Nature chemical biology最新文献_第2页

Peptide surfactants with post-translational C-methylations that promote bacterial development 翻译后c -甲基化的肽表面活性剂促进细菌发育

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-22 DOI: 10.1038/s41589-025-01882-8

Chen Zhang, Yuchen Li, Ellysia N. Overton, Mohammad R. Seyedsayamdost

引用次数: 0

Design principles imprinted by evolution 进化留下的设计原则

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-18 DOI: 10.1038/s41589-025-01880-w

Martin Grininger

引用次数: 0

Chemical-based epigenetic reprogramming to advance pluripotency and totipotency 基于化学的表观遗传重编程以促进多能性和全能性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-18 DOI: 10.1038/s41589-025-01874-8

Shanshan Wen, Ran Zheng, Cheguo Cai, Wei Jiang

引用次数: 0

Plug-and-play engineering of modular polyketide synthases 模块化聚酮合成酶的即插即用工程

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-18 DOI: 10.1038/s41589-025-01878-4

Zilei Huang, Shengling Xie, Run-Zhou Liu, Changjun Xiang, Shunyu Yao, Lihan Zhang

{"title":"Plug-and-play engineering of modular polyketide synthases","authors":"Zilei Huang, Shengling Xie, Run-Zhou Liu, Changjun Xiang, Shunyu Yao, Lihan Zhang","doi":"10.1038/s41589-025-01878-4","DOIUrl":"https://doi.org/10.1038/s41589-025-01878-4","url":null,"abstract":"Modular polyketide synthases (PKSs) are multidomain, assembly line enzymes that biosynthesize complex antibiotics such as erythromycin and rapamycin. The modular characteristic of PKSs makes them an ideal platform for the custom production of designer polyketides by combinatorial biosynthesis. However, engineered hybrid PKS pathways often exhibit severe loss of enzyme activity, and a general principle for PKS reprogramming has not been established. Here we present a widely applicable strategy for designing hybrid PKSs. We reveal that two conserved motifs are robust cut sites to connect modules from different PKS pathways and demonstrate the custom production of polyketides with different starter units, extender units and variable reducing states. Furthermore, we expand the applicability of these cut sites to construct hybrid pathways involving cis-AT PKS, trans-AT PKS and even nonribosomal peptide synthetase. Collectively, our findings enable plug-and-play reprogramming of modular PKSs and facilitate the application of assembly line enzymes toward the bioproduction of designer molecules.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"29 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846759","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

Expanding catalytic versatility of modular polyketide synthases for alcohol biosynthesis 扩展模块化聚酮合成酶在醇生物合成中的催化多功能性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-18 DOI: 10.1038/s41589-025-01883-7

Shunyu Yao, Shengling Xie, Run-Zhou Liu, Zilei Huang, Lihan Zhang

引用次数: 0

Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks 诱导接近PML保护TDP-43不通过sumo -泛素网络聚集

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-17 DOI: 10.1038/s41589-025-01886-4

Kristina Wagner, Jan Keiten-Schmitz, Bikash Adhikari, Upayan Patra, Koraljka Husnjak, François McNicoll, Dorothee Dormann, Michaela Müller-McNicoll, Georg Tascher, Elmar Wolf, Stefan Müller

{"title":"Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks","authors":"Kristina Wagner, Jan Keiten-Schmitz, Bikash Adhikari, Upayan Patra, Koraljka Husnjak, François McNicoll, Dorothee Dormann, Michaela Müller-McNicoll, Georg Tascher, Elmar Wolf, Stefan Müller","doi":"10.1038/s41589-025-01886-4","DOIUrl":"https://doi.org/10.1038/s41589-025-01886-4","url":null,"abstract":"The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation–ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO–ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"74 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841662","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

JAMMing inflammation 干扰炎症

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-17 DOI: 10.1038/s41589-025-01905-4

Grant Miura

{"title":"JAMMing inflammation","authors":"Grant Miura","doi":"10.1038/s41589-025-01905-4","DOIUrl":"https://doi.org/10.1038/s41589-025-01905-4","url":null,"abstract":"BRCC36 is a Zn2+-dependent JAMM/MPN deubiquitinase (DUB) and is an essential component of the BRCC36 isopeptidase complex (BRISC), which blocks K63-linked ubiquitination and degradation of type I interferon receptor (IFNAR1) to enhance inflammatory signaling. The zinc-binding pocket of BRCC36 is conserved with other JAMM/MPN members, which makes selectively targeting BRCC36 difficult. To identify BRISC inhibitors, Chandler et al. conducted a biochemical screen examining changes in a K63-linked ubiquitin substrate using a library of kinase inhibitors. Characterization of potential hits revealed JMS-175-2 as a BRISC-selective inhibitor that blocked cleavage of ubiquitin chains but spared other DUB members. The JMS-175-2 compound series inhibited BRISC in a non-competitive manner, suggesting the compound was unlikely to target the zinc-binding pocket required for catalysis. Structural characterization by cryo-electron microscopy and mass photometry showed that JMS-175-2 acts as a molecular glue and promotes formation of a BRISC dimer complex composed of 16 subunits. Subsequently, these compounds were designated as BLUEs (BRISC molecular glues). Structural and hydrogen deuterium exchange–mass spectrometry analysis revealed that BLUEs contacted BRCC36 and two other BRISC subunits (Abraxas2 and BRCC45) to mediate a higher order dimer formation, which inhibited activity by blocking active site access and preventing ubiquitin binding. BLUE treatment in normal cells and cells derived from patients with an autoimmune disorder decreased IFNAR1 signaling and interferon-stimulated gene expression owing to increased IFNAR1 ubiquitination and reduced IFNAR1 cell surface levels. Although the efficacy of BLUEs to reduce inflammation in vivo requires further evaluation, the work from Chandler et al. reveals a unique strategy to selectively inhibit a DUB.Original reference: Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-025-01517-5 (2025)","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"108 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841901","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

Dissociation for living 为生存而分离

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-17 DOI: 10.1038/s41589-025-01906-3

Yiyun Song

{"title":"Dissociation for living","authors":"Yiyun Song","doi":"10.1038/s41589-025-01906-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01906-3","url":null,"abstract":"N6-methyladenosine (m6A) is one of the most abundant RNA modifications and has an important role in many biological processes. The major writer for m6A is the METTL3–METTL14 complex, whereby METTL3 acts as the catalytic methyltransferase while METTL14 is thought to determine substrate specificity. However, it is unclear whether the interaction between METTL3 and METTL14 can be regulated to affect m6A deposition. To address this question, Huang, Zhang, Cun, Ye, Ren et al. conducted a genome-wide CRISPR–Cas9 screen and identified the acetyltransferase p300 and the kinase PAK2 as key negative regulators of the interaction between METTL3 and METTL14.The well-known function of p300 is to catalyze acetylation of histone 3 at lysine 27 (H3K27ac) — a histone marker found in active enhancers and promoters that represents actively transcribed chromatin regions. Now, the team has shown that p300 mediates the acetylation of METTL3 specifically at H3K27ac-marked chromatin regions. Acetylation reduces the affinity of METTL3 for METTL14 bound to these regions, leading to the dissociation of METTL3 from the chromatin. As a result, m6A levels on RNA transcribed from these enhancer and promoters decrease. The reduced m6A modification increases the stability of these enhancer and promoter RNAs, which in turn promotes the expression of genes related to ferroptosis inhibition as well as tumor cell survival.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"17 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841902","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

In silico prohormone processing 在硅激素原加工

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-17 DOI: 10.1038/s41589-025-01904-5

Gene Chong

{"title":"In silico prohormone processing","authors":"Gene Chong","doi":"10.1038/s41589-025-01904-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01904-5","url":null,"abstract":"Peptide hormones are processed from larger proteins by endopeptidases and have diverse biological functions. For example, glucagon-like peptide-1 (GLP-1) is well known for regulating blood glucose levels and has been used to treat diabetes and obesity. However, there are a vast number of peptides that are potentially processed by endopeptidases to create functional peptide hormones. Now, Coassolo et al. have developed a computational tool called Peptide Predictor for discovering unknown peptide hormones. The tool screens the human secretome for amino acid sequences containing at least four instances of dibasic motifs KR, RR, RK, and KK that are recognized and cleaved by peptidases from the prohormone convertase family to process at least five potential peptide hormones. From 2,082 proteins in the secretome, the team identified 373 proteins that generated 2,683 peptides. They used the existing tools PeptideRanker and MultiPep to predict that 21–23% of the peptides were bioactive. To validate their approach, Coassolo et al. screened a library of 100 of the peptides — each only homologous to their precursor protein — for expression of the gene Fos, which is associated with the bioactivity of peptides. They focused on the peptide BRP, which had increased Fos expression by greater than tenfold. BRP was found to be processed from the precursor BRINP2, primarily expressed in the brain. BRP suppressed food intake dose dependently in both lean mice that were fasted and in diet-induced obese mice. Mechanistically, BRP treatment led to the activation of protein kinase A, phosphorylation of the protein CREB, and increased expression of FOS in specific regions of the hypothalamus and other parts of the brain. An AlphaFold model and mutagenesis showed Leu8 as a key residue for BRP activity. Thus, this study shows the advantage of computational tools for proteome-wide scanning of cleavage sites by proteases for the discovery of therapeutic peptides.Original reference: Nature https://doi.org/10.1038/s41586-025-08683-y (2025)","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841903","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

Sweetening ferroptosis spread 甜味下垂扩散

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-17 DOI: 10.1038/s41589-025-01889-1

Tiantian Sun, Jin Gao, Quan Chen

引用次数: 0