Nature chemical biology最新文献_第6页

Multicellular artificial neural network-type architectures demonstrate computational problem solving 多细胞人工神经网络型架构展示计算问题解决方法

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-16 DOI: 10.1038/s41589-024-01711-4

Deepro Bonnerjee, Saswata Chakraborty, Biyas Mukherjee, Ritwika Basu, Abhishek Paul, Sangram Bagh

{"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":"10.1038/s41589-024-01711-4","url":null,"abstract":"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. A modular multicellular system has been created by mixing and matching discrete engineered bacterial cells in an artificial neural network-type architecture. The system is capable of solving multiple computational decision problems like identifying a number as prime and a letter as a vowel.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 11","pages":"1524-1534"},"PeriodicalIF":12.9,"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}

引用次数: 0

Biosynthesis of peptide–nucleobase hybrids in ribosomal peptides 核糖体肽中肽-核碱基杂交的生物合成

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-16 DOI: 10.1038/s41589-024-01736-9

Zeng-Fei Pei, Natalia M. Vior, Lingyang Zhu, Andrew W. Truman, Satish K. Nair

{"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":"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.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"23 1","pages":""},"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}

引用次数: 0

Incorporation of nitrogen in antinutritional Solanum alkaloid biosynthesis 抗营养茄科生物碱生物合成中的氮结合

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-13 DOI: 10.1038/s41589-024-01735-w

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

{"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":"Steroidal glycoalkaloids (SGAs) are specialized metabolites produced by hundreds of Solanum 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 Solanum. We report that GAME12, a neofunctionalized γ-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 GAME12 alone in engineered S. nigrum 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 Solanum species for incorporating a nitrogen to a steroidal-specialized metabolite backbone and form defensive alkaloids.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"69 1","pages":""},"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}

引用次数: 0

Control of DNA demethylation by superoxide anion in plant stem cells 超氧阴离子对植物干细胞 DNA 去甲基化的控制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-12 DOI: 10.1038/s41589-024-01737-8

Shiwen Wang, Min Liu, Dongping Hu, Zhicheng Dong, Zhong Zhao

引用次数: 0

Customizable gene sensing and response without altering endogenous coding sequences 无需改变内源编码序列即可定制基因感应和响应

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-12 DOI: 10.1038/s41589-024-01733-y

Fabio Caliendo, Elvira Vitu, Junmin Wang, Shuo-Hsiu Kuo, Hayden Sandt, Casper Nørskov Enghuus, Jesse Tordoff, Neslly Estrada, James J. Collins, Ron Weiss

{"title":"Customizable gene sensing and response without altering endogenous coding sequences","authors":"Fabio Caliendo, Elvira Vitu, Junmin Wang, Shuo-Hsiu Kuo, Hayden Sandt, Casper Nørskov Enghuus, Jesse Tordoff, Neslly Estrada, James J. Collins, Ron Weiss","doi":"10.1038/s41589-024-01733-y","DOIUrl":"https://doi.org/10.1038/s41589-024-01733-y","url":null,"abstract":"Synthetic biology aims to modify cellular behaviors by implementing genetic circuits that respond to changes in cell state. Integrating genetic biosensors into endogenous gene coding sequences using clustered regularly interspaced short palindromic repeats and Cas9 enables interrogation of gene expression dynamics in the appropriate chromosomal context. However, embedding a biosensor into a gene coding sequence may unpredictably alter endogenous gene regulation. To address this challenge, we developed an approach to integrate genetic biosensors into endogenous genes without modifying their coding sequence by inserting into their terminator region single-guide RNAs that activate downstream circuits. Sensor dosage responses can be fine-tuned and predicted through a mathematical model. We engineered a cell stress sensor and actuator in CHO-K1 cells that conditionally activates antiapoptotic protein BCL-2 through a downstream circuit, thereby increasing cell survival under stress conditions. Our gene sensor and actuator platform has potential use for a wide range of applications that include biomanufacturing, cell fate control and cell-based therapeutics.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"9 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170880","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

Enriching productive mutational paths accelerates enzyme evolution 丰富富有成效的突变途径可加速酶的进化

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-11 DOI: 10.1038/s41589-024-01712-3

David Patsch, Thomas Schwander, Moritz Voss, Daniela Schaub, Sean Hüppi, Michael Eichenberger, Peter Stockinger, Lisa Schelbert, Sandro Giger, Francesca Peccati, Gonzalo Jiménez-Osés, Mojmír Mutný, Andreas Krause, Uwe T. Bornscheuer, Donald Hilvert, Rebecca M. Buller

{"title":"Enriching productive mutational paths accelerates enzyme evolution","authors":"David Patsch, Thomas Schwander, Moritz Voss, Daniela Schaub, Sean Hüppi, Michael Eichenberger, Peter Stockinger, Lisa Schelbert, Sandro Giger, Francesca Peccati, Gonzalo Jiménez-Osés, Mojmír Mutný, Andreas Krause, Uwe T. Bornscheuer, Donald Hilvert, Rebecca M. Buller","doi":"10.1038/s41589-024-01712-3","DOIUrl":"10.1038/s41589-024-01712-3","url":null,"abstract":"Darwinian evolution has given rise to all the enzymes that enable life on Earth. Mimicking natural selection, scientists have learned to tailor these biocatalysts through recursive cycles of mutation, selection and amplification, often relying on screening large protein libraries to productively modulate the complex interplay between protein structure, dynamics and function. Here we show that by removing destabilizing mutations at the library design stage and taking advantage of recent advances in gene synthesis, we can accelerate the evolution of a computationally designed enzyme. In only five rounds of evolution, we generated a Kemp eliminase—an enzymatic model system for proton transfer from carbon—that accelerates the proton abstraction step >108-fold over the uncatalyzed reaction. Recombining the resulting variant with a previously evolved Kemp eliminase HG3.17, which exhibits similar activity but differs by 29 substitutions, allowed us to chart the topography of the designer enzyme’s fitness landscape, highlighting that a given protein scaffold can accommodate several, equally viable solutions to a specific catalytic problem. By enriching productive mutational paths, a Kemp eliminase that speeds up proton abstraction >108-fold was developed in only five evolution rounds. Recombining it with a variant differing by 29 substitutions revealed the underlying fitness landscape.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 12","pages":"1662-1669"},"PeriodicalIF":12.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41589-024-01712-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Substrate interactions guide cyclase engineering and lasso peptide diversification 底物相互作用引导环化酶工程和套索肽多样化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-11 DOI: 10.1038/s41589-024-01727-w

Susanna E. Barrett, Song Yin, Peter Jordan, John K. Brunson, Jessica Gordon-Nunez, Gabriella Costa Machado da Cruz, Christopher Rosario, Bethany K. Okada, Kelsey Anderson, Thomas A. Pires, Ruoyang Wang, Diwakar Shukla, Mark J. Burk, Douglas A. Mitchell

{"title":"Substrate interactions guide cyclase engineering and lasso peptide diversification","authors":"Susanna E. Barrett, Song Yin, Peter Jordan, John K. Brunson, Jessica Gordon-Nunez, Gabriella Costa Machado da Cruz, Christopher Rosario, Bethany K. Okada, Kelsey Anderson, Thomas A. Pires, Ruoyang Wang, Diwakar Shukla, Mark J. Burk, Douglas A. Mitchell","doi":"10.1038/s41589-024-01727-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01727-w","url":null,"abstract":"Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site. Predicted peptide cyclase molecular contacts were validated by rationally engineering multiple, phylogenetically diverse lasso cyclases to accept substrates rejected by the wild-type enzymes. Finally, we demonstrate the utility of lasso cyclase engineering by robustly producing previously inaccessible variants that tightly bind to integrin αvβ8, which is a primary activator of transforming growth factor β and, thus, an important anti-cancer target.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"83 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166059","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

Complex structure and activation mechanism of arginine kinase McsB by McsA 精氨酸激酶 McsB 的复合结构和 McsA 激活机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-04 DOI: 10.1038/s41589-024-01720-3

Kai Lu, Bingnan Luo, Xuan Tao, Yongbo Luo, Mingjun Ao, Bin Zheng, Xiang Xu, Xiaoyan Ma, Jingling Niu, Huinan Li, Yanxuan Xie, Zhennan Zhao, Peng Zheng, Guanbo Wang, Song Gao, Chao Wang, Wei Xia, Zhaoming Su, Zong-Wan Mao

{"title":"Complex structure and activation mechanism of arginine kinase McsB by McsA","authors":"Kai Lu, Bingnan Luo, Xuan Tao, Yongbo Luo, Mingjun Ao, Bin Zheng, Xiang Xu, Xiaoyan Ma, Jingling Niu, Huinan Li, Yanxuan Xie, Zhennan Zhao, Peng Zheng, Guanbo Wang, Song Gao, Chao Wang, Wei Xia, Zhaoming Su, Zong-Wan Mao","doi":"10.1038/s41589-024-01720-3","DOIUrl":"https://doi.org/10.1038/s41589-024-01720-3","url":null,"abstract":"Protein phosphorylation is a pivotal post-translational modification modulating various cellular processes. In Gram-positive bacteria, the protein arginine kinase McsB, along with its activator McsA, has a key role in labeling misfolded and damaged proteins during stress. However, the activation mechanism of McsB by McsA remains elusive. Here we report the cryo-electron microscopy structure of a tetrameric McsA–McsB complex at 3.41 Å resolution. Biochemical analysis indicates that the homotetrameric assembly is essential for McsB’s kinase activity. The conserved C-terminal zinc finger of McsA interacts with an extended loop in McsB, optimally orienting a critical catalytic cysteine residue. In addition, McsA binding decreases the CtsR’s affinity for McsB, enhancing McsB’s kinase activity and accelerating the turnover rate of CtsR phosphorylation. Furthermore, McsA binding also increases McsB’s thermostability, ensuring its activity under heat stress. These findings elucidate the structural basis and activation mechanism of McsB in stress response.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"8 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130900","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

Endogenous cell membrane interactome mapping for the GLP-1 receptor in different cell types 不同细胞类型中 GLP-1 受体的内源性细胞膜相互作用组图谱

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-03 DOI: 10.1038/s41589-024-01714-1

Ting Dang, Jie Yu, Zhihe Cao, Bingjie Zhang, Shanshan Li, Ye Xin, Lingyun Yang, Ronghui Lou, Min Zhuang, Wenqing Shui

引用次数: 0

Illuminating GPCR trafficking 阐明 GPCR 的贩运

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-02 DOI: 10.1038/s41589-024-01699-x

Michelle L. Halls

引用次数: 0