Nature chemical biology最新文献

{"title":"A tRNA modification with aminovaleramide facilitates AUA decoding in protein synthesis","authors":"Kenjyo Miyauchi, Satoshi Kimura, Naho Akiyama, Kazuki Inoue, Kensuke Ishiguro, Thien-Son Vu, Veerasak Srisuknimit, Kenta Koyama, Gosuke Hayashi, Akiko Soma, Asuteka Nagao, Mikako Shirouzu, Akimitsu Okamoto, Matthew K. Waldor, Tsutomu Suzuki","doi":"10.1038/s41589-024-01726-x","DOIUrl":"https://doi.org/10.1038/s41589-024-01726-x","url":null,"abstract":"<p>Modified tRNA anticodons are critical for proper mRNA translation during protein synthesis. It is generally thought that almost all bacterial tRNAs^Ile use a modified cytidine—lysidine (L)—at the first position (34) of the anticodon to decipher the AUA codon as isoleucine (Ile). Here we report that tRNAs^Ile from plant organelles and a subset of bacteria contain a new cytidine derivative, designated 2-aminovaleramididine (ava²C). Like L34, ava²C34 governs both Ile-charging ability and AUA decoding. Cryo-electron microscopy structural analyses revealed molecular details of codon recognition by ava²C34 with a specific interaction between its terminal amide group and an mRNA residue 3′-adjacent to the AUA codon. These findings reveal the evolutionary variation of an essential tRNA modification and demonstrate the molecular basis of AUA decoding mediated by a unique tRNA modification.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245854","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":"Compact RNA editors with natural miniature Cas13j nucleases","authors":"Guo Li, Yaxian Cheng, Jingwen Yu, Yunfei Zhu, Hongru Ma, Yuqiao Zhou, Zhongji Pu, Guanglin Zhu, Yichen Yuan, Ziyue Zhang, Xinzhi Zhou, Kairen Tian, Jianjun Qiao, Xiaoxiang Hu, Xue-xin Chen, Quanjiang Ji, Xingxu Huang, Bin Ma, Yuan Yao","doi":"10.1038/s41589-024-01729-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01729-8","url":null,"abstract":"<p>Clustered regularly interspaced short palindromic repeats–Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as <i>APOC3</i>^D65N and <i>SCN9A</i>^R896Q, to the wild-type forms. In addition, we developed an optimized system, Chi-RESCUE-S-mini3, which pioneered efficient in vivo C-to-U RNA editing of <i>PCSK9</i> in mice through single-AAV delivery, resulting in reduced total cholesterol levels. These results highlight the potential of Cas13j to treat human diseases.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245855","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":"Beware of extreme calculated lipophilicity when designing cyclic peptides","authors":"Vasanthanathan Poongavanam, Duc Duy Vo, Jan Kihlberg","doi":"10.1038/s41589-024-01715-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01715-0","url":null,"abstract":"Orally bioavailable, high molecular weight macrocyclic peptides that inhibit difficult-to-drug protein–protein interactions are of high therapeutic value, and rules for their design were proposed recently. Here, we emphasize the danger of rules that provide a false impression of the lipophilicity required of a clinical candidate.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245856","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":"An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes","authors":"Yuanjin Zhang, Zhonglin Liu, Marscha Hirschi, Oleg Brodsky, Eric Johnson, Sang Joon Won, Asako Nagata, Divya Bezwada, Matthew D. Petroski, Jaimeen D. Majmudar, Sherry Niessen, Todd VanArsdale, Adam M. Gilbert, Matthew M. Hayward, Al E. Stewart, Andrew R. Nager, Bruno Melillo, Benjamin F. Cravatt","doi":"10.1038/s41589-024-01738-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01738-7","url":null,"abstract":"<p>More than half of the ~20,000 protein-encoding human genes have paralogs. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to subsets of paralogous proteins. Here we explore whether such covalent compound–cysteine interactions can be used to discover ligandable pockets in paralogs lacking the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we substituted the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide–CCNE1-N112C interaction into in vitro NanoBRET (bioluminescence resonance energy transfer) and in cellulo activity-based protein profiling assays capable of identifying compounds that reversibly inhibit both the N112C mutant and wild-type CCNE1:CDK2 (cyclin-dependent kinase 2) complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings, thus, show how electrophile–cysteine interactions mapped by chemical proteomics can extend the understanding of protein ligandability beyond covalent chemistry.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236856","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":"Sweet RNA","authors":"Yiyun Song","doi":"10.1038/s41589-024-01746-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01746-7","url":null,"abstract":"<p>By coupling rPAL to enzymatic glycan cleavage and sequential window acquisition of all theoretical mass spectra (SWATH-MS), the team found that acp³U was the most enriched linker (although other putative linker substrates were identified). Importantly, knocking out DTWD2, an enzyme responsible for installing acp³U in tRNAs, reduced glycoRNA levels. This study provides not only a useful tool for glycoRNA detection, but also the first direct evidence of a covalent linkage between a secretory N-glycan and RNA, paving the way for future functional studies.</p><p><b>Original reference:</b> <i>Cell</i> https://doi.org/10.1016/j.cell.2024.07.044 (2024)</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236740","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":"Anti-aggregate activity","authors":"Russell Johnson","doi":"10.1038/s41589-024-01745-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01745-8","url":null,"abstract":"<p>The formation of pathological protein aggregates occurs in many neurodegenerative diseases, such as the aggregation of the protein tau in patients with Alzheimer’s disease. Removing these aggregates offers a possible route to treat these protein misfolding diseases; however, targeting the aggregated form of a protein while sparing the monomeric form, which is required for normal cellular function, remains a challenge. Now, Benn, Cheng et al. have shown that fusing an E3 ligase-containing protein to a target-specific nanobody enables the construction of RING–nanobody (R-Nb) degraders that can target and selectively remove proteins that have assembled into protein aggregates.</p><p>The E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) induces degradation by the clustering and cross-activation of the RING domains of TRIM21. The team hypothesized that the structure of fibrillar aggregates may enable dense clustering of R-Nb degraders and therefore activation of the degradation pathway, whereas monomeric tau would not induce clustering of R-Nbs and therefore would not induce degradation. Tuning the affinity of the nanobody could also affect clustering and thereby provides another route to mediate protein degradation.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236739","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":"Breaking down taurine","authors":"Grant Miura","doi":"10.1038/s41589-024-01747-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01747-6","url":null,"abstract":"<p><i>N-</i>acetyltaurine is a metabolite whose levels fluctuate with diet and exercise and that undergoes hydrolysis to form taurine and acetate. However, the enzymes that facilitate this reaction were not known. In an effort to address this, Wei et al. used liquid chromatography–mass spectrometry-based activity guided analysis of mouse tissues, detecting high <i>N-</i>acetyltaurine hydrolysis activity in kidney and liver tissues, with reduced <i>N-</i>acetyltaurine levels and a corresponding increase in taurine. Fractionation of kidney cytosol fractions combined with size exclusion chromatography identified a peak of activity. Proteomic analysis revealed a series of candidates with exogenous expression of phosphotriesterase-related (PTER), an orphan metal-dependent hydrolase, sufficient to increase <i>N-</i>acetyltaurine hydrolytic activity in cells. <i>Pter-</i>deficient mice confirmed the loss of hydrolysis activity with targeted metabolomic analysis of <i>N</i>-acetylated amino acids showing only alterations in <i>N</i>-acetyltaurine levels with minimal changes in other <i>N</i>-acetyl amino acids. Previous work has shown a connection between <i>PTER</i> polymorphisms and early onset obesity, so the team examined <i>Pter</i>-deficient mice on a high-fat diet while supplemented with taurine or exposed to treadmill running. In both cases, the mice exhibited lower body weight and food intake with improved glucose homeostasis, suggesting a complex interplay between increased <i>N</i>-acetyltaurine, diet and exercise. The beneficial metabolic effects were attributed to the brainstem, where PTER was expressed and is known to regulate food intake. The addition of an antibody against a candidate brainstem regulator, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), blocked the effects of exogenous <i>N</i>-acetyltaurine. Although there remain open questions about the metabolic regulation between the brainstem and peripheral tissues and the identity of the enzymes required for <i>N</i>-acetyltaurine, the findings from Wei et al. offer the first step to understanding the metabolic and functional roles of <i>N</i>-acetyltaurine.</p><p><b>Original reference:</b> <i>Nature</i> <b>633</b>, 182–188 (2024)</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236777","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":"Multicellular artificial neural network-type architectures demonstrate computational problem solving","authors":"Deepro Bonnerjee, Saswata Chakraborty, Biyas Mukherjee, Ritwika Basu, Abhishek Paul, Sangram Bagh","doi":"10.1038/s41589-024-01711-4","DOIUrl":"https://doi.org/10.1038/s41589-024-01711-4","url":null,"abstract":"<p>Here, we report a modular multicellular system created by mixing and matching discrete engineered bacterial cells. This system can be designed to solve multiple computational decision problems. The modular system is based on a set of engineered bacteria that are modeled as an ‘artificial neurosynapse’ that, in a coculture, formed a single-layer artificial neural network-type architecture that can perform computational tasks. As a demonstration, we constructed devices that function as a full subtractor and a full adder. The system is also capable of solving problems such as determining if a number between 0 and 9 is a prime number and if a letter between A and L is a vowel. Finally, we built a system that determines the maximum number of pieces of a pie that can be made for a given number of straight cuts. This work may have importance in biocomputer technology development and multicellular synthetic biology.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234469","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 peptide–nucleobase hybrids in ribosomal peptides","authors":"Zeng-Fei Pei, Natalia M. Vior, Lingyang Zhu, Andrew W. Truman, Satish K. Nair","doi":"10.1038/s41589-024-01736-9","DOIUrl":"https://doi.org/10.1038/s41589-024-01736-9","url":null,"abstract":"<p>The main biopolymers in nature are oligonucleotides and polypeptides. However, naturally occurring peptide–nucleobase hybrids are rare. Here we report the characterization of the founding member of a class of peptide–nucleobase hybrid natural products with a pyrimidone motif from a widely distributed ribosomally synthesized and post-translationally modified (RiPP) biosynthetic pathway. This pathway features two steps where a heteromeric RRE–YcaO–dehydrogenase complex catalyzes the formation of a six-membered pyrimidone ring from an asparagine residue on the precursor peptide, and an acyl esterase selectively recognizes this moiety to cleave the C-terminal follower peptide. Mechanistic studies reveal that the pyrimidone formation occurs in a substrate-assisted catalysis manner, requiring a His residue in the precursor to activate asparagine for heterocyclization. Our study expands the chemotypes of RiPP natural products and the catalytic scope of YcaO enzymes. This discovery opens avenues to create artificial biohybrid molecules that resemble both peptide and nucleobase, a modality of growing interest.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234470","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":"Incorporation of nitrogen in antinutritional Solanum alkaloid biosynthesis","authors":"Dagny Grzech, Samuel J. Smit, Ryan M. Alam, Marianna Boccia, Yoko Nakamura, Benke Hong, Ranjit Barbole, Sarah Heinicke, Maritta Kunert, Wibke Seibt, Veit Grabe, Lorenzo Caputi, Benjamin R. Lichman, Sarah E. O’Connor, Asaph Aharoni, Prashant D. Sonawane","doi":"10.1038/s41589-024-01735-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01735-w","url":null,"abstract":"<p>Steroidal glycoalkaloids (SGAs) are specialized metabolites produced by hundreds of <i>Solanum</i> species including food crops, such as tomato, potato and eggplant. Unlike true alkaloids, nitrogen is introduced at a late stage of SGA biosynthesis through an unknown transamination reaction. Here, we reveal the mechanism by which GLYCOALKALOID METABOLISM12 (GAME12) directs the biosynthesis of nitrogen-containing steroidal alkaloid aglycone in <i>Solanum</i>. We report that GAME12, a neofunctionalized <i>γ</i>-aminobutyric acid (GABA) transaminase, undergoes changes in both active site specificity and subcellular localization to switch from its renown and generic activity in core metabolism to function in a specialized metabolic pathway. Moreover, overexpression of <i>GAME12</i> alone in engineered <i>S.</i> <i>nigrum</i> leaves is sufficient for de novo production of nitrogen-containing SGAs. Our results highlight how hijacking a core metabolism GABA shunt enzyme is crucial in numerous <i>Solanum</i> species for incorporating a nitrogen to a steroidal-specialized metabolite backbone and form defensive alkaloids.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174912","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}