RSC Chemical Biology最新文献_第6页

Dissecting the functional divergence of DCAF11 isoforms in protein degradation. 剖析DCAF11亚型在蛋白质降解中的功能差异。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-10 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00119j

Xiaokang Jin, Xiaoyu Zhang

引用次数: 0

Biosynthesis of orthoester natural products. 正畸酯天然产物的生物合成。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-06 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00155f

Yi Yang, Takayoshi Awakawa, Ikuro Abe

{"title":"Biosynthesis of orthoester natural products.","authors":"Yi Yang, Takayoshi Awakawa, Ikuro Abe","doi":"10.1039/d6cb00155f","DOIUrl":"10.1039/d6cb00155f","url":null,"abstract":"Orthoesters are unique functional groups consisting of three alkoxy substituents attached to a central carbon atom, which endow orthoester-bearing compounds with structural complexity and therapeutically valuable bioactivity. As orthoester natural products are rarely encountered in nature, their biosynthesis is poorly understood, particularly regarding the generation of their orthoester functionalities. Over the past decade, the isolation of putative biosynthetic precursors of orthoester natural products in plants and animals as well as the discovery of orthoester-forming enzymes in four species of microorganisms including bacteria and fungi have shed light on the cryptic biosynthetic machinery behind orthoester biogenesis. Protein structural analyses and biochemical enzymatic investigations have since revealed a variety of unique catalytic strategies for activating substrate scaffolds and stabilizing reactive intermediates to enable the formation of highly constrained orthoester moieties. Accordingly, this review summarizes recent advances made in the biosynthesis of orthoester natural products, highlighting the structural bases of unusual enzymatic mechanisms involved in orthoester formation. Additionally, established and putative biosynthetic pathways of prominent orthoester compounds are examined to inform future studies for discovering new orthoester natural products as well as for uncovering novel biocatalysts for the generation of orthoester compounds.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1703-1715"},"PeriodicalIF":3.9,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ribosomal RNA tentacles are targets of free radical damage in mammalian cells during oxidative and inflammatory stress. 核糖体RNA触须是哺乳动物细胞在氧化和炎症应激过程中自由基损伤的目标。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-03 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00068a

Aaron M Fleming, Justin C Dingman, Cynthia J Burrows

{"title":"Ribosomal RNA tentacles are targets of free radical damage in mammalian cells during oxidative and inflammatory stress.","authors":"Aaron M Fleming, Justin C Dingman, Cynthia J Burrows","doi":"10.1039/d6cb00068a","DOIUrl":"10.1039/d6cb00068a","url":null,"abstract":"Chemical damage to ribosomal RNA (rRNA) during oxidative or inflammatory stress can impact protein synthesis. Human cells were exposed to an H2O2 titration to induce oxidative stress, or tumor necrosis factor-α (TNF-α) over a time course to induce inflammation, followed by direct nanopore RNA sequencing of cytosolic and mitochondrial rRNAs to reveal damage sites. Guanosine (G) oxidation and deamination of adenosine to inosine (A-to-I) and cytidine to uridine (C-to-U) were identified by changes in the base-called data. Both stressors induced G oxidation in cytosolic rRNA, whereas mitochondrial rRNA was less oxidatively modified. Nitrosative stress during inflammation caused deamination lesions in rRNAs in both compartments. Inspection of highly modified sites found that GC-rich tentacles in the 28S rRNA expansion sequences were hotspots for G oxidation and C deamination in the cytosolic ribosome. Outside of tentacles, lesions generally occurred on surface nucleotides. The minimalist mitochondrial ribosome structure, compared to the cytosolic ribosome, alters reaction patterns such that nucleotides on the surface or in functionally relevant regions are damaged. These patterns suggest that tentacles on cytosolic rRNA direct reactive oxygen and nitrogen species away from the catalytic core to maintain activity during stress, while the mitochondrial ribosome is damaged in regions that can deactivate protein synthesis. These results provide molecular insight into metabolic dysfunction and suggest a new function for the GC-rich tentacles evolved in mammalian cells.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1766-1776"},"PeriodicalIF":3.9,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148431219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of acid sphingomyelinase links sphingolipid remodeling to necroptotic cell death. 抑制酸性鞘磷脂酶将鞘脂重塑与坏死性细胞死亡联系起来。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-02 eCollection Date: 2026-09-02 DOI: 10.1039/d6cb00087h

Luis Agustin E Pilapil, Shweta Chitkara, G Ekin Atilla-Gokcumen

{"title":"Inhibition of acid sphingomyelinase links sphingolipid remodeling to necroptotic cell death.","authors":"Luis Agustin E Pilapil, Shweta Chitkara, G Ekin Atilla-Gokcumen","doi":"10.1039/d6cb00087h","DOIUrl":"10.1039/d6cb00087h","url":null,"abstract":"Necroptosis is a lytic form of programmed cell death that requires activation of the RIPK1/3-MLKL complex and results in plasma membrane permeabilization. Although the protein components governing necroptosis are well defined, the lipid determinants of this process remain poorly understood. Here, we combined lipidomics, pharmacological perturbations of sphingolipid metabolism and functional assays to identify sphingolipid pathways that contribute to necroptotic cell death. Using a panel of small molecule inhibitors, we found that inhibition of acid sphingomyelinase (ASMase) with ARC39 restored cell viability and membrane integrity during necroptosis without altering canonical necroptotic signaling. Lipidomic analysis revealed that ARC39 treatment prevented ceramide accumulation in necroptosis, linking reduced ceramide levels to decreased membrane permeability. Interestingly, ARC39 treatment did not reduce total cellular levels of phosphorylated MLKL (pMLKL) nor its membrane association, suggesting that the observed decrease in membrane permeability arises downstream of MLKL activation. Instead, our findings support a model in which the reduction of ceramide levels impairs productive membrane interactions by pMLKL. Consistent with this interpretation, genetic knockdown of ASMase similarly resulted in increased cell viability, decreased membrane permeabilization, and decreased ceramide levels during necroptosis, further linking ceramide homeostasis to necroptotic membrane damage. Together, these results indicate that ASMase-derived ceramides are important for efficient MLKL-mediated membrane permeabilization in necroptosis.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1751-1765"},"PeriodicalIF":3.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148425190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemical basis of fluorogenic substrate probe design: revisiting the past to discover the new in biochemistry. 荧光底物探针设计的化学基础：回顾过去，发现新的生物化学。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-01 eCollection Date: 2026-08-05 DOI: 10.1039/d6cb00125d

Toru Komatsu, Yasuteru Urano

引用次数: 0

Exclusion of RNA-binding domains from G-quadruplex condensates by G-quadruplex ligands. g -四联体配体对g -四联体缩合物中rna结合域的排除。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-01 eCollection Date: 2026-08-05 DOI: 10.1039/d6cb00020g

Yoshiki Hashimoto, Ryosuke Suzuki, Mizuho Aya, Nagisa Takamiya, Mitsuki Tsuruta, Takeru Torii, Toshiyuki Goto, Keiko Kawauchi, Daisuke Miyoshi

{"title":"Exclusion of RNA-binding domains from G-quadruplex condensates by G-quadruplex ligands.","authors":"Yoshiki Hashimoto, Ryosuke Suzuki, Mizuho Aya, Nagisa Takamiya, Mitsuki Tsuruta, Takeru Torii, Toshiyuki Goto, Keiko Kawauchi, Daisuke Miyoshi","doi":"10.1039/d6cb00020g","DOIUrl":"10.1039/d6cb00020g","url":null,"abstract":"Biomolecular liquid-liquid phase separation, which forms droplets in living cells, plays a crucial role in the regulation of gene expression. Dysfunction of liquid-liquid phase separation leads to aberrant aggregates that sequester RNA-binding proteins, thereby impairing their functions, which potentially leads to the onset of neurodegenerative diseases. Preventing and reversing the sequestration of RNA-binding proteins from droplets represent a promising therapeutic approach. Noteworthily, the G-quadruplex, a non-canonical secondary structure of nucleic acids formed by a guanine-rich sequence, is an essential structural motif that triggers liquid-liquid phase separation with a partner protein. Thus, a G-quadruplex ligand, which selectively binds and stabilizes the G-quadruplex, can be promising for controlling liquid-liquid phase separation of G-quadruplexes and partner proteins. In this study, we investigated the effects of G-quadruplex ligands on the liquid-liquid phase separation of RNA G-quadruplexes and RGG domain-derived cationic peptides. It was found that G-quadruplex ligands formed aggregates with the target G-quadruplexes and excluded the G-quadruplex-binding peptides from these aggregates. Moreover, structure-selective G-quadruplex ligands induced aggregates only with the G-quadruplex but not with other secondary structures. These findings demonstrate for the first time that the structure-selectivity of G-quadruplex ligands plays a key role in modulating condensates.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1578-1588"},"PeriodicalIF":3.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13359080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism-based inhibition of zinc-dependent histone deacetylases. 基于机制的锌依赖性组蛋白去乙酰化酶抑制。

IF 3.9

RSC Chemical Biology Pub Date : 2026-07-01 eCollection Date: 2026-08-05 DOI: 10.1039/d6cb00150e

David W Christianson

{"title":"Mechanism-based inhibition of zinc-dependent histone deacetylases.","authors":"David W Christianson","doi":"10.1039/d6cb00150e","DOIUrl":"10.1039/d6cb00150e","url":null,"abstract":"The hallmark of a mechanism-based inhibitor is a chemical transformation that occurs upon binding in an enzyme active site that typically yields a more potent inhibitory species. A mechanism-based enzyme inhibitor can be a closely-related analogue of the native substrate, or it can be strikingly different in its structure. Here, the discovery of mechanism-based inhibitors is briefly reviewed to establish a foundation for understanding the mechanism-based inhibition of zinc-dependent histone deacetylases (HDACs), enzymes that play critical roles in epigenetics and the regulation of myriad cellular processes. Notably, the discovery of mechanism-based HDAC inhibition was an unexpected surprise emanating from X-ray crystal structures of enzyme-inhibitor complexes. In each example discussed, the C[double bond, length as m-dash]O, C[double bond, length as m-dash]N, or C[triple bond, length as m-dash]N group of an inhibitor undergoes nucleophilic attack by zinc-bound water in the same manner as the C[double bond, length as m-dash]O group of the native HDAC substrate; however, nucleophilic attack at the bound inhibitor leads to the formation of a tightly-bound enzyme-inhibitor complex. The dual requirements of steric fit as well as fitness for chemical activation can be exploited in unique strategies to enhance inhibitory potency and selectivity.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1444-1455"},"PeriodicalIF":3.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148370190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ArpA-like regulatory control and discovery of new biosynthetic genes driving scleric acid biosynthesis. 类arpa调控和新生物合成基因的发现驱动萨德尔酸的生物合成。

IF 3.9

RSC Chemical Biology Pub Date : 2026-06-26 eCollection Date: 2026-08-05 DOI: 10.1039/d6cb00137h

Jingfan Zhang, Lijiang Song, Manuela Tosin, Christophe Corre, Fabrizio Alberti

{"title":"ArpA-like regulatory control and discovery of new biosynthetic genes driving scleric acid biosynthesis.","authors":"Jingfan Zhang, Lijiang Song, Manuela Tosin, Christophe Corre, Fabrizio Alberti","doi":"10.1039/d6cb00137h","DOIUrl":"10.1039/d6cb00137h","url":null,"abstract":"Scleric acid is a natural product that was discovered by heterologous expression of the silent scl gene cluster from Streptomyces sclerotialus in Streptomyces albidoflavus and rational de-repression of the biosynthetic genes through deletion of the ArpA-like regulator SclM4. It is a weak inhibitor of the cancer-associated enzyme nicotinamide N-methyltransferase (NNMT). In this work we aimed to improve understanding of scleric acid biosynthesis and of gene regulation of the scl gene cluster. We performed CRISPR/Cas9-mediated deletion of the biosynthetic gene sclG, which confirmed the essential role of the corresponding ATP-grasp family enzyme in the biosynthesis of scleric acid. We also carried out whole-genome Nanopore long-read sequencing of S. sclerotialus to investigate the borders of the scl gene cluster, which led us to discover two additional genes, sclC and sclK, proposed to be involved in biosynthetic precursor supply. Transcriptomics analyses were performed to investigate the effect of the deletion of the ArpA-like gene sclM4 on the expression of the scl biosynthetic genes, shedding light on the role of the corresponding transcriptional repressor. The present work improves understanding of scleric acid biosynthesis and provides new insights into the ArpA-like mediated regulation of biosynthetic gene expression in Streptomyces bacteria.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1642-1649"},"PeriodicalIF":3.9,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13307308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SuFEx chemistry for nucleosides, nucleotides, and nucleic acids. 核苷、核苷酸和核酸的SuFEx化学。

IF 3.9

RSC Chemical Biology Pub Date : 2026-06-26 eCollection Date: 2026-08-05 DOI: 10.1039/d6cb00056h

Mikołaj Chromiński, Mikołaj Żmudziński, Jacek Jemielity

{"title":"SuFEx chemistry for nucleosides, nucleotides, and nucleic acids.","authors":"Mikołaj Chromiński, Mikołaj Żmudziński, Jacek Jemielity","doi":"10.1039/d6cb00056h","DOIUrl":"10.1039/d6cb00056h","url":null,"abstract":"Sulfur(vi) fluoride exchange (SuFEx) reactions were introduced as next-generation click transformations that form robust sulfur(vi)-based linkages under mild conditions. Their defining feature is the unusual behaviour of the S-F bond: it is thermodynamically stable, yet can be selectively substituted when a suitable nucleophile is properly positioned. This balance has made SuFEx a valuable platform in chemical biology, enabling novel covalent probes, inhibitors and conjugation strategies in complex aqueous environments. In contrast, SuFEx applications to nucleosides, nucleotides and nucleic acids remain comparatively scarce and are only now beginning to mature. Progress has been limited by scaffold-specific synthetic and workflow constraints, including the scarcity of broadly enabling methodological studies and limited compatibility with standard oligonucleotide workflows. Even so, recent reports show that these barriers can be overcome in selected settings and that SuFEx can be translated into functional nucleic-acid constructs. This review summarises current advances with a focus on concepts and practical design rules. The first part is chemistry-centered: it compares the most successful strategies for installing sulfur(vi)-fluoride electrophiles on nucleoside, nucleotide, and oligonucleotide frameworks, and discusses reagent choices, linker designs and warhead positioning. The second part focuses on applications, outlining how these synthetic advances are turned into chemical biology tools where proximity effects convert reversible recognition into durable capture. We conclude by highlighting key bottlenecks and the most promising opportunities for progress.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1482-1504"},"PeriodicalIF":3.9,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The structural chemistry and biosynthesis of chlorophylls. 叶绿素的结构化学和生物合成。

IF 3.9

RSC Chemical Biology Pub Date : 2026-06-25 eCollection Date: 2026-07-08 DOI: 10.1039/d6cb00082g

C Neil Hunter, Felix S Morey-Burrows

{"title":"The structural chemistry and biosynthesis of chlorophylls.","authors":"C Neil Hunter, Felix S Morey-Burrows","doi":"10.1039/d6cb00082g","DOIUrl":"10.1039/d6cb00082g","url":null,"abstract":"Chlorophylls (Chls) harvest the solar energy that drives photosynthesis, which underpins most of the food chains on our planet. Starting from protoporphyrin IX, just seven biosynthetic reactions culminate in the synthesis of Chl a, the major light-absorbing pigment on Earth. Other such pigments, Chls b, c, d and f, widen the absorption range in the visible and red regions of the spectrum, and several bacteriochlorophylls (BChls), BChls a, b and g in particular, open new spectral windows allowing organisms to harvest near infra-red light. This perspective surveys the structural features of porphyrins, chlorins and bacteriochlorins that impart their characteristic absorption features, then presents a similar analysis of the biosynthetic intermediates leading to Chls a, b, c, d and f. The interlinked Chl and BChl biosynthetic pathways are summarised, then the rest of the perspective focusses on the enzymes that synthesise Chls a, b, c, d and f. AlphaFold 3 was used to model a complete set of structures for Chl biosynthesis enzymes, predicting intersubunit associations and the arrangements of cofactors and bound substrates, and providing insights into catalytic mechanisms. A new scheme for binding substrates and transferring products between pathway enzymes suggests how synthetic biology approaches can assemble hybrid Chl and BChl pathways to expand the spectral range for harvesting and using solar energy.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" ","pages":"1134-1166"},"PeriodicalIF":3.9,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13297055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0