Nature chemical biology最新文献_第10页

Metabolic determinants of germinal center B cell formation and responses 生殖中心 B 细胞形成和反应的代谢决定因素

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01690-6

Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang

{"title":"Metabolic determinants of germinal center B cell formation and responses","authors":"Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang","doi":"10.1038/s41589-024-01690-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01690-6","url":null,"abstract":"Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764443","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}

引用次数: 0

Splice-modifying drug mechanisms 改变拼接的药物机制

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01678-2

Jorge Herrero-Vicente, Douglas L. Black, Juan Valcárcel

引用次数: 0

Genetically engineered synthetic cells activate cargo release upon temperature shift 基因工程合成细胞在温度变化时激活货物释放。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-25 DOI: 10.1038/s41589-024-01701-6

引用次数: 0

Unlocking saponin biosynthesis in soapwort 揭开肥皂草中皂甙生物合成的神秘面纱

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-23 DOI: 10.1038/s41589-024-01681-7

Seohyun Jo, Amr El-Demerdash, Charlotte Owen, Vikas Srivastava, Dewei Wu, Shingo Kikuchi, James Reed, Hannah Hodgson, Alex Harkess, Shengqiang Shu, Chris Plott, Jerry Jenkins, Melissa Williams, Lori-Beth Boston, Elia Lacchini, Tongtong Qu, Alain Goossens, Jane Grimwood, Jeremy Schmutz, Jim Leebens-Mack, Anne Osbourn

{"title":"Unlocking saponin biosynthesis in soapwort","authors":"Seohyun Jo, Amr El-Demerdash, Charlotte Owen, Vikas Srivastava, Dewei Wu, Shingo Kikuchi, James Reed, Hannah Hodgson, Alex Harkess, Shengqiang Shu, Chris Plott, Jerry Jenkins, Melissa Williams, Lori-Beth Boston, Elia Lacchini, Tongtong Qu, Alain Goossens, Jane Grimwood, Jeremy Schmutz, Jim Leebens-Mack, Anne Osbourn","doi":"10.1038/s41589-024-01681-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01681-7","url":null,"abstract":"Soapwort (Saponaria officinalis) is a flowering plant from the Caryophyllaceae family with a long history of human use as a traditional source of soap. Its detergent properties are because of the production of polar compounds (saponins), of which the oleanane-based triterpenoid saponins, saponariosides A and B, are the major components. Soapwort saponins have anticancer properties and are also of interest as endosomal escape enhancers for targeted tumor therapies. Intriguingly, these saponins share common structural features with the vaccine adjuvant QS-21 and, thus, represent a potential alternative supply of saponin adjuvant precursors. Here, we sequence the S. officinalis genome and, through genome mining and combinatorial expression, identify 14 enzymes that complete the biosynthetic pathway to saponarioside B. These enzymes include a noncanonical cytosolic GH1 (glycoside hydrolase family 1) transglycosidase required for the addition of d-quinovose. Our results open avenues for accessing and engineering natural and new-to-nature pharmaceuticals, drug delivery agents and potential immunostimulants.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750316","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}

引用次数: 0

Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms 大环内酯类药物以细菌核糖体和 DNA 回旋酶为靶标，可规避抗药性机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-22 DOI: 10.1038/s41589-024-01685-3

Elena V. Aleksandrova, Cong-Xuan Ma, Dorota Klepacki, Faezeh Alizadeh, Nora Vázquez-Laslop, Jian-Hua Liang, Yury S. Polikanov, Alexander S. Mankin

{"title":"Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms","authors":"Elena V. Aleksandrova, Cong-Xuan Ma, Dorota Klepacki, Faezeh Alizadeh, Nora Vázquez-Laslop, Jian-Hua Liang, Yury S. Polikanov, Alexander S. Mankin","doi":"10.1038/s41589-024-01685-3","DOIUrl":"https://doi.org/10.1038/s41589-024-01685-3","url":null,"abstract":"Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141737004","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}

引用次数: 0

Targeting Smurf1 to block PDK1–Akt signaling in KRAS-mutated colorectal cancer 靶向 Smurf1 阻断 KRAS 突变结直肠癌中的 PDK1-Akt 信号传导

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-22 DOI: 10.1038/s41589-024-01683-5

Zhiqiang Peng, Wei Fang, Bo Wu, Ming He, Shaohua Li, Jun Wei, Yang Hao, Lujia Jin, Mingqiu Liu, Xin Zhang, Yange Wei, Yingwei Ge, Yinghua Wei, Haili Qian, Yangjun Zhang, Junyi Jiang, Zhijie Chang, Yu Rao, Xueli Zhang, Chun-Ping Cui, Lingqiang Zhang

{"title":"Targeting Smurf1 to block PDK1–Akt signaling in KRAS-mutated colorectal cancer","authors":"Zhiqiang Peng, Wei Fang, Bo Wu, Ming He, Shaohua Li, Jun Wei, Yang Hao, Lujia Jin, Mingqiu Liu, Xin Zhang, Yange Wei, Yingwei Ge, Yinghua Wei, Haili Qian, Yangjun Zhang, Junyi Jiang, Zhijie Chang, Yu Rao, Xueli Zhang, Chun-Ping Cui, Lingqiang Zhang","doi":"10.1038/s41589-024-01683-5","DOIUrl":"https://doi.org/10.1038/s41589-024-01683-5","url":null,"abstract":"The phosphoinositide 3-kinase (PI3K)–Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K–Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K–Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1–Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K–Akt pathway and KRAS mutant cancer therapy.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141737002","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}

引用次数: 0

Machine learning in preclinical drug discovery 临床前药物发现中的机器学习

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-19 DOI: 10.1038/s41589-024-01679-1

Denise B. Catacutan, Jeremie Alexander, Autumn Arnold, Jonathan M. Stokes

{"title":"Machine learning in preclinical drug discovery","authors":"Denise B. Catacutan, Jeremie Alexander, Autumn Arnold, Jonathan M. Stokes","doi":"10.1038/s41589-024-01679-1","DOIUrl":"10.1038/s41589-024-01679-1","url":null,"abstract":"Drug-discovery and drug-development endeavors are laborious, costly and time consuming. These programs can take upward of 12 years and cost US $2.5 billion, with a failure rate of more than 90%. Machine learning (ML) presents an opportunity to improve the drug-discovery process. Indeed, with the growing abundance of public and private large-scale biological and chemical datasets, ML techniques are becoming well positioned as useful tools that can augment the traditional drug-development process. In this Perspective, we discuss the integration of algorithmic methods throughout the preclinical phases of drug discovery. Specifically, we highlight an array of ML-based efforts, across diverse disease areas, to accelerate initial hit discovery, mechanism-of-action (MOA) elucidation and chemical property optimization. With advances in the application of ML across diverse therapeutic areas, we posit that fully ML-integrated drug-discovery pipelines will define the future of drug-development programs. This Perspective discusses the application of algorithmic methods throughout the preclinical phases of drug discovery to accelerate initial hit discovery, mechanism-of-action elucidation and chemical property optimization.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726003","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}

引用次数: 0

Inter-kingdom electromechanical communication 王国之间的机电交流

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-19 DOI: 10.1038/s41589-024-01687-1

Joshua T. Atkinson

引用次数: 0

Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis 赖氨酸 l-乳化是糖酵解诱导的主要乳化异构体

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-19 DOI: 10.1038/s41589-024-01680-8

Di Zhang, Jinjun Gao, Zhijun Zhu, Qianying Mao, Zhiqiang Xu, Pankaj K. Singh, Cornelius C. Rimayi, Carlos Moreno-Yruela, Shuling Xu, Gongyu Li, Yi-Cheng Sin, Yue Chen, Christian A. Olsen, Nathaniel W. Snyder, Lunzhi Dai, Lingjun Li, Yingming Zhao

{"title":"Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis","authors":"Di Zhang, Jinjun Gao, Zhijun Zhu, Qianying Mao, Zhiqiang Xu, Pankaj K. Singh, Cornelius C. Rimayi, Carlos Moreno-Yruela, Shuling Xu, Gongyu Li, Yi-Cheng Sin, Yue Chen, Christian A. Olsen, Nathaniel W. Snyder, Lunzhi Dai, Lingjun Li, Yingming Zhao","doi":"10.1038/s41589-024-01680-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01680-8","url":null,"abstract":"Lysine l-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by l-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and d-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in l-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726002","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}

引用次数: 0

Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants 直接观察致病突变体模板化蛋白质错误折叠的朊病毒式传播

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-15 DOI: 10.1038/s41589-024-01672-8

Krishna Neupane, Abhishek Narayan, Supratik Sen Mojumdar, Gaurav Adhikari, Craig R. Garen, Michael T. Woodside

{"title":"Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants","authors":"Krishna Neupane, Abhishek Narayan, Supratik Sen Mojumdar, Gaurav Adhikari, Craig R. Garen, Michael T. Woodside","doi":"10.1038/s41589-024-01672-8","DOIUrl":"10.1038/s41589-024-01672-8","url":null,"abstract":"Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers. Protein misfolding can spread from one molecule to another in infectious prion diseases. The propagation of protein misfolding has been directly observed in single protein molecules. These results showed that pathogenic mutants of the protein superoxide dismutase-1 (SOD1), which causes familial amyotrophic lateral sclerosis, imprint their misfolding onto native wild-type molecules.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618270","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}

引用次数: 0