ACS Chemical Biology最新文献_第8页

A Stable Dehydratase Complex Catalyzes the Formation of Dehydrated Amino Acids in a Class V Lanthipeptide. 一种稳定的脱氢酶复合物催化 V 类anthipeptide 中脱水氨基酸的形成。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-11-25 DOI: 10.1021/acschembio.4c00637

George T Randall, Emily S Grant-Mackie, Shayhan Chunkath, Elyse T Williams, Martin J Middleditch, Meifeng Tao, Paul W R Harris, Margaret A Brimble, Ghader Bashiri

{"title":"A Stable Dehydratase Complex Catalyzes the Formation of Dehydrated Amino Acids in a Class V Lanthipeptide.","authors":"George T Randall, Emily S Grant-Mackie, Shayhan Chunkath, Elyse T Williams, Martin J Middleditch, Meifeng Tao, Paul W R Harris, Margaret A Brimble, Ghader Bashiri","doi":"10.1021/acschembio.4c00637","DOIUrl":"10.1021/acschembio.4c00637","url":null,"abstract":"Lanthipeptides are ribosomally synthesized and post-translationally modified peptides that bear the characteristic lanthionine (Lan) or methyllanthionine (MeLan) thioether linkages. (Me)Lan moieties bestow lanthipeptides with robust stability and diverse antimicrobial, anticancer, and antiallodynic activities. Installation of (Me)Lan requires dehydration of serine and threonine residues to 2,3-dehydroalanine (Dha) and (Z)-2,3-dehydrobutyrine (Dhb), respectively. LxmK and LxmY enzymes comprise the biosynthetic machinery of a newly discovered class V lanthipeptide, lexapeptide, and are proposed to catalyze the dehydration of serine and threonine residues in the precursor peptide. We demonstrate that LxmK and LxmY form a stable dehydratase complex to dehydrate precursor peptides. In addition, we present crystal structures of the LxmKY heterodimer, revealing structural and mechanistic features that enable iterative phosphorylation and elimination by the LxmKY complex. These findings provide molecular insights into class V lanthionine synthetases and lay the foundation for their applications as enzymatic tools in the biosynthesis of exquisitely modified peptides.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2548-2556"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Correction to "Structure and Biosynthesis of Hectoramide B, a Linear Depsipeptide from Marine Cyanobacterium Moorena producens JHB Discovered via Coculture with Candida albicans". 更正 "通过与白色念珠菌共培养发现的海洋蓝藻 Moorena producens JHB 的线性去肽 Hectoramide B 的结构和生物合成"。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-11-26 DOI: 10.1021/acschembio.4c00739

Thuan-Ethan Ngo, Andrew Ecker, Byeol Ryu, Aurora Guild, Ariana Remmel, Paul D Boudreau, Kelsey L Alexander, C Benjamin Naman, Evgenia Glukhov, Nicole E Avalon, Vikram V Shende, Lamar Thomas, Samira Dahesh, Victor Nizet, Lena Gerwick, William H Gerwick

引用次数: 0

Characterization of a Dual Function Peptide Cyclase in Graspetide Biosynthesis. 草肽生物合成中双功能肽环化酶的研究。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-12-04 DOI: 10.1021/acschembio.4c00626

Garret M Rubin, Krishna P Patel, Yujia Jiang, Alivia C Ishee, Gustavo Seabra, Steven D Bruner, Yousong Ding

{"title":"Characterization of a Dual Function Peptide Cyclase in Graspetide Biosynthesis.","authors":"Garret M Rubin, Krishna P Patel, Yujia Jiang, Alivia C Ishee, Gustavo Seabra, Steven D Bruner, Yousong Ding","doi":"10.1021/acschembio.4c00626","DOIUrl":"10.1021/acschembio.4c00626","url":null,"abstract":"Graspetides are a diverse family of ribosomally synthesized and post-translationally modified peptides with unique macrocyclic structures formed by ATP-grasp enzymes. Group 11 graspetides, including prunipeptin, feature both macrolactone and macrolactam cross-links. Despite the known involvement of a single ATP-grasp cyclase in the dual macrocyclizations of groups 5, 7, and 11 graspetides, detailed mechanistic insights into these enzymes remain limited. Here, we reconstructed prunipeptin biosynthesis from Streptomyces coelicolor using recombinant PruA and PruB macrocyclase. PruB exhibited kinetic behavior similar to other characterized graspetide cyclases, with a notably higher kcat, likely due to utilization of an ATP-regeneration system. The X-ray crystal structure of PruB revealed distinct features as compared to groups 1 and 2 enzymes. Site-directed mutagenesis identified critical roles of key residues for the PruB reaction, including the DxR motif conserved in other graspetide cyclases. Additionally, computational modeling of the PruA/PruB cocomplex uncovered substrate interactions and suggested that PruB first catalyzes a macrolactone bond formation on PruA. This study enhances our understanding of ATP-grasp enzyme mechanisms in graspetide biosynthesis and provides insights for engineering these enzymes for future applications.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2525-2534"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Bioorthogonal Cyclopropenones for Investigating RNA Structure. 生物正交环丙烯研究RNA结构。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-12-06 DOI: 10.1021/acschembio.4c00633

Sharon Chen, Christopher D Sibley, Brandon Latifi, Sumirtha Balaratnam, Robert S Dorn, Andrej Lupták, John S Schneekloth, Jennifer A Prescher

{"title":"Bioorthogonal Cyclopropenones for Investigating RNA Structure.","authors":"Sharon Chen, Christopher D Sibley, Brandon Latifi, Sumirtha Balaratnam, Robert S Dorn, Andrej Lupták, John S Schneekloth, Jennifer A Prescher","doi":"10.1021/acschembio.4c00633","DOIUrl":"10.1021/acschembio.4c00633","url":null,"abstract":"RNA sequences encode structures that impact protein production and other cellular processes. Misfolded RNAs can also potentiate disease, but a complete picture is lacking. To establish more comprehensive and accurate RNA structure-function relationships, new methods are needed to interrogate RNA in native environments. Existing tools rely primarily on electrophiles that are constitutively \"on\" or triggered by UV light, often resulting in high background. Here we describe an alternative, chemically triggered approach to cross-link RNAs using bioorthogonal cyclopropenones (CpOs). These reagents selectively react with phosphines to provide ketenes─electrophiles that can trap neighboring nucleophiles to forge covalent cross-links. As a proof-of-concept, we conjugated a CpO motif to thiazole orange (TO-1). TO-1-CpO bound selectively to a model RNA aptamer (Mango) with nanomolar affinity, as confirmed by fluorescence turn-on. After phosphine administration, covalent cross-links were formed between the CpO and RNA. Cross-linking was both time and dose dependent. We further applied the chemically triggered tools to model RNAs under biologically relevant conditions. Collectively, this work expands the toolkit of probes for studying RNA and its native conformations.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2406-2411"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Mapping the FGF2 Interactome Identifies a Functional Proteoglycan Coreceptor

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 DOI: 10.1021/acschembio.4c0047510.1021/acschembio.4c00475

Meg Critcher, Jia Meng Pang and Mia L. Huang*,

{"title":"Mapping the FGF2 Interactome Identifies a Functional Proteoglycan Coreceptor","authors":"Meg Critcher, Jia Meng Pang and Mia L. Huang*, ","doi":"10.1021/acschembio.4c0047510.1021/acschembio.4c00475","DOIUrl":"https://doi.org/10.1021/acschembio.4c00475https://doi.org/10.1021/acschembio.4c00475","url":null,"abstract":"Fibroblast growth factor 2 (FGF2) is a multipotent growth factor and signaling protein that exhibits broad functions across multiple cell types. These functions are often initiated by binding to growth factor receptors and fine-tuned by glycosaminoglycan (GAG)-modified proteins called proteoglycans. The various outputs of FGF2 signaling and functions arise from a dynamic and cell type-specific set of binding partners. However, the interactome of FGF2 has yet to be comprehensively determined. Moreover, the identity of the proteoglycan proteins carrying GAG chains is often overlooked and remains unknown in most cell contexts. Here, we perform peroxidase-catalyzed live cell proximity labeling using an engineered APEX2-FGF2 fusion protein to map the interactome of FGF2. Across two cell lines with established and distinct FGF2-driven functions, we greatly expand upon the known FGF2 interactome, identifying >600 new putative FGF2 interactors. Notably, our results demonstrate a key role for the GAG binding capacity of FGF2 in modulating its interactome.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 1","pages":"105–116 105–116"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143085578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The Emergence of Oligonucleotide Building Blocks in the Multispecific Proximity-Inducing Drug Toolbox of Destruction

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 DOI: 10.1021/acschembio.4c0031110.1021/acschembio.4c00311

Kevin Xiao Tong Zhou, and , Katherine E. Bujold*,

{"title":"The Emergence of Oligonucleotide Building Blocks in the Multispecific Proximity-Inducing Drug Toolbox of Destruction","authors":"Kevin Xiao Tong Zhou,  and , Katherine E. Bujold*, ","doi":"10.1021/acschembio.4c0031110.1021/acschembio.4c00311","DOIUrl":"https://doi.org/10.1021/acschembio.4c00311https://doi.org/10.1021/acschembio.4c00311","url":null,"abstract":"Oligonucleotides are a rapidly emerging class of therapeutics. Their most well-known examples are informational drugs that modify gene expression by binding mRNA. Despite inducing proximity between biological machinery and mRNA when applied to modulating gene expression, oligonucleotides are not typically labeled as “proximity-inducing” in literature. Yet, they have recently been explored as building blocks for multispecific proximity-inducing drugs (MPIDs). MPIDs are unique because they can direct endogenous biological machinery to destroy targeted molecules and cells, in contrast to traditional drugs that inhibit only their functions. The unique mechanism of action of MPIDs has enabled the targeting of previously “undruggable” molecular entities that cannot be effectively inhibited. However, the development of MPIDs must ensure that these molecules will selectively direct a potent, destruction-based mechanism of action toward intended targets over healthy tissues to avoid causing life-threatening toxicities. Oligonucleotides have emerged as promising building blocks for the design of MPIDs because they are sequence-controlled molecules that can be rationally designed to program multispecific binding interactions. In this Review, we examine the emergence of oligonucleotide-containing MPIDs in the proximity induction space, which has been dominated by antibody and small molecule MPID modalities. Moreover, examples of oligonucleotides developed as MPID candidates in immunotherapy and protein degradation are discussed to demonstrate the utility of oligonucleotides in expanding the scope and selectivity of the MPID toolbox. Finally, we discuss the utility of programming “AND” gates into oligonucleotide scaffolds to encode conditional responses that have the potential to be incorporated into MPIDs, which can further enhance their selectivity, thus increasing the scope of this drug category.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 1","pages":"3–18 3–18"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143085404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Molecular Targeted Engagement of DPP9 in Rat Tissue Using CETSA, SP3 Processing, and Absolute Quantitation Mass Spectrometry. 利用CETSA、SP3处理和绝对定量质谱技术在大鼠组织中靶向参与DPP9。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-12-06 DOI: 10.1021/acschembio.4c00563

Matthew T Mazur, Baojen Shyong, Qian Huang, Stacey L Polsky-Fisher, Carl J Balibar, Weixun Wang

{"title":"Molecular Targeted Engagement of DPP9 in Rat Tissue Using CETSA, SP3 Processing, and Absolute Quantitation Mass Spectrometry.","authors":"Matthew T Mazur, Baojen Shyong, Qian Huang, Stacey L Polsky-Fisher, Carl J Balibar, Weixun Wang","doi":"10.1021/acschembio.4c00563","DOIUrl":"10.1021/acschembio.4c00563","url":null,"abstract":"The cellular thermal shift assay (CETSA) provides a means of understanding the extent to which a small molecule ligand associates with a protein target of therapeutic interest, thereby inferring target engagement. Better analytical detection methods, including mass spectrometry, are being implemented to improve quantitation within these assays, providing both absolute quantitation and a very high analyte specificity. To understand the target engagement, and hence inhibition, of the protein dipeptidyl peptidase 9 (DPP9) in rat tissue, CETSA experiments, coupled with single-pot, solid-phase-enhanced sample preparation (\"SP3\") and absolute quantitation by high-resolution mass spectrometry, demonstrated a temperature-dependent \"melting curve\" by ex vivo incubation of compound with rat tissue and further demonstrated in vivo engagement by a dose-dependent response to treatment. These experiments illustrate the ability to extend the CETSA to in vivo dosed-animal samples using absolute quantitation of DPP9 by mass spectrometry and demonstrate a viable path for interrogating therapeutic molecules for drug discovery.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2477-2486"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress. 发现一种抑制 IRE1α S-亚硝基化并在亚硝基胁迫下保护内质网应激反应的化合物

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-11-12 DOI: 10.1021/acschembio.4c00403

Haruna Kurogi, Nobumasa Takasugi, Sho Kubota, Ashutosh Kumar, Takehiro Suzuki, Naoshi Dohmae, Daisuke Sawada, Kam Y J Zhang, Takashi Uehara

{"title":"Discovery of a Compound That Inhibits IRE1α S-Nitrosylation and Preserves the Endoplasmic Reticulum Stress Response under Nitrosative Stress.","authors":"Haruna Kurogi, Nobumasa Takasugi, Sho Kubota, Ashutosh Kumar, Takehiro Suzuki, Naoshi Dohmae, Daisuke Sawada, Kam Y J Zhang, Takashi Uehara","doi":"10.1021/acschembio.4c00403","DOIUrl":"10.1021/acschembio.4c00403","url":null,"abstract":"Inositol-requiring enzyme 1α (IRE1α) is a sensor of endoplasmic reticulum (ER) stress and drives ER stress response pathways. Activated IRE1α exhibits RNase activity and cleaves mRNA encoding X-box binding protein 1, a transcription factor that induces the expression of genes that maintain ER proteostasis for cell survival. Previously, we showed that IRE1α undergoes S-nitrosylation, a post-translational modification induced by nitric oxide (NO), resulting in reduced RNase activity. Therefore, S-nitrosylation of IRE1α compromises the response to ER stress, making cells more vulnerable. We conducted virtual screening and cell-based validation experiments to identify compounds that inhibit the S-nitrosylation of IRE1α by targeting nitrosylated cysteine residues. We ultimately identified a compound (1ACTA) that selectively inhibits the S-nitrosylation of IRE1α and prevents the NO-induced reduction of RNase activity. Furthermore, 1ACTA reduces the rate of NO-induced cell death. Our research identified S-nitrosylation as a novel target for drug development for IRE1α and provides a suitable screening strategy.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2429-2437"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Single-Cell Multiomics Identifies Glycan Epitope LacNAc as a Potential Cell-Surface Effector Marker of Peripheral T Cells in Bladder Cancer Patients. 单细胞多组学发现糖表位 LacNAc 是膀胱癌患者外周 T 细胞的潜在细胞表面效应标志物

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-11-24 DOI: 10.1021/acschembio.4c00635

Xiangyu Wu, Zihan Zhao, Wenhao Yu, Siyang Liu, Meng Zhou, Ning Jiang, Xiang Du, Xin Yang, Jinbang Chen, Hongqian Guo, Rong Yang

{"title":"Single-Cell Multiomics Identifies Glycan Epitope LacNAc as a Potential Cell-Surface Effector Marker of Peripheral T Cells in Bladder Cancer Patients.","authors":"Xiangyu Wu, Zihan Zhao, Wenhao Yu, Siyang Liu, Meng Zhou, Ning Jiang, Xiang Du, Xin Yang, Jinbang Chen, Hongqian Guo, Rong Yang","doi":"10.1021/acschembio.4c00635","DOIUrl":"10.1021/acschembio.4c00635","url":null,"abstract":"Cancer is a systemic disease continuously monitored and responded to by the human global immune system. Peripheral blood immune cells, integral to this surveillance, exhibit variable phenotypes during tumor progression. Glycosylation, as one of the most prevalent and significant post-translational modifications of proteins, plays a crucial role in immune system recognition and response. Glycan analysis has become a key method for biomarker discovery. LacNAc, a prominent glycosylation modification, regulates immune cell activity and function. Therefore, we applied our previously developed single-cell glycomic multiomics to analyze peripheral blood in cancer patients. This platform utilizes chemoenzymatic labeling with DNA barcodes for detecting and quantifying LacNAc levels at single-cell resolution without altering the transcriptional status of immune cells. For the first time, we systematically integrated single-cell transcriptome, T cell receptor (TCR) repertoire, and glycan epitope LacNAc analyses in tumor-patient-derived peripheral blood. Our integrated analysis reveals that lower-stage bladder cancer patients showed significantly higher levels of LacNAc in peripheral T cells, and peripheral T cells with high levels of cell-surface LacNAc exhibit higher cytotoxicity and TCR clonal expansion. In summary, we identified LacNAc as a potential cell-surface effector marker for peripheral T cells in bladder cancer patients, which enhances our understanding of peripheral immune cells and offers potential advancements in liquid biopsy.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2535-2547"},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Understanding Polysulfide-Mediated Papain Inhibition and Differentiating between Disulfide vs Persulfide Formation. 了解多硫化物介导的木瓜蛋白酶抑制作用并区分二硫化物与过硫化物的形成。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-20 Epub Date: 2024-11-15 DOI: 10.1021/acschembio.4c00573

Meg Shieh, Anna Y Chung, Stephen Lindahl, Melany Veliz, Charlotte A Bain, Ming Xian

引用次数: 0