Nature chemical biology最新文献_第2页

Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding 揭示阿尔茨海默氏症的复杂性与独特的a β42纤维类型和特异性AV-45结合

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-10 DOI: 10.1038/s41589-025-01921-4

Qinyue Zhao, Youqi Tao, Yuxuan Yao, Kaien Liu, Shiran Lv, Bingyao Cui, Weidi Xiao, Tianyi Cao, Weidong Li, Feng Gao, Yong Shen, Chu Wang, Chao Ma, Wenying Qiu, Cong Liu, Dan Li

{"title":"Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding","authors":"Qinyue Zhao, Youqi Tao, Yuxuan Yao, Kaien Liu, Shiran Lv, Bingyao Cui, Weidi Xiao, Tianyi Cao, Weidong Li, Feng Gao, Yong Shen, Chu Wang, Chao Ma, Wenying Qiu, Cong Liu, Dan Li","doi":"10.1038/s41589-025-01921-4","DOIUrl":"https://doi.org/10.1038/s41589-025-01921-4","url":null,"abstract":"Abnormal aggregation of amyloid-β protein (1–42) (Aβ42) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ42 fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed ‘soluble’ during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ42 fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ42 fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ42 fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ42 fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"215 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252664","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}

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Receptors from an ADAR trick 来自ADAR的受体

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-09 DOI: 10.1038/s41589-025-01935-y

Hayase Hakariya, Thorsten Stafforst

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Publisher Correction: Acetylation profiling by Iseq-Kac reveals insights into HSC aging and lineage decision 出版商更正：Iseq-Kac乙酰化分析揭示了HSC衰老和血统决定的见解

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-04 DOI: 10.1038/s41589-025-01955-8

Yanqiu Gong, Huiwen Zhan, Ni Wei, Min Liu, Yu Liu, Pengbo Guan, Yusi Xie, Yujun Deng, Qianlun Pu, Xiaoxian Lou, Xiaodong Wang, Rou Zhang, Ping Wang, Xiuxiu Jin, Xiuxuan Wang, Zhiqiang Xu, Li Gao, Xinyuan Wang, Siyu He, Ying Lu, Meng Hu, Wanmeng Li, Kun Zheng, Yong Peng, Peng Lei, Heng Xu, Yujun Shi, Jun Qin, Hongbo Hu, Huiyuan Zhang, Lunzhi Dai

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Ipecac alkaloid biosynthesis in two evolutionarily distant plants 两种进化距离较远的植物中吐根生物碱的生物合成

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-03 DOI: 10.1038/s41589-025-01926-z

Maite Colinas, Clara Morweiser, Olivia Dittberner, Bianca Chioca, Ryan Alam, Helena Leucke, Yoko Nakamura, Delia Ayled Serna Guerrero, Sarah Heinicke, Maritta Kunert, Jens Wurlitzer, Kerstin Ploss, Benke Hong, Veit Grabe, Adriana A. Lopes, Sarah E. O’Connor

{"title":"Ipecac alkaloid biosynthesis in two evolutionarily distant plants","authors":"Maite Colinas, Clara Morweiser, Olivia Dittberner, Bianca Chioca, Ryan Alam, Helena Leucke, Yoko Nakamura, Delia Ayled Serna Guerrero, Sarah Heinicke, Maritta Kunert, Jens Wurlitzer, Kerstin Ploss, Benke Hong, Veit Grabe, Adriana A. Lopes, Sarah E. O’Connor","doi":"10.1038/s41589-025-01926-z","DOIUrl":"https://doi.org/10.1038/s41589-025-01926-z","url":null,"abstract":"Ipecac alkaloids are medicinal monoterpenoid-derived tetrahydroisoquinoline alkaloids found in two distantly related plants: Carapichea ipecacuanha (Gentianales) and Alangium salviifolium (Cornales). Here we provide evidence suggesting that both plants initiate ipecac alkaloid biosynthesis through a nonenzymatic Pictet–Spengler reaction and we elucidate the biosynthetic fate of both the 1R and 1S stereoisomers that are produced in this nonstereoselective reaction. Although the biosynthesis of the 1S-derived protoemetine proceeds according to the same chemical logic in both species, each plant uses a distinct monoterpene precursor. Phylogenetic analyses show examples of independent pathway evolution through parallel and convergently evolved enzymes. This work provides insight into how nature can capitalize on highly reactive starting substrates and the manner in which multistep pathways can arise and lays the foundation for metabolic engineering of these important medicinal compounds.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201473","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}

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A consortium to synthesize lignans 合成木脂素的联合体

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-03 DOI: 10.1038/s41589-025-01930-3

Nicolas Gautron, Nicolas Papon, Vincent Courdavault

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A fat-fueled fatality 脂肪引发的死亡

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-03 DOI: 10.1038/s41589-025-01932-1

Hannah L. Glover, Stephen W. G. Tait

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Chemical biology approaches to resolve the subcellular GPCR signaling landscape 化学生物学方法解决亚细胞GPCR信号景观

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-02 DOI: 10.1038/s41589-025-01928-x

Andreas Bock, Braden T. Lobingier, Miriam Stoeber, Nikoleta G. Tsvetanova

引用次数: 0

Programmable RNA acetylation with CRISPR–Cas13 CRISPR-Cas13的可编程RNA乙酰化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-02 DOI: 10.1038/s41589-025-01922-3

Jihwan Yu, Juae Jin, Eury Kwon, Hyunsoo Jang, Sang-kun Choi, Donggyun Kim, Chaemin Kim, Seungkyu Son, Ki-Jun Yoon, Won Do Heo

{"title":"Programmable RNA acetylation with CRISPR–Cas13","authors":"Jihwan Yu, Juae Jin, Eury Kwon, Hyunsoo Jang, Sang-kun Choi, Donggyun Kim, Chaemin Kim, Seungkyu Son, Ki-Jun Yoon, Won Do Heo","doi":"10.1038/s41589-025-01922-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01922-3","url":null,"abstract":"Recent studies claim that N4-acetylcytidine (ac4C) modification of RNA confers crucial regulatory roles, such as increasing translation efficiency and prolonging its half-life. However, the absence of methods for selectively acetylating specific RNA molecules hampers linking ac4C to cell physiology. Here, we developed an efficient molecular tool that incorporates ac4C on a specific transcript of interest. Through protein engineering, we developed a hyperactive variant of N-acetyltransferase 10 (NAT10), designated enhanced NAT10 (eNAT10). When fused to the programmable RNA-targeting protein dCas13, eNAT10 enables robust acetylation of various target RNAs in multiple contexts. RNA acetylation by dCas13–eNAT10 was highly dependent on co-transfected guide RNA, highlighting its specificity. We also describe the programmable RNA chemical modification in vivo using dual-adeno-associated virus. Using our system, we found that acetylation of RNA may modulate the subcellular localization of modified transcripts. We anticipate that our tool will facilitate numerous studies on ac4C functions across different cellular and disease contexts.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"25 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193062","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

Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures 药物抑制PSPH可降低丝氨酸水平和癫痫发作

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-06-02 DOI: 10.1038/s41589-025-01920-5

Longze Sha, Yanbing Wang, Peixin Meng, Yu Deng, Ting Chen, Xiuneng Zhang, Yousong Ye, Qi Xu

{"title":"Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures","authors":"Longze Sha, Yanbing Wang, Peixin Meng, Yu Deng, Ting Chen, Xiuneng Zhang, Yousong Ye, Qi Xu","doi":"10.1038/s41589-025-01920-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01920-5","url":null,"abstract":"Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy. Lowering the levels of N-methyl-d-aspartate receptor (NMDAR) ligands has been suggested as a promising therapeutic strategy for TLE. d-Serine gates synaptic NMDARs in the hippocampus but the effect of d-serine on seizure activity remains poorly understood. Here, we show that serine levels in the hippocampus were increased in persons with TLE and in a mouse model of TLE. Eliminating d-serine or blocking its binding with NMDARs suppressed seizures in mouse models. Astrocyte-derived l-serine was found to regulate interstitial d-serine levels and seizure activity through a process controlled by phosphoserine phosphatase (PSPH). We identified a potent PSPH inhibitor, Z218484536, and found that its systemic administration reduced spontaneous epileptic discharges in mouse and cynomolgus monkey models of TLE. Overall, these results indicate that PSPH is a promising therapeutic target for TLE and support further preclinical studies of Z218484536.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"29 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193150","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}

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Remodeling and retooling metabolism 重塑和重组新陈代谢

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-30 DOI: 10.1038/s41589-025-01941-0

引用次数: 0