutagenesis or conformationally due to environmental pH) results in a KatG that is substantially compromised in the sustained degradation of H2O2. This can be overcome provided that KatG retains its ability to utilize the proximal Trp as a site of protein-based oxidation and has a PxED available to repair protein oxidation events. However, if both the Arg switch and the proximal Trp are absent, rapid H2O2-dependent inactivation is observed, and PxEDs are unable to effectively intervene to preserve KatG’s catalase activity.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"26 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141659828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.3389/fchbi.2024.1394645
A. Levina, Gonzalo Scalese, D. Gambino, D. Crans, Peter A. Lay
Introduction: Glioblastoma is a brain cancer difficult to treat but recently mixed-ligand vanadium(V) Schiff base/catecholato complexes have exhibited high in vitro anti-proliferative activity. Hence, we explored the activity of [VVOL1L2], which contains two iron chelating ligands, 2-hydroxy-1-naphthylaldehyde iso-nicotinoyhydrazone (L1H2) and clioquinol (L2H). This complex was previously reported to be very effective against Trypanosoma cruzi, the causative agent of Chagas disease. These studies explored the possibility that a compound with efficacy against Trypanosoma cruzi also has efficacy against human glioblastoma cancer cells. Since [VVOL1L2] was poorly soluble in water and the clioquinol ligand dissociated from the complex upon addition to an aqueous environment, an understanding of the speciation was very important to interpret its biological activity.Methods: Stability studies in cell media were followed by UV/Vis spectroscopy to determine speciation of relevance to the in vitro anti-proliferative activity of the complex with T98G glioblastoma cells, which was also measured in the absence and presence of Fe(III).Results and Discussion: The current work demonstrated that the mixed-ligand vanadium coordination complex had high in vitro anti-proliferative activity against the human glioblastoma (T98G) cell line. The enhanced anti-proliferative effects of the mixed-ligand vanadium complex against T98G cells could be due to either hydrolysis of complex and release of the toxic clioquinol, or the rapid uptake of the lipophilic complex prior to hydrolysis. The speciation studies showed that at least part of the potent toxicity of the mixed-ligand coordination complex stemmed from release of the bioactive clioquinol ligand from the complex, which depended on whether Fe(III) was present. The studies also showed that the [VV(O)2 (L1H)] coordination complex was the most potent complex that remained intact and, hence, the complex that is the most biological active. Thus, future development of complexes should focus on the one-ligand intact complexes or making any mixed-ligand complex more water soluble, stable in aqueous solution, or designed to be rapidly taken up by diseased cells prior to hydrolysis.
{"title":"Solution chemistry and anti-proliferative activity against glioblastoma cells of a vanadium(V) complex with two bioactive ligands","authors":"A. Levina, Gonzalo Scalese, D. Gambino, D. Crans, Peter A. Lay","doi":"10.3389/fchbi.2024.1394645","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1394645","url":null,"abstract":"Introduction: Glioblastoma is a brain cancer difficult to treat but recently mixed-ligand vanadium(V) Schiff base/catecholato complexes have exhibited high in vitro anti-proliferative activity. Hence, we explored the activity of [VVOL1L2], which contains two iron chelating ligands, 2-hydroxy-1-naphthylaldehyde iso-nicotinoyhydrazone (L1H2) and clioquinol (L2H). This complex was previously reported to be very effective against Trypanosoma cruzi, the causative agent of Chagas disease. These studies explored the possibility that a compound with efficacy against Trypanosoma cruzi also has efficacy against human glioblastoma cancer cells. Since [VVOL1L2] was poorly soluble in water and the clioquinol ligand dissociated from the complex upon addition to an aqueous environment, an understanding of the speciation was very important to interpret its biological activity.Methods: Stability studies in cell media were followed by UV/Vis spectroscopy to determine speciation of relevance to the in vitro anti-proliferative activity of the complex with T98G glioblastoma cells, which was also measured in the absence and presence of Fe(III).Results and Discussion: The current work demonstrated that the mixed-ligand vanadium coordination complex had high in vitro anti-proliferative activity against the human glioblastoma (T98G) cell line. The enhanced anti-proliferative effects of the mixed-ligand vanadium complex against T98G cells could be due to either hydrolysis of complex and release of the toxic clioquinol, or the rapid uptake of the lipophilic complex prior to hydrolysis. The speciation studies showed that at least part of the potent toxicity of the mixed-ligand coordination complex stemmed from release of the bioactive clioquinol ligand from the complex, which depended on whether Fe(III) was present. The studies also showed that the [VV(O)2 (L1H)] coordination complex was the most potent complex that remained intact and, hence, the complex that is the most biological active. Thus, future development of complexes should focus on the one-ligand intact complexes or making any mixed-ligand complex more water soluble, stable in aqueous solution, or designed to be rapidly taken up by diseased cells prior to hydrolysis.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":" 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141676332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-09DOI: 10.3389/fchbi.2024.1400481
Claudia Foerster, Andrea Müller-Sepúlveda, M. Copetti, A. Arrúa, Liliam Monsalve, María Laura Ramirez, Adriana M. Torres
Mycotoxins are natural metabolites produced by species of filamentous fungi belonging mainly to the genera Aspergillus, Fusarium, Penicillium, and Alternaria, which can grow in various crops and foodstuffs. The South American climate is diverse, varying from tropical, temperate, and arid to cold, ideal for the growth of different types of fungi and mycotoxin production. This mini review aimed to describe the natural occurrence of mycotoxin in food in South America from 2018 to 2023, identifying research gaps and challenges in an era of climate change. We analyzed 53 studies, 21 from Brazil. Most of the mycotoxins analyzed in South America were the traditional and regulated mycotoxins, with variable occurrences depending on the region, climatic conditions, and methodology used. Emerging and modified mycotoxins have only been studied in Argentina and Brazil, where some studies have shown high occurrences. Given this, it is essential to strengthen food safety laboratories and surveillance capabilities and establish early warning systems. It is also essential to continue working to raise awareness of mycotoxins as a public health issue and to study and prevent the impact of climate change on soil microbial population, the new prevalence of fungi, and the profile of toxigenic species. An effective connection and collaboration between disciplines and sectors in different countries is needed to meet this research challenge.
{"title":"A mini review of mycotoxin’s occurrence in food in South America in the last 5 years: research gaps and challenges in a climate change era","authors":"Claudia Foerster, Andrea Müller-Sepúlveda, M. Copetti, A. Arrúa, Liliam Monsalve, María Laura Ramirez, Adriana M. Torres","doi":"10.3389/fchbi.2024.1400481","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1400481","url":null,"abstract":"Mycotoxins are natural metabolites produced by species of filamentous fungi belonging mainly to the genera Aspergillus, Fusarium, Penicillium, and Alternaria, which can grow in various crops and foodstuffs. The South American climate is diverse, varying from tropical, temperate, and arid to cold, ideal for the growth of different types of fungi and mycotoxin production. This mini review aimed to describe the natural occurrence of mycotoxin in food in South America from 2018 to 2023, identifying research gaps and challenges in an era of climate change. We analyzed 53 studies, 21 from Brazil. Most of the mycotoxins analyzed in South America were the traditional and regulated mycotoxins, with variable occurrences depending on the region, climatic conditions, and methodology used. Emerging and modified mycotoxins have only been studied in Argentina and Brazil, where some studies have shown high occurrences. Given this, it is essential to strengthen food safety laboratories and surveillance capabilities and establish early warning systems. It is also essential to continue working to raise awareness of mycotoxins as a public health issue and to study and prevent the impact of climate change on soil microbial population, the new prevalence of fungi, and the profile of toxigenic species. An effective connection and collaboration between disciplines and sectors in different countries is needed to meet this research challenge.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140997658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.3389/fchbi.2024.1389620
Lauren B Coco, C. F. Freel Meyers
This work reports an alkyl acetylphosphonate (alkylAP) activity-based probe (ABP) for 1-deoxy-d-xylulose 5-phosphate synthase DXPS, a promising antimicrobial target. This essential thiamin diphosphate (ThDP)-dependent enzyme operates at a branchpoint in bacterial central metabolism and is believed to play key roles in pathogen adaptation during infection. How different bacterial pathogens harness DXPS activity to adapt and survive within host environments remains incompletely understood, and tools for probing DXPS function in different contexts of infection are lacking. Here, we have developed alkylAP-based ABP 1, designed to react with the ThDP cofactor on active DXPS to form a stable C2α-phosphonolactylThDP adduct which subsequently crosslinks to the DXPS active site upon photoactivation. ABP 1 displays low micromolar potency against DXPS and dose-dependent labeling of DXPS that is blocked by alkylAP-based inhibitors. The probe displays selectivity for DXPS over ThDP-dependent enzymes and is capable of detecting active DXPS in a complex proteome. These studies represent an important advance toward development of tools to probe DXPS function in different contexts of bacterial infection, and for drug discovery efforts on this target.
{"title":"An activity-based probe for antimicrobial target DXP synthase, a thiamin diphosphate-dependent enzyme","authors":"Lauren B Coco, C. F. Freel Meyers","doi":"10.3389/fchbi.2024.1389620","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1389620","url":null,"abstract":"This work reports an alkyl acetylphosphonate (alkylAP) activity-based probe (ABP) for 1-deoxy-d-xylulose 5-phosphate synthase DXPS, a promising antimicrobial target. This essential thiamin diphosphate (ThDP)-dependent enzyme operates at a branchpoint in bacterial central metabolism and is believed to play key roles in pathogen adaptation during infection. How different bacterial pathogens harness DXPS activity to adapt and survive within host environments remains incompletely understood, and tools for probing DXPS function in different contexts of infection are lacking. Here, we have developed alkylAP-based ABP 1, designed to react with the ThDP cofactor on active DXPS to form a stable C2α-phosphonolactylThDP adduct which subsequently crosslinks to the DXPS active site upon photoactivation. ABP 1 displays low micromolar potency against DXPS and dose-dependent labeling of DXPS that is blocked by alkylAP-based inhibitors. The probe displays selectivity for DXPS over ThDP-dependent enzymes and is capable of detecting active DXPS in a complex proteome. These studies represent an important advance toward development of tools to probe DXPS function in different contexts of bacterial infection, and for drug discovery efforts on this target.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"9 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141004419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.3389/fchbi.2024.1398873
Nádia Ribeiro, Isabel Correia
Cancer inflicts a tremendous burden on modern society, and more effective and selective treatments need to be developed. Metallodrugs have been extensively explored as alternatives to current chemotherapeutic regimens that suffer from shortcomings such as severe side effects and acquired resistance. Hydrazide-hydrazones are a family of organic molecules containing the hydrazone functionality attached to a carbonyl group (−C=N−NH−CO). These molecules are extremely versatile and can be obtained from modular reactions between hydrazides and aldehydes or ketones, of which a large library is commercially available. Hydrazide-hydrazones show numerous therapeutic effects, and typically, their metal complexes exhibit increased potency. This review aims to highlight the potential of hydrazide-hydrazone metal complexes in the field of anticancer research. It focuses on the literature published in the last 10 years (2013-2023) and describes their biological effects, their antiproliferative activity and their mechanisms of action. It is organized by metal ion, including Cu, Ru, Pt, Pd, V, other d-block, lanthanide, and Ga and Sn ions. It highlights the diversity of molecules being developed and can be used as a guide for developing new hydrazide–hydrazones as efficient anticancer agents.
{"title":"A review of hydrazide-hydrazone metal complexes’ antitumor potential","authors":"Nádia Ribeiro, Isabel Correia","doi":"10.3389/fchbi.2024.1398873","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1398873","url":null,"abstract":"Cancer inflicts a tremendous burden on modern society, and more effective and selective treatments need to be developed. Metallodrugs have been extensively explored as alternatives to current chemotherapeutic regimens that suffer from shortcomings such as severe side effects and acquired resistance. Hydrazide-hydrazones are a family of organic molecules containing the hydrazone functionality attached to a carbonyl group (−C=N−NH−CO). These molecules are extremely versatile and can be obtained from modular reactions between hydrazides and aldehydes or ketones, of which a large library is commercially available. Hydrazide-hydrazones show numerous therapeutic effects, and typically, their metal complexes exhibit increased potency. This review aims to highlight the potential of hydrazide-hydrazone metal complexes in the field of anticancer research. It focuses on the literature published in the last 10 years (2013-2023) and describes their biological effects, their antiproliferative activity and their mechanisms of action. It is organized by metal ion, including Cu, Ru, Pt, Pd, V, other d-block, lanthanide, and Ga and Sn ions. It highlights the diversity of molecules being developed and can be used as a guide for developing new hydrazide–hydrazones as efficient anticancer agents.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"62 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-10DOI: 10.3389/fchbi.2024.1360027
Natalia Casado, Judith Gañán, Sonia Morante-Zarcero, I. Sierra
The food control of tropane and pyrrolizidine alkaloids has become in recent years in Europe one of the main priorities within the food safety field due to the exponential increase in food alerts related to the concerning levels of these natural toxins in foods. This awareness has led to increasing progress in the research and determination of these compounds. Hence, this mini-review provides a brief and comprehensive overview of the evolution of these food alerts, highlighting the main food products frequently contaminated with these alkaloids and reviewing the analytical advances in their determination within the las 3 years (from 2020 to 2023).
{"title":"Recent food alerts and analytical advances related to the contamination of tropane and pyrrolizidine alkaloids in food","authors":"Natalia Casado, Judith Gañán, Sonia Morante-Zarcero, I. Sierra","doi":"10.3389/fchbi.2024.1360027","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1360027","url":null,"abstract":"The food control of tropane and pyrrolizidine alkaloids has become in recent years in Europe one of the main priorities within the food safety field due to the exponential increase in food alerts related to the concerning levels of these natural toxins in foods. This awareness has led to increasing progress in the research and determination of these compounds. Hence, this mini-review provides a brief and comprehensive overview of the evolution of these food alerts, highlighting the main food products frequently contaminated with these alkaloids and reviewing the analytical advances in their determination within the las 3 years (from 2020 to 2023).","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140717682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.3389/fchbi.2024.1386220
Sina Khorsandi, Kristin Huntoon, Jacques Lux
Engaging the immune sensing Stimulator of Interferon Genes (STING) pathway has emerged as a potentially powerful approach to cancer therapy. However, current STING agonists lack stability and specificity, resulting in toxic adverse effects and disappointing patient outcomes. Therefore, novel delivery vehicles are needed to mitigate negative results and improve the efficacy of STING agonists. Here we discuss innovative particle-based strategies and how they have increased the therapeutic results seen with STING agonists. We review ultrasound-responsive vehicles, pH-responsive particles, inorganic particles, carriers for extended release, and particles that act as both STING agonists and/or drug carriers. Further optimization of these strategies can potentially enable the clinical use of STING agonists for cancer therapy.
{"title":"Putting the sting back in STING therapy: novel delivery vehicles for improved STING activation","authors":"Sina Khorsandi, Kristin Huntoon, Jacques Lux","doi":"10.3389/fchbi.2024.1386220","DOIUrl":"https://doi.org/10.3389/fchbi.2024.1386220","url":null,"abstract":"Engaging the immune sensing Stimulator of Interferon Genes (STING) pathway has emerged as a potentially powerful approach to cancer therapy. However, current STING agonists lack stability and specificity, resulting in toxic adverse effects and disappointing patient outcomes. Therefore, novel delivery vehicles are needed to mitigate negative results and improve the efficacy of STING agonists. Here we discuss innovative particle-based strategies and how they have increased the therapeutic results seen with STING agonists. We review ultrasound-responsive vehicles, pH-responsive particles, inorganic particles, carriers for extended release, and particles that act as both STING agonists and/or drug carriers. Further optimization of these strategies can potentially enable the clinical use of STING agonists for cancer therapy.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":"13 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140738754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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