Nature chemical biology最新文献

{"title":"Learning from CoQ10 history","authors":"Francesco Zamberlan","doi":"10.1038/s41589-025-01877-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01877-5","url":null,"abstract":"<p>Coenzyme Q (CoQ), or ubiquinone, is a redox active molecule used to transport electrons in the oxidative respiratory chain that generates ATP in mitochondria. CoQ consists of a benzoquinone ring and a polyisoprenoid side chain that varies in length; CoQ₁₀, which is present in humans, has a side chain of 10 isoprenoids units comprising 50 carbon atoms, whereas land plants have either CoQ₉ or CoQ₁₀ as the predominant form. However, little is known about the genetic basis that causes this variation in plants, or the selectivity switch that determines the chain length in the <i>trans</i>-isoprenyl diphosphate synthase Coq1. Now, Xu, Lei, Zhang, Li et al. have used phylogenetic analyses to understand the distribution of CoQ₉ and CoQ₁₀ in land plants, as well as the key amino acid changes for this selectivity in Coq1. Based on this, the team have also reported the gene editing of rice and wheat as sources of CoQ₁₀ for human consumption.</p><p>After analyzing over 1,000 plant species, the researchers find that CoQ₉ has evolved in separated clades independently from CoQ₁₀, and prevails in Poaceae, Asteraceae and Cucurbitaceae. Using homology modeling of the Coq1 enzymes across all species, Xu et al. identified that site 240 in the conserved catalytic domain is crucial for controlling the isoprenoid chain length; substitutions such as Met240 or Ile240 shift the selectivity to CoQ₉ for herbaceous plants, while Leu240 is the key residue in the ancestral form of the CoQ₁₀-synthesizing enzymes. There are also other important residues at proximal locations 243, 254 and 255.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"61 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677726","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}

{"title":"Phage-fueled defense system","authors":"Yiyun Song","doi":"10.1038/s41589-025-01875-7","DOIUrl":"https://doi.org/10.1038/s41589-025-01875-7","url":null,"abstract":"<p>In response to phage infection, bacterial cells produce cyclic nucleotides or cyclic ADP-ribose as second messengers, which activate downstream effector proteins that induce cell death or directly suppress phage replication. However, it is not clear whether other molecules also act as bacterial immune signaling molecules. Now, Zeng, Hu, Zhao, Rao et al. identified an anti-phage defense system in <i>Escherichia coli</i> that produces deoxyinosine 5′-triphosphate (dITP) as a second messenger molecule. The team pinpointed this system using comparative genomic analyses, which they validated with genetic and biochemical characterizations.</p><p>The system is composed of three genes (<i>komA</i>, <i>komB</i> and <i>komC</i>), encoding an adenosine deaminase (KomA), a dITP-binding protein (KomB) and an NADase (KomC), respectively. The team reconstructed the dITP biosynthesis pathway, revealing that KomA collaborates with a phage-encoded dNMP kinase (DNK) and the host’s dNDP kinase (NDK) to convert dAMP into dITP. Phages with mutations in the gene encoding DNK are resistant to this three-gene immune system. Upon dITP binding, KomB and KomC form an effector complex that degrades NAD⁺ (an essential metabolic cofactor for bacterial cells), leading to the elimination of infected cells from the population. Given that the system co-opts the phage’s own DNK enzyme to initiate the immune response, the researchers named it Kongming, a nod to the ancient Chinese strategist renowned for tactical ingenuity.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"183 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677730","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}

{"title":"Guiding chemoenzymatic synthesis","authors":"Gene Chong","doi":"10.1038/s41589-025-01876-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01876-6","url":null,"abstract":"<p>Chemoenzymatic methods combine chemical synthesis with enzymatic reactions that work under milder reaction conditions and can offer advantages in stereospecificity and regioselectivity. However, transitioning between different chemical and biological reactions can require separation and purification steps that are time intensive and costly. Now, Anand et al. have developed a computational synthesis planning tool called minChemBio that provides synthetic routes that minimize such transitions. To set up minChemBio, the team curated a dataset of 1,808,938 chemical reactions from the USPTO database and 57,541 biological reactions from the MetaNetX database, removing duplicate and incorrectly annotated reactions. For further data processing, each reaction is defined as the transformation of the most structurally similar molecules, designated as the main reactant and product, and given a reaction ID. Each molecule in a reaction is given a chemical ID, which together with the reaction ID, is used to navigate the search space for reaction pathways. Next, the solutions are filtered using an algorithm to minimize the total number of biological to chemical, chemical to biological, and chemical to chemical reaction transitions. Lastly, the team implemented a tool, dGpredictor, to assess the thermodynamic favorability of the reactions. To demonstrate the potential of their approach, Anand et al. used minChemBio to guide the chemoenzymatic synthesis of a bioplastic precursor, 2,5-furandicarboxylic acid, from the cheap and abundant starting molecule glucose. Although other computational tools could provide a solution, they required starting molecules that were more expensive than the product. There is, however, room for improvement: minChemBio currently does not label major and minor products in reactions and its performance is affected by misannotations and data upkeep in the databases sourced. Nevertheless, despite these limitations, minChemBio provides an advantage in allowing the choice of cheaper precursor molecules and minimizing costly reaction transitions to enable efficient chemoenzymatic syntheses.</p><p><b>Original reference:</b> <i>ACS Synth. Biol</i>. https://doi.org/10.1021/acssynbio.4c00692 (2025)</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"94 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677727","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}

{"title":"CLYBL averts vitamin B12 depletion by repairing malyl-CoA","authors":"Corey M. Griffith, Jean-François Conrotte, Parisa Paydar, Xinqiang Xie, Ursula Heins-Marroquin, Floriane Gavotto, Christian Jäger, Kenneth W. Ellens, Carole L. Linster","doi":"10.1038/s41589-025-01857-9","DOIUrl":"https://doi.org/10.1038/s41589-025-01857-9","url":null,"abstract":"<p>Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of <i>CLYBL</i> loss of function with reduced circulating vitamin B₁₂ levels was proposed to result from inhibition of the B₁₂-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of <i>CLYBL</i> across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that <i>CLYBL</i> knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B₁₂ deficiency observed in individuals with <i>CLYBL</i> loss of function.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"25 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654241","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}

{"title":"Recycling for a cleaner metabolism","authors":"Adam Chatoff, Nathaniel W. Snyder","doi":"10.1038/s41589-025-01852-0","DOIUrl":"https://doi.org/10.1038/s41589-025-01852-0","url":null,"abstract":"Cellular metabolism produces reactive metabolites as both main and side products, requiring recycling pathways to detoxify these products. A study uncovers a recycling pathway that protects vitamin B12 from inactivating covalent modification.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"32 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654243","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}

{"title":"Biosynthesis of poly(ester amide)s in engineered Escherichia coli","authors":"Tong Un Chae, So Young Choi, Da-Hee Ahn, Woo Dae Jang, Haemin Jeong, Jihoon Shin, Sang Yup Lee","doi":"10.1038/s41589-025-01842-2","DOIUrl":"https://doi.org/10.1038/s41589-025-01842-2","url":null,"abstract":"<p>The development of biobased polymers to substitute their current petroleum-based counterparts is crucial for fostering a sustainable plastic industry. Here we report the biosynthesis and characterization of a group of biopolymers, poly(ester amide)s (PEAs), in <i>Escherichia coli</i>. PEAs are biosynthesized by constructing a new-to-nature amino acid polymerization pathway, comprising amino acid activation by β-alanine CoA transferase and subsequent polymerization of amino acyl-CoA by polyhydroxyalkanoate synthase. The engineered <i>E.</i> <i>coli</i> strains harboring this pathway are capable of biosynthesizing various PEAs, each incorporating different amino acid monomers in varying fractions. Examination of the physical, thermal and mechanical properties reveals a dependence of molecular weight on the type of polyhydroxyalkanoate synthase, a decrease in melting temperature and crystallinity as the 3-aminopropionate monomer fraction increases and enhanced elongation at break compared to its polyester analog. The engineered bacterial system will prove beneficial for the biobased production of various PEAs using renewable resources.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"14 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640513","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}

{"title":"A bacterial platform for the bio-based production of poly(ester amide)s","authors":"","doi":"10.1038/s41589-025-01859-7","DOIUrl":"https://doi.org/10.1038/s41589-025-01859-7","url":null,"abstract":"Poly(ester amide)s (PEAs) have various applications but their synthesis is currently limited to chemical methods. Now, the biosynthesis of various PEAs in engineered Escherichia coli is presented. The PEAs incorporate different amino acid monomers in varying fractions, which influences their physical, thermal and mechanical properties.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640830","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}

{"title":"De novo biosynthesis of plant lignans by synthetic yeast consortia","authors":"Ruibing Chen, Xianghui Chen, Yu Chen, Jindong Yang, Wansheng Chen, Yongjin J. Zhou, Lei Zhang","doi":"10.1038/s41589-025-01861-z","DOIUrl":"https://doi.org/10.1038/s41589-025-01861-z","url":null,"abstract":"<p>Reconstructing the biosynthesis of complex natural products such as lignans in yeast is challenging and can result in metabolic promiscuity, affecting the biosynthetic efficiency. Here we divide the lignan biosynthetic pathway across a synthetic yeast consortium with obligated mutualism and use ferulic acid as a metabolic bridge. This cooperative system successfully overcomes the metabolic promiscuity and synthesizes the common precursor, coniferyl alcohol. Furthermore, combined with systematic engineering strategies, we achieve the de novo synthesis of key lignan skeletons, pinoresinol and lariciresinol, and verify the scalability of the consortium by synthesizing complex lignans, including antiviral lariciresinol diglucoside. These results provide a starting engineering platform for the heterologous synthesis of lignans. In particular, the study illustrates that the yeast consortium with obligate mutualism is a promising strategy that mimics the metabolic division of labor among multiple plant cells, thereby improving the biosynthesis of long pathways and complex natural products.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"16 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635298","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}

{"title":"Author Correction: A cell-free biosensor signal amplification circuit with polymerase strand recycling","authors":"Yueyi Li, Tyler Lucci, Matias Villarruel Dujovne, Jaeyoung Kirsten Jung, Daiana A. Capdevila, Julius B. Lucks","doi":"10.1038/s41589-025-01884-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01884-6","url":null,"abstract":"<p>Correction to: <i>Nature Chemical Biology</i> https://doi.org/10.1038/s41589-024-01816-w, published online 13 January 2025.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"109 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635297","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}

{"title":"Post-translational modifications orchestrate the intrinsic signaling bias of GPR52","authors":"Bingjie Zhang, Wei Ge, Mengna Ma, Shanshan Li, Jie Yu, Guang Yang, Huilan Wang, Jingwen Li, Qingrun Li, Rong Zeng, Boxun Lu, Wenqing Shui","doi":"10.1038/s41589-025-01864-w","DOIUrl":"https://doi.org/10.1038/s41589-025-01864-w","url":null,"abstract":"<p>Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifications (PTMs) remains largely unexplored. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G-protein activity that is emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. After profiling the <i>N</i>-glycosylation and phosphorylation patterns, we found that these two types of PTMs differentially shape the intrinsic signaling bias of GPR52. While N-terminal <i>N</i>-glycosylation promotes constitutive G_s signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and attenuates receptor internalization. In addition, we uncovered the counteracting roles of <i>N</i>-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein in brain striatal cells. Our study provides new insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR through distinct PTMs in different motifs.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"23 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618341","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}