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Discovery and Accurate Detection of Rare Nucleic Acid Modifications 发现并准确检测罕见的核酸修饰
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-24 DOI: 10.1002/ijch.202400024
Ru-Jia Luo, Hong-Xuan Chen, Jin-Wen Kong, Zhang Zhang, Nabieh Ayoub, Guan-Zheng Luo

Nucleic acid modifications play essential roles in diverse biological processes, ranging from gene expression regulation to stress response. While traditional research focused on common modifications like methylation, recent discoveries are unveiling a wide range of rare modifications with potentially crucial functions. However, accurately detecting and mapping these modifications pose significant challenges due to their low abundance and diverse chemical properties. This article summarizes the recent discoveries of rare DNA and RNA modifications across various organisms, highlighting their potential biological significance. Furthermore, it critically evaluates the limitations of current mapping techniques, including potential sources of false positives and negatives. Finally, the article discusses emerging strategies for overcoming these challenges and future opportunities in the field of rare nucleic acid modification detection.

核酸修饰在从基因表达调控到应激反应等各种生物过程中发挥着至关重要的作用。传统的研究侧重于甲基化等常见的修饰,而最近的发现则揭示了具有潜在重要功能的各种罕见修饰。然而,由于这些修饰的丰度低、化学性质多样,准确检测和绘制这些修饰的图谱是一项重大挑战。本文总结了最近在各种生物体内发现的稀有 DNA 和 RNA 修饰,强调了它们潜在的生物学意义。此外,文章还批判性地评估了当前图谱绘制技术的局限性,包括假阳性和假阴性的潜在来源。最后,文章讨论了克服这些挑战的新策略以及稀有核酸修饰检测领域的未来机遇。
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引用次数: 0
Expanding the Scope of Ribosome-Mediated Biosynthesis in vitro using tRNA-Aminoacylating Ribozyme 利用 tRNA 氨基酰化核糖体酶扩大核糖体介导的体外生物合成的范围
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-17 DOI: 10.1002/ijch.202300174
Namjin Cho, Haneul Jin, Hyewon Jeon, Kanghun Lee, Joongoo Lee

Proteins are synthesized within ribosomes through the polymerization of amino acids (AAs). This process requires prior activation of AAs through aminoacylation that attaches them to their corresponding transfer RNAs (tRNAs). Within cells, this attachment is facilitated by aminoacyl-tRNA synthetase, resulting in a tRNA:AA conjugate. A set of ribozymes developed to acylate tRNA with non-canonical substrates enables this process outside the confines of living cells, thereby facilitating the synthesis of novel bio-based products. In modern biotechnology, aminoacylating ribozymes contribute to the production of innovative bio-based materials bearing functional non-canonical chemical substrates (NCSs) and fill the gaps in synthesizing unique polymeric backbones, extending the scope beyond traditional peptide bonds. This review summarizes current understanding of flexizymes at the molecular level and their application in generating exceptional polymeric backbones through ribosome-mediated synthesis in vitro.

蛋白质是在核糖体内通过氨基酸(AA)的聚合作用合成的。这一过程需要事先通过氨基酰化激活 AA,使其附着到相应的转移核糖核酸(tRNA)上。在细胞内,氨酰-tRNA 合成酶会促进这种连接,从而产生 tRNA:AA 共轭物。为使 tRNA 与非经典底物酰化而开发的一组核糖酶可在活细胞外实现这一过程,从而促进新型生物基产品的合成。在现代生物技术中,氨基酰化核糖酶有助于生产带有功能性非规范化学底物(NCS)的创新生物基材料,并填补了合成独特聚合物骨架的空白,将范围扩展到传统肽键之外。本综述总结了目前对柔性酶在分子水平上的理解,以及它们在通过核糖体介导的体外合成生成特殊聚合物骨架方面的应用。
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引用次数: 0
Anionic Calixarenes in Biomembrane Transport of Peptides 多肽生物膜传输中的阴离子钙钛矿
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-17 DOI: 10.1002/ijch.202400023
Justin Neumann, Andreas Hennig

Biomembranes function as hydrophobic barriers for hydrophilic substances enabling compartmentalization in biological systems. This poses, however, a problem for the targeted introduction of cargo into cells. The result is a high demand for delivery pathways into cells with the goal to investigate biological processes or to treat diseases by improved delivery. Polycationic cell-penetrating peptides (CPPs) are interesting as they can cross cell membranes and transport attached cargos directly into the cytosol. Their efficiency can be improved by anionic amphiphilic counterion activators, which bind to the CPPs to form charge-neutralized counterion-CPP complexes with sufficient hydrophobicity to cross the lipid bilayer membrane. This review summarizes recent results, which establish amphiphilic calixarenes as a new class of biocompatible and non-cytotoxic counterion activators with very high transport activities at nanomolar concentrations. We also include a brief summary of fluorescence-based assays with large unilamellar vesicles (LUVs) to investigate counterion-activated transport. Current methods use liposome-encapsulated, supramolecular host-dye reporter pairs including calixarenes, which provide new mechanistic insights and enable rapid in vitro identification of suitable activators. Taken together, amphiphilic calixarenes are currently emerging as prime candidates for counterion activation of membrane transport, which are highly modifiable and can be specifically tailored towards different cargoes and membrane types.

生物膜是亲水性物质的疏水屏障,可实现生物系统的分隔。然而,这给有针对性地将货物引入细胞带来了问题。因此,为了研究生物过程或通过改善输送来治疗疾病,对进入细胞的输送途径提出了很高的要求。多阳离子细胞穿透肽(CPPs)可以穿过细胞膜,将附着的货物直接输送到细胞质中,因此非常有趣。阴离子两亲性反离子激活剂可提高它们的效率,这种激活剂可与 CPP 结合,形成电荷中和的反离子-CPP 复合物,具有足够的疏水性,可穿过脂质双层膜。本综述总结了最近的研究成果,这些成果将两亲性钙钛矿作为一类新的生物兼容且无毒的反离子激活剂,在纳摩尔浓度下具有极高的运输活性。我们还简要介绍了基于荧光的大型单酰胺囊泡 (LUV) 检测方法,以研究反离子激活的转运。目前的方法使用脂质体封装的超分子宿主-染料报告物对(包括钙烯类),这提供了新的机理见解,并能快速体外鉴定合适的激活剂。总之,两亲性钙钛矿目前正成为反离子激活膜运输的主要候选物,它们具有高度可调控性,可专门针对不同货物和膜类型进行定制。
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引用次数: 0
Practical Applications of Supramolecular Macrocyclic Hosts in the Field of Herbal Medicines 超分子大环宿主在中草药领域的实际应用
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-14 DOI: 10.1002/ijch.202300179
Huijuan Yu, Kejing Niu, Yuting Zhao, Yuefei Wang

Herbal medicines (HMs) are gaining increasing popularity and recognition worldwide due to their eco-friendliness and efficacy. With their multi-compounds, multi-targets, and multi-pathways characteristics, HMs have been used in treatment of various diseases. However, the clinical applications of preparations containing HMs have been limited due to their inherent physicochemical properties, including low water solubility, poor stability, and unsatisfactory bioavailability of bioactive compounds. Supramolecular macrocyclic hosts, like cyclodextrins, calixarenes, cucurbiturils, and pillararenes, are important objects of researches in supramolecular chemistry. These hosts have been utilized to encapsulate the ingredients, improve the solubility of poorly water-soluble components, enhance the stability of the tested compounds, increase the bioavailability of bioactive compounds, and ensure the safety of HMs. Herein, we provide a brief introduction to the theories of supramolecular chemistry and summarize the extensive applications of supramolecular macrocyclic hosts in the field of HMs. These applications encompass the screening of bioactive compounds in HMs and the enhancement of druggability for HMs. We hope this review can provide a strategy for dealing with the challenges of HMs, thereby enabling their better applications and development.

草药(HMs)因其生态友好性和疗效日益受到全世界的欢迎和认可。HMs 具有多化合物、多靶点和多途径的特点,已被用于治疗各种疾病。然而,由于其固有的理化特性,包括水溶性低、稳定性差、生物活性化合物的生物利用度不理想等,含有 HMs 的制剂的临床应用一直受到限制。超分子大环宿主,如环糊精、钙烯、葫芦烯和支柱烯,是超分子化学研究的重要对象。这些宿主被用来封装成分,改善水溶性差的成分的溶解性,提高被测化合物的稳定性,增加生物活性化合物的生物利用度,并确保 HMs 的安全性。在此,我们简要介绍了超分子化学理论,并总结了超分子大环宿主在 HMs 领域的广泛应用。这些应用包括在 HMs 中筛选生物活性化合物和提高 HMs 的可药性。我们希望这篇综述能为应对 HMs 的挑战提供策略,从而使 HMs 得到更好的应用和发展。
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引用次数: 0
The Great Codon Escape: Vacating Codons for Genetic Code Expansion and Ribosome Stalling 密码子大逃亡空缺密码子促进遗传密码扩展和核糖体停滞
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-12 DOI: 10.1002/ijch.202400012
Antonius J. P. Hopstaken, Enno Große Wichtrup, Dr. Seino A. K. Jongkees

In ribosomal synthesis of peptides and proteins, genetic information is translated into an amino acid polymer according to the genetic code, which describes the translational command encoded by each codon. However, parts of the genetic code can be adjusted to customize translations. One option is to remove decoding for a specific codon, resulting in a vacant codon. Such vacant codons can be used to stall the ribosome for mechanistic studies and display techniques. Alternatively, the liberated codon can be assigned to encode for incorporation of a noncanonical building block for expansion of the genetic code. In this review we provide an overview of the methods currently available for vacating codons in prokaryotic translation (agnostic of how these are later applied), targeting factors such as amino-acyl tRNA synthetases, tRNA, release factors, and the initiation machinery. Moreover, we assess applicability and compatibility of the currently available techniques and discuss which have the potential to develop into even more powerful approaches in the future.

在核糖体合成肽和蛋白质的过程中,遗传信息会根据遗传密码被翻译成氨基酸聚合物,遗传密码描述了每个密码子所编码的翻译指令。不过,遗传密码的部分内容可以调整,以定制翻译。一种方法是取消对特定密码子的解码,从而产生空缺密码子。这种空置的密码子可用于阻滞核糖体进行机理研究和展示技术。另外,释放的密码子也可用于编码非规范构建模块,以扩展遗传密码。在这篇综述中,我们概述了目前可用于原核翻译中空位密码子的方法(与这些方法以后如何应用无关),这些方法针对的因素包括氨基酰 tRNA 合成酶、tRNA、释放因子和启动机制。此外,我们还评估了现有技术的适用性和兼容性,并讨论了哪些技术有可能在未来发展成为更强大的方法。
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引用次数: 0
Supramolecular Approaches to the Detoxification of Nerve Agents 神经毒剂的超分子解毒方法
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-11 DOI: 10.1002/ijch.202400019
Prof. Dr. Stefan Kubik

A promising, but not yet practiced, approach to the treatment of neurotoxic organophosphate poisoning is the administration of a scavenger that rapidly deactivates the nerve agent before it can exert its toxic effects. The detoxification rates required for successful use of this therapy can currently only be achieved with enzymes, but synthetic scavengers, whose mode of action is based on key concepts of supramolecular chemistry, are an attractive alternative. Considerable progress has recently been made in the development of such scavengers, and compounds from several receptor classes are now available that not only bind nerve agents but also degrade them at promising rates. This review provides an overview of the field and highlights recent developments.

治疗神经毒性有机磷中毒的一种前景广阔但尚未付诸实践的方法是施用一种清除剂,在神经毒剂产生毒性作用之前迅速使其失活。目前,只有酶才能达到成功使用这种疗法所需的解毒率,但合成清除剂的作用模式基于超分子化学的关键概念,是一种有吸引力的替代方法。最近,此类清除剂的研发取得了长足的进步,目前已有多种受体类别的化合物不仅能与神经毒剂结合,还能以可喜的速度降解神经毒剂。本综述概述了这一领域,并重点介绍了最新进展。
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引用次数: 0
Spatially and Single-Cell Resolved Profiling of RNA Life Cycle and Epitranscriptomics 以空间和单细胞分辨率剖析 RNA 生命周期和外显子转录组学
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-06-03 DOI: 10.1002/ijch.202400028
Qiyang Zhou, Jianting Guo, Xiao Wang

The intricate network of cell functions relies on gene expression programs, where the whole RNA life cycle from DNA to protein is subjected to extensive transcriptional and post-transcriptional gene regulation events. Established bulk RNA sequencing methods provide an averaged, transcriptome-wide quantification of the RNA life cycle, including transcription, processing, translation, transport, and degradation through RNA-protein interactions. Furthermore, numerous studies using bulk epitranscriptomic profiling unveiled that dynamic RNA modifications (e. g., N6-Methyladenosine), add another layer of gene regulations. However, many regulatory events are cell-type specific, subcellularly localized, and subjected to cell-cell communications within the native tissue environment. Thanks to the advances in single-cell sequencing, spatial sequencing, and highly multiplexed imaging methods, we can routinely measure single-cell and spatial transcriptomics. Yet more comprehensive methods to profile every step of the RNA life cycle with single-cell and spatial information are still lacking. In this review, we will summarize and compare early explorations in developing state-of-the-art methods for spatially and single-cell resolved mapping of RNA kinetics, translation, RNA-protein interactions, and epitranscriptomics. It is promising that these new techniques will greatly facilitate our understanding of the RNA-centered regulation landscapes in different cell types and how the post-transcriptional regulations are interconnected within cellular and tissue architecture.

细胞功能的复杂网络依赖于基因表达程序,从 DNA 到蛋白质的整个 RNA 生命周期都受到大量转录和转录后基因调控事件的影响。现有的大容量 RNA 测序方法可提供 RNA 生命周期的平均、全转录组量化,包括转录、加工、翻译、转运以及通过 RNA 蛋白相互作用的降解。此外,许多使用大容量表转录组剖析的研究揭示,动态 RNA 修饰(如 N6-甲基腺苷)增加了基因调控的另一层含义。然而,许多调控事件具有细胞类型特异性、亚细胞定位性,并受制于原生组织环境中的细胞间通讯。由于单细胞测序、空间测序和高度复用成像方法的进步,我们可以对单细胞和空间转录组学进行常规测量。然而,利用单细胞和空间信息对 RNA 生命周期的每一步进行剖析的更全面的方法仍然缺乏。在这篇综述中,我们将总结和比较在开发最先进的 RNA 动力学、翻译、RNA 蛋白相互作用和表观转录组学空间和单细胞解析图谱方法方面的早期探索。这些新技术有望极大地促进我们对不同细胞类型中以 RNA 为中心的调控图谱以及转录后调控如何在细胞和组织结构中相互关联的理解。
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引用次数: 0
Direct, Quantitative, and Base-Resolution Sequencing of DNA and RNA Modifications 对 DNA 和 RNA 修饰进行直接、定量和碱基分辨率测序
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-05-31 DOI: 10.1002/ijch.202400007
Haiqi Xu, Chun-Xiao Song

Cellular DNA and RNA are decorated with diverse chemical modifications, which add new layers to gene regulation and play crucial roles across development and disease progression. Interest in understanding the functions of DNA and RNA modifications, as well as the related molecular mechanisms, has been growing, driving progress in developing chemical and biochemical tools to detect specific modifications. New technologies are important not only for uncovering biological functions, but also for driving conceptual revolutions. In this review, we highlighted our recent advances in developing new chemical tools to detect DNA and RNA modifications in a direct, quantitative, and base-resolution manner. These includes a novel borane reduction chemistry for DNA methylation sequencing; new cytosine modificaiton oxdation chemistry for enhanced DNA hydroxymethylation sequencing; and a novel bromoacrylamide cyclization chemistry for RNA pseudouridylation sequencing. We present a mechanistic overview of these tools and their applications in epigenetic and epitranscriptomic research.

细胞 DNA 和 RNA 上有多种多样的化学修饰,它们为基因调控增添了新的层次,并在发育和疾病进程中发挥着至关重要的作用。人们对了解 DNA 和 RNA 修饰的功能以及相关分子机制的兴趣与日俱增,推动了检测特定修饰的化学和生化工具的开发进展。新技术不仅对揭示生物功能很重要,而且对推动概念革命也很重要。在这篇综述中,我们重点介绍了最近在开发新的化学工具以直接、定量和碱基分辨的方式检测 DNA 和 RNA 修饰方面取得的进展。其中包括用于 DNA 甲基化测序的新型硼烷还原化学;用于增强 DNA 羟甲基化测序的新型胞嘧啶修饰氧化化学;以及用于 RNA 伪尿嘧啶化测序的新型溴丙烯酰胺环化化学。我们从机理上概述了这些工具及其在表观遗传学和表观转录组学研究中的应用。
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引用次数: 0
Ethnic Variation and Structure‐Function Analysis of Tauopathy‐Associated PERK Alleles 与 Tauopathy 相关的 PERK 等位基因的种族差异和结构功能分析
IF 3.2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-05-24 DOI: 10.1002/ijch.202300173
Goonho Park, Angela Galdamez, Keon‐Hyoung Song, Masako Le, Kyle Kim, Jonathan H. Lin
EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss‐of‐function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS‐MODEL, we identified structural perturbations in the ER stress‐sensing luminal domain dimers/oligomers of tauopathy‐associated PERK variants, Haplotypes A and B, in combination with another tauopathy‐linked R240H mutation. Recombinant expression of disease‐associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non‐disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.
EIF2AK3 又称 PERK,在细胞蛋白稳态中发挥着关键作用,协调着折叠蛋白反应(UPR)和综合应激反应(ISR)途径。除了在细胞内应力调控中的核心地位外,人类 GWAS 还发现 EIF2AK3 是 tau 病(由 tau 蛋白异常积累引起的神经退行性疾病)的风险因素。在这些基因组指标的指导下,我们的研究对人类 PERK 变异进行了系统分析,重点关注那些与牛头蛋白病有潜在联系的变异。我们参考 gnomAD、Ensembl 和 NCBI 数据库,收集了与 Wolcott Rallison 综合征(WRS)、tauopathies 和生物信息学预测的功能缺失相关的人类 PERK 变异的综合数据集。我们发现,与陶陶病相关的常见 PERK 多态性的发生率存在广泛的种族/民族差异。利用 SWISS-MODEL,我们确定了与牛磺酸脑病相关的 PERK 变体 Haplotypes A 和 B 与另一种与牛磺酸脑病相关的 R240H 突变相结合的 ER 应激传感腔域二聚体/高聚体的结构扰动。在体外重组表达疾病相关变体时发现,与占主导地位的非疾病变体相比,PERK 信号转导动力学对 ER 压力的响应发生了改变。总之,我们的数据进一步证实,在牛磺酸脑病基因研究中发现的人类 PERK 变异对 PERK 的结构、功能和下游信号转导产生了负面影响,而且在不同种族和民族群体中的发生率存在显著差异。
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引用次数: 0
Porous Crystalline Organic Cages Made by Design 设计制造的多孔结晶有机笼
IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-05-15 DOI: 10.1002/ijch.202400025
Dr. Svetlana Ivanova, Prof. Dr. Florian Beuerle

Shape-persistent organic cages are an intriguing class of molecular porous materials. Through hierarchical molecular design, size and shape of the intrinsic molecular voids are controlled by dynamic covalent chemistry, while pore structure and topology are governed by noncovalent alignment in the solid state. However, the predictable and reliable crystallization of organic cages is still challenging since long-range superstructures are solely based on weak and rather unidirectional supramolecular interactions. In this tutorial review, we provide a general classification of porous solid-state materials and discuss specific design principles regarding the dynamic covalent reactions, the small-molecule building blocks and solid-state engineering. Furthermore, we introduce the most important analytical techniques for porous materials with a special focus on organic cages.

形状持久的有机笼是一类引人入胜的分子多孔材料。通过分层分子设计,固有分子空隙的大小和形状由动态共价化学反应控制,而孔隙结构和拓扑则由固态非共价排列控制。然而,有机笼的可预测和可靠结晶仍然具有挑战性,因为长程超结构完全基于微弱和相当单向的超分子相互作用。在这篇教程综述中,我们对多孔固态材料进行了总体分类,并讨论了有关动态共价反应、小分子构建模块和固态工程的具体设计原则。此外,我们还介绍了多孔材料最重要的分析技术,并特别关注有机笼。
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引用次数: 0
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Israel Journal of Chemistry
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