Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.06.016
Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky
BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.
{"title":"Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor","authors":"Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky","doi":"10.1016/j.chembiol.2024.06.016","DOIUrl":"10.1016/j.chembiol.2024.06.016","url":null,"abstract":"<div><div>BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1815-1826.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141769251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.09.001
Beste Mutlu , Kfir Sharabi , Jee Hyung Sohn , Bo Yuan , Pedro Latorre-Muro , Xin Qin , Jin-Seon Yook , Hua Lin , Deyang Yu , João Paulo G. Camporez , Shingo Kajimura , Gerald I. Shulman , Sheng Hui , Theodore M. Kamenecka , Patrick R. Griffin , Pere Puigserver
Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.
{"title":"Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation","authors":"Beste Mutlu , Kfir Sharabi , Jee Hyung Sohn , Bo Yuan , Pedro Latorre-Muro , Xin Qin , Jin-Seon Yook , Hua Lin , Deyang Yu , João Paulo G. Camporez , Shingo Kajimura , Gerald I. Shulman , Sheng Hui , Theodore M. Kamenecka , Patrick R. Griffin , Pere Puigserver","doi":"10.1016/j.chembiol.2024.09.001","DOIUrl":"10.1016/j.chembiol.2024.09.001","url":null,"abstract":"<div><div>Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1772-1786.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.08.001
Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai
Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant Physcomitrium patens, offer opportunities for plant synthetic genomics. The shared characteristics between P. patens and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate P. patens genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with P. patens as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.
{"title":"Plant synthetic genomics: Big lessons from the little yeast","authors":"Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai","doi":"10.1016/j.chembiol.2024.08.001","DOIUrl":"10.1016/j.chembiol.2024.08.001","url":null,"abstract":"<div><div>Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant <em>Physcomitrium patens</em>, offer opportunities for plant synthetic genomics. The shared characteristics between <em>P. patens</em> and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate <em>P. patens</em> genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with <em>P. patens</em> as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1745-1754"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A photocatalytic click chemistry approach, offering a significant advancement over conventional methods in RNA function modulation is described. This innovative method, utilizing light-activated small molecules, provides a high level of precision and control in RNA regulation, particularly effective in intricate cellular processes. By applying this strategy to CRISPR-Cas9 gene editing, we demonstrate its effectiveness in enhancing gene editing specificity and markedly reducing off-target effects. Our approach employs a vinyl ether modification in RNA, which activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. This method not only represents an advancement in genomic interventions but also offers broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.
{"title":"Reducing CRISPR-Cas9 off-target effects by optically controlled chemical modifications of guide RNA","authors":"Qianqian Qi , Xingyu Liu , Wei Xiong , Kaisong Zhang , Wei Shen , Yuanyuan Zhang , Xinyan Xu , Cheng Zhong , Yan Zhang , Tian Tian , Xiang Zhou","doi":"10.1016/j.chembiol.2024.09.006","DOIUrl":"10.1016/j.chembiol.2024.09.006","url":null,"abstract":"<div><div>A photocatalytic click chemistry approach, offering a significant advancement over conventional methods in RNA function modulation is described. This innovative method, utilizing light-activated small molecules, provides a high level of precision and control in RNA regulation, particularly effective in intricate cellular processes. By applying this strategy to CRISPR-Cas9 gene editing, we demonstrate its effectiveness in enhancing gene editing specificity and markedly reducing off-target effects. Our approach employs a vinyl ether modification in RNA, which activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. This method not only represents an advancement in genomic interventions but also offers broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1839-1851.e8"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.09.005
Christopher J. Good , Casey E. Butrico , Madeline E. Colley , Lauren N. Emmerson , Katherine N. Gibson-Corley , James E. Cassat , Jeffrey M. Spraggins , Richard M. Caprioli
Osteomyelitis occurs when Staphylococcus aureus invades the bone microenvironment, resulting in a bone marrow abscess with a spatially defined architecture of cells and biomolecules. Imaging mass spectrometry and microscopy are tools that can be employed to interrogate the lipidome of S. aureus-infected murine femurs and reveal metabolic and signaling consequences of infection. Here, nearly 250 lipids were spatially mapped to healthy and infection-associated morphological features throughout the femur, establishing composition profiles for tissue types. Ether lipids and arachidonoyl lipids were altered between cells and tissue structures in abscesses, suggesting their roles in abscess formation and inflammatory signaling. Sterols, triglycerides, bis(monoacylglycero)phosphates, and gangliosides possessed ring-like distributions throughout the abscess, suggesting a hypothesized dysregulation of lipid metabolism in a population of cells that cannot be discerned with traditional microscopy. These data provide insight into the signaling function and metabolism of cells in the fibrotic border of abscesses, likely characteristic of lipid-laden macrophages.
{"title":"Uncovering lipid dynamics in Staphylococcus aureus osteomyelitis using multimodal imaging mass spectrometry","authors":"Christopher J. Good , Casey E. Butrico , Madeline E. Colley , Lauren N. Emmerson , Katherine N. Gibson-Corley , James E. Cassat , Jeffrey M. Spraggins , Richard M. Caprioli","doi":"10.1016/j.chembiol.2024.09.005","DOIUrl":"10.1016/j.chembiol.2024.09.005","url":null,"abstract":"<div><div>Osteomyelitis occurs when <em>Staphylococcus aureus</em> invades the bone microenvironment, resulting in a bone marrow abscess with a spatially defined architecture of cells and biomolecules. Imaging mass spectrometry and microscopy are tools that can be employed to interrogate the lipidome of <em>S. aureus</em>-infected murine femurs and reveal metabolic and signaling consequences of infection. Here, nearly 250 lipids were spatially mapped to healthy and infection-associated morphological features throughout the femur, establishing composition profiles for tissue types. Ether lipids and arachidonoyl lipids were altered between cells and tissue structures in abscesses, suggesting their roles in abscess formation and inflammatory signaling. Sterols, triglycerides, bis(monoacylglycero)phosphates, and gangliosides possessed ring-like distributions throughout the abscess, suggesting a hypothesized dysregulation of lipid metabolism in a population of cells that cannot be discerned with traditional microscopy. These data provide insight into the signaling function and metabolism of cells in the fibrotic border of abscesses, likely characteristic of lipid-laden macrophages.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1852-1868.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-17DOI: 10.1016/j.chembiol.2024.07.014
Sarah J. McAnulty
In this Stories piece, Sarah J. McAnulty, the executive director of Skype a Scientist and an assistant research professor at the University of Connecticut, discusses the importance of scientists connecting with their local communities to promote trust in and engagement with science.
在这篇《故事》文章中，Skype a Scientist 的执行主任、康涅狄格大学助理研究教授莎拉-J.-麦卡诺尔蒂（Sarah J. McAnulty）讨论了科学家与当地社区建立联系以促进人们对科学的信任和参与的重要性。
{"title":"Inviting new connections with science with public art in Philadelphia","authors":"Sarah J. McAnulty","doi":"10.1016/j.chembiol.2024.07.014","DOIUrl":"10.1016/j.chembiol.2024.07.014","url":null,"abstract":"<div><div>In this Stories piece, Sarah J. McAnulty, the executive director of Skype a Scientist and an assistant research professor at the University of Connecticut, discusses the importance of scientists connecting with their local communities to promote trust in and engagement with science.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1741-1744"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.
{"title":"Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer","authors":"Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu","doi":"10.1016/j.chembiol.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.09.004","url":null,"abstract":"Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including <em>SMARCA4</em> and <em>ARID1A</em> in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog <em>SMARCA2</em> is synthetic lethal to <em>SMARCA4</em> suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in <em>SMARCA4</em>-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of <em>SMARCA4</em>-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in <em>SMARCA4</em>-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against <em>SMARCA4</em>-mutant lung cancers.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"9 27 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.chembiol.2024.09.002
Xu-Hua Mo, Qing-Yin Pu, Tilo Lübken, Gui-Hong Yu, Mert Malay, Paul M. D’Agostino, Tobias A.M. Gulder
Biosynthesis of sodorifen with a unique C16-bicyclo[3.2.1]octene framework requires an S-adenosyl methionine-dependent methyltransferase SodC and terpene cyclase SodD. While bioinformatic analyses reveal a wide distribution of the sodCD genes organization in bacteria, their functional diversity remains largely unknown. Herein, two sodorifen-type gene clusters, pcch and pcau, from Pseudomonas sp. are heterologously expressed in Escherichia coli, leading to the discovery of two C16 terpenoids. Enzymatic synthesis of these compounds is achieved using the two (SodCD-like) pathway-specific enzymes. Enzyme assays using different combinations of methyltransferases and terpene synthases across the pcch, pcau, and sod pathways reveal a unifying biosynthetic mechanism: all three SodC-like enzymes methylate farnesyl pyrophosphate (FPP) with subsequent cyclization to a common intermediate, pre-sodorifen pyrophosphate. Structural diversification of this joint precursor solely occurs by the subsequently acting individual terpene synthases. Our findings expand basic biosynthetic understanding and structural diversity of unusual C16-terpenoids.
{"title":"Discovery and biosynthesis of non-canonical C16-terpenoids from Pseudomonas","authors":"Xu-Hua Mo, Qing-Yin Pu, Tilo Lübken, Gui-Hong Yu, Mert Malay, Paul M. D’Agostino, Tobias A.M. Gulder","doi":"10.1016/j.chembiol.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.09.002","url":null,"abstract":"Biosynthesis of sodorifen with a unique C<sub>16</sub>-bicyclo[3.2.1]octene framework requires an <em>S</em>-adenosyl methionine-dependent methyltransferase SodC and terpene cyclase SodD. While bioinformatic analyses reveal a wide distribution of the <em>sodCD</em> genes organization in bacteria, their functional diversity remains largely unknown. Herein, two sodorifen-type gene clusters, <em>pcch</em> and <em>pcau</em>, from <em>Pseudomonas</em> sp. are heterologously expressed in <em>Escherichia coli</em>, leading to the discovery of two C<sub>16</sub> terpenoids. Enzymatic synthesis of these compounds is achieved using the two (SodCD-like) pathway-specific enzymes. Enzyme assays using different combinations of methyltransferases and terpene synthases across the <em>pcch</em>, <em>pcau</em>, and <em>sod</em> pathways reveal a unifying biosynthetic mechanism: all three SodC-like enzymes methylate farnesyl pyrophosphate (FPP) with subsequent cyclization to a common intermediate, pre-sodorifen pyrophosphate. Structural diversification of this joint precursor solely occurs by the subsequently acting individual terpene synthases. Our findings expand basic biosynthetic understanding and structural diversity of unusual C<sub>16</sub>-terpenoids.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"35 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.chembiol.2024.08.014
Lara Kern, Ignacio Mastandrea, Anna Melekhova, Eran Elinav
Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the ‘sterile’ host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.
{"title":"Mechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration","authors":"Lara Kern, Ignacio Mastandrea, Anna Melekhova, Eran Elinav","doi":"10.1016/j.chembiol.2024.08.014","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.08.014","url":null,"abstract":"Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the ‘sterile’ host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"22 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.chembiol.2024.08.013
Cigall Kadoch, Jason M. Sheltzer, Hang Yin
In early October, the Nobel Prizes will honor groundbreaking discoveries. After the anticipated recognition of Katalin Karikó and Drew Weissman in 2023 for the development of RNA modifications that enabled the SARS-CoV-2 mRNA vaccine, we eagerly consider the next topics to be awarded. In the September 30th anniversary special issue of Cell Chemical Biology, we ask researchers from a range of backgrounds, what topic do you think deserves the next Nobel Prize in chemistry or in physiology or medicine, and why?
{"title":"The next Nobel Prize in chemistry or in physiology or medicine","authors":"Cigall Kadoch, Jason M. Sheltzer, Hang Yin","doi":"10.1016/j.chembiol.2024.08.013","DOIUrl":"10.1016/j.chembiol.2024.08.013","url":null,"abstract":"<div><p>In early October, the Nobel Prizes will honor groundbreaking discoveries. After the anticipated recognition of Katalin Karikó and Drew Weissman in 2023 for the development of RNA modifications that enabled the SARS-CoV-2 mRNA vaccine, we eagerly consider the next topics to be awarded. In the September 30<sup>th</sup> anniversary special issue of <em>Cell Chemical Biology</em>, we ask researchers from a range of backgrounds, what topic do you think deserves the next Nobel Prize in chemistry or in physiology or medicine, and why?</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1566-1567"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号