{"title":"Chemical strategies for trapping fleeting enzymatic complexes in nucleosome ubiquitylation","authors":"Yun Liu, Qi Shu, Huasong Ai","doi":"10.1016/j.cbpa.2025.102651","DOIUrl":"10.1016/j.cbpa.2025.102651","url":null,"abstract":"<div><div>Site-specific ubiquitylation of nucleosomal histones, catalyzed by E3 ubiquitin ligase, plays a pivotal role in chromatin-templated processes, including transcriptional activation, gene silencing, and DNA damage repair. However, the inherently transient and dynamic interactions between the ubiquitin enzymes and the nucleosome substrate during the ubiquitylation cascade pose significant challenges to stabilizing functional complexes for structural and biochemical interrogation, thereby impeding mechanistic dissection. Recent advances in chemical biology strategies have emerged as powerful tools for resolving ternary ubiquitylation complexes of E3 ligase, E2∼Ub, and substrate. In this review, we systematically survey these innovative chemical approaches for trapping labile nucleosome ubiquitylation intermediates and consolidate the mechanistic insights into chromatin ubiquitylation biology.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"90 ","pages":"Article 102651"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922194","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}
{"title":"Bridging or exchanging partners? A supramolecular perspective on bifunctional molecules and their potential for triggerable enzyme therapy","authors":"Leila Motiei, Martín López-Vidal, David Margulies","doi":"10.1016/j.cbpa.2025.102650","DOIUrl":"10.1016/j.cbpa.2025.102650","url":null,"abstract":"<div><div>Bifunctional molecules are commonly regarded as proximity-inducing compounds (PICs) that bridge two proteins to generate novel biological outcomes. Here, we highlight a distinct and emerging subclass, termed partner-exchanging molecules (PEMs), which cannot bind both protein partners simultaneously. Instead, they act through a partner-swapping mechanism, enabling one protein to unnaturally activate another. This perspective examines their mechanisms of action and surveys potential applications such as protein sensing, prodrug activation, controlled release, and the reconfiguration of intracellular signaling. Because PEMs offer a simple route to build triggerable enzymes, we further discuss them in the context of artificial zymogens, emphasizing their promise to mediate activation of therapeutic proenzyme systems via non-enzyme proteins and to render native enzymes triggerable in cells. By positioning PEMs as a conceptual link between bifunctional molecules and artificial zymogens, we aim to broaden our understanding of bifunctional regulators and expand the scope of artificial proenzyme design.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"90 ","pages":"Article 102650"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916338","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}
{"title":"Small RNAs, big potential: Engineering microRNA-based synthetic gene circuits","authors":"Archismita Kundu , Roman Jerala","doi":"10.1016/j.cbpa.2026.102652","DOIUrl":"10.1016/j.cbpa.2026.102652","url":null,"abstract":"<div><div>MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression. Their dysregulation is closely associated with various diseases, positioning them as biomarkers of cellular state. Synthetic biology has leveraged these properties to engineer miR-based genetic circuits capable of sensing and interpreting endogenous miR levels. Early miR-OFF systems relied on reporter gene repression but were limited by ambiguous signal interpretation. Subsequent advances introduced miR-ON architectures, logic-based classifiers integrating multiple miRs, and layered regulatory strategies combining transcriptional, translational, and cleavage-based modules to enhance sensitivity and specificity. Recent innovations include CRISPR-associated miR-responsive systems and incoherent feed-forward loop (iFFL) architectures that stabilize gene expression amid cellular variability, shifting applications from passive sensing to therapeutic intervention. Despite challenges such as leakage, cellular resource resources, and delivery, progress in orthogonal miR toolkits, computational modeling, and RNA-based delivery platforms is rapidly driving miR-based circuits toward diagnostic and therapeutic applications.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"90 ","pages":"Article 102652"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073750","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}
{"title":"Chemical dissection of microbiology and microbiota","authors":"Catherine L. Grimes, Howard C. Hang","doi":"10.1016/j.cbpa.2025.102641","DOIUrl":"10.1016/j.cbpa.2025.102641","url":null,"abstract":"","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"90 ","pages":"Article 102641"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808451","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}
{"title":"Synthetic biology for phytohormone production","authors":"Pattarawan Intasian , Ninlapan Kimprasoot , Duangthip Trisrivirat, Pimchai Chaiyen","doi":"10.1016/j.cbpa.2025.102649","DOIUrl":"10.1016/j.cbpa.2025.102649","url":null,"abstract":"<div><div>Phytohormones are compounds produced by plants that can control the processes of plant development and are involved in defense mechanisms. They can serve as sustainable enhancers for plant growth and are also better alternatives to agrochemicals because of their bio-based nature and optimal safety profile towards mammalian cells. Although phytohormones are essential for plant growth, they are naturally synthesized by plants in varying quantities, influenced both by environmental and genetic factors. The synthesis of phytohormones, however, faces several hurdles, including challenges in optimizing the production process as well as difficulties in the extraction of these compounds for downstream applications. In this review, we critically evaluate synthetic biology approaches for phytohormone production, which provides a sustainable method for the production of important phytohormones including auxin, gibberellin (GA), and salicylic acid (SA). These three compounds are highly significant for the agricultural industry because of their widespread utilization.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"90 ","pages":"Article 102649"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839135","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}
{"title":"Emerging trends in chemoproteomics: Mapping the landscape of protein–metabolite interactions","authors":"Ning Wan , Chenguang Liu , Haiping Hao , Hui Ye","doi":"10.1016/j.cbpa.2025.102631","DOIUrl":"10.1016/j.cbpa.2025.102631","url":null,"abstract":"<div><div>Protein-metabolite interactions (PMIs) are fundamental regulators of cellular metabolism, influencing essential processes such as energy homeostasis, signal transduction, and gene expression. However, their transient and dynamic nature presents significant challenges for detection. Chemoproteomics has emerged as a powerful and versatile strategy for capturing and characterizing PMIs with proteome-wide resolution. These approaches can be broadly categorized into derivatization-based methods, which utilize chemically modified probes to enrich protein targets, and derivatization-free methods, which detect changes in protein physicochemical properties upon metabolite binding, aided by highly sensitive proteomic analysis. In this review, we discuss recent advancements in both strategies, highlighting their applications in mapping PMIs and their potential to deepen our understanding of cellular metabolism and disease mechanisms.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"89 ","pages":"Article 102631"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134890","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}
{"title":"Editorial Overview: Converging innovations in chemical proteomics","authors":"Jing Yang, Wenqing Shui","doi":"10.1016/j.cbpa.2025.102640","DOIUrl":"10.1016/j.cbpa.2025.102640","url":null,"abstract":"","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"89 ","pages":"Article 102640"},"PeriodicalIF":6.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561937","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}
{"title":"Evolving advances of proximity labeling in capturing biomolecular interactions","authors":"Ting Dang , Wenqing Shui","doi":"10.1016/j.cbpa.2025.102629","DOIUrl":"10.1016/j.cbpa.2025.102629","url":null,"abstract":"<div><div>Proximity labeling (PL), with its capability to resolve spatiotemporal dynamics of biomolecular interactions, has become a pivotal technology for interrogating protein–protein interaction networks, subcellular proteomics, and intercellular communication. This review focuses on the breakthrough developments in PL from 2023 to 2025, highlighting three major frontiers: (1) catalytic system innovation, including the development of new enzymes, cascade reactions, and environment-responsive labeling systems, which collectively lead to increased spatiotemporal resolution and enhanced <em>in vivo</em> applicability; (2) new strategies to address endogenous targets, facilitating interactome mapping in native tissues and live animals; and (3) determination of the labeling radius for different PL tools using super-resolution imaging or DNA nanostructures. We also briefly discuss the desired innovation in the next-generation PL research.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"88 ","pages":"Article 102629"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044511","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}
{"title":"In vivo cross-linking mass spectrometry: Advances and challenges in decoding protein conformational dynamics and complex regulatory networks in living cells","authors":"Jing Chen , Qun Zhao , Yukui Zhang , Lihua Zhang","doi":"10.1016/j.cbpa.2025.102630","DOIUrl":"10.1016/j.cbpa.2025.102630","url":null,"abstract":"<div><div><em>In vivo</em> chemical cross-linking mass spectrometry (XL-MS) has emerged as a powerful technique for high-throughput, proteome-wide mapping of intramolecular conformations and intermolecular interactions of protein complexes in living cells. By providing distance constraints between specific residues, XL-MS enables the characterization of protein conformations and interaction networks under near-physiological conditions, greatly facilitating the analysis of biomacromolecular functions and regulatory mechanisms. The information obtained from cross-linking is particularly valuable at the systems level, and its value continues to increase with improvements in the density of cross-link identification, the precision of distance constraints, and the spatiotemporal resolution. In recent years, advances in cross-linker design, cross-linked peptide enrichment methods, mass spectrometry analysis, and artificial intelligence-assisted data analysis have significantly expanded the capabilities of <em>in vivo</em> XL-MS. This article systematically reviews the latest progress in <em>in vivo</em> XL-MS for protein conformation and interaction network analysis, highlights its unique advantages, discusses current technical challenges, and explores further development.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"88 ","pages":"Article 102630"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044512","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}
Wensi Zhao , Jun Zhang , Kaifeng Chen , Jian Yuan , Linhui Zhai , Minjia Tan
{"title":"Mass spectrometry-based characterization of histone post-translational modification","authors":"Wensi Zhao , Jun Zhang , Kaifeng Chen , Jian Yuan , Linhui Zhai , Minjia Tan","doi":"10.1016/j.cbpa.2025.102622","DOIUrl":"10.1016/j.cbpa.2025.102622","url":null,"abstract":"<div><div>Histone post-translational modifications (PTMs) play critical roles in regulating chromatin dynamics and gene expression. Increasing evidence demonstrates that the dysregulation of histone PTMs is closely associated with the pathogenesis of various diseases. Traditional methods for detecting histone PTMs, such as western blot (WB) and chromatin immunoprecipitation sequencing (ChIP-seq), are often limited by their dependence on specific antibodies and relatively low analytical throughput. Mass spectrometry (MS)-based proteomics offers a powerful and unbiased approach for comprehensive characterization of histone PTMs. This review focuses on the advanced development of MS-based strategies for characterizing histone PTMs. These strategies include histone extraction, enzymatic digestion, labeling, enrichment, and MS-based detection. These techniques not only enable comprehensive identification and quantitative analysis of classical modifications, such as acetylation and methylation, but also substantially facilitate the discovery of less-characterized histone PTMs, including succinylation, lactylation, crotonylation, and monoaminylation. Consequently, these findings significantly enhance the complexity of histone code. Collectively, MS-based approaches have profoundly advanced our understanding of histone PTM landscapes and their potential epigenetic regulatory mechanisms in both physiology and pathology contexts.</div></div>","PeriodicalId":291,"journal":{"name":"Current Opinion in Chemical Biology","volume":"88 ","pages":"Article 102622"},"PeriodicalIF":6.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697031","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}