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Discovery and biosynthesis of non-canonical C16-terpenoids from Pseudomonas 从假单胞菌中发现非典型 C16-三萜类化合物并进行生物合成
IF 8.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.chembiol.2024.09.002
Xu-Hua Mo, Qing-Yin Pu, Tilo Lübken, Gui-Hong Yu, Mert Malay, Paul M. D’Agostino, Tobias A.M. Gulder
Biosynthesis of sodorifen with a unique C16-bicyclo[3.2.1]octene framework requires an S-adenosyl methionine-dependent methyltransferase SodC and terpene cyclase SodD. While bioinformatic analyses reveal a wide distribution of the sodCD genes organization in bacteria, their functional diversity remains largely unknown. Herein, two sodorifen-type gene clusters, pcch and pcau, from Pseudomonas sp. are heterologously expressed in Escherichia coli, leading to the discovery of two C16 terpenoids. Enzymatic synthesis of these compounds is achieved using the two (SodCD-like) pathway-specific enzymes. Enzyme assays using different combinations of methyltransferases and terpene synthases across the pcch, pcau, and sod pathways reveal a unifying biosynthetic mechanism: all three SodC-like enzymes methylate farnesyl pyrophosphate (FPP) with subsequent cyclization to a common intermediate, pre-sodorifen pyrophosphate. Structural diversification of this joint precursor solely occurs by the subsequently acting individual terpene synthases. Our findings expand basic biosynthetic understanding and structural diversity of unusual C16-terpenoids.
具有独特 C16-双环[3.2.1]辛烯框架的索多里芬的生物合成需要依赖 S-腺苷蛋氨酸的甲基转移酶 SodC 和萜烯环化酶 SodD。虽然生物信息学分析表明 SodCD 基因在细菌中广泛分布,但它们的功能多样性在很大程度上仍然未知。在本文中,来自假单胞菌的两个 sodorifen 型基因簇 pcch 和 pcau 在大肠杆菌中进行了异源表达,从而发现了两种 C16 类萜类化合物。这两种(类似 SodCD)途径特异性酶实现了这些化合物的酶合成。利用 pcch、pcau 和 sod 途径中不同组合的甲基转移酶和萜烯合成酶进行的酶测定揭示了一种统一的生物合成机制:所有三种 SodC 样酶都将焦磷酸法尼酯(FPP)甲基化,随后环化成一种共同的中间体--焦磷酸前索多瑞芬。这种联合前体的结构多样化仅通过随后作用的单个萜烯合成酶来实现。我们的发现拓展了对不常见的 C16-萜类化合物的基本生物合成认识和结构多样性。
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引用次数: 0
Mechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration 微生物衍生代谢物对神经退行性病变产生影响的机制
IF 8.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1016/j.chembiol.2024.08.014
Lara Kern, Ignacio Mastandrea, Anna Melekhova, Eran Elinav
Recent developments in microbiome research suggest that the gut microbiome may remotely modulate central and peripheral neuronal processes, ranging from early brain development to age-related changes. Dysbiotic microbiome configurations have been increasingly associated with neurological disorders, such as neurodegeneration, but causal understanding of these associations remains limited. Most mechanisms explaining how the microbiome may induce such remote neuronal effects involve microbially modulated metabolites that influx into the ‘sterile’ host. Some metabolites are able to cross the blood-brain barrier (BBB) to reach the central nervous system, where they can impact a variety of cells and processes. Alternatively, metabolites may directly signal to peripheral nerves to act as neurotransmitters or exert modulatory functions, or impact immune responses, which, in turn, modulate neuronal function and associated disease propensity. Herein, we review the current knowledge highlighting microbiome-modulated metabolite impacts on neuronal disease, while discussing unknowns, controversies and prospects impacting this rapidly evolving research field.
微生物组研究的最新进展表明,肠道微生物组可能会远程调节中枢和外周神经元过程,包括从早期大脑发育到与年龄相关的变化。微生物组配置失调与神经系统疾病(如神经变性)的关系日益密切,但对这些关联的因果关系的了解仍然有限。解释微生物群如何诱发神经元远端效应的大多数机制都涉及微生物调节的代谢物流入 "无菌 "宿主体内。一些代谢物能够穿过血脑屏障(BBB)到达中枢神经系统,对各种细胞和过程产生影响。另外,代谢物也可能直接向周围神经发出信号,充当神经递质或发挥调节功能,或影响免疫反应,进而调节神经元功能和相关疾病倾向。在此,我们将回顾目前的知识,重点介绍微生物组调控的代谢物对神经元疾病的影响,同时讨论影响这一快速发展的研究领域的未知因素、争议和前景。
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引用次数: 0
The next Nobel Prize in chemistry or in physiology or medicine 下一个诺贝尔化学奖、生理学奖或医学奖
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.013

In early October, the Nobel Prizes will honor groundbreaking discoveries. After the anticipated recognition of Katalin Karikó and Drew Weissman in 2023 for the development of RNA modifications that enabled the SARS-CoV-2 mRNA vaccine, we eagerly consider the next topics to be awarded. In the September 30th anniversary special issue of Cell Chemical Biology, we ask researchers from a range of backgrounds, what topic do you think deserves the next Nobel Prize in chemistry or in physiology or medicine, and why?

十月初,诺贝尔奖将表彰突破性的发现。在卡塔林-卡里科(Katalin Karikó)和德鲁-魏斯曼(Drew Weissman)因开发RNA修饰技术使SARS-CoV-2 mRNA疫苗得以实现而有望在2023年获得诺贝尔奖之后,我们热切地考虑着下一个获奖课题。在 9 月 30 日的《细胞化学生物学》周年特刊上,我们向来自不同背景的研究人员提问:您认为下一个诺贝尔化学奖、生理学奖或医学奖应该授予哪个主题,为什么?
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引用次数: 0
The best of both worlds: Chemigenetic fluorescent sensors for biological imaging 两全其美:用于生物成像的化学基因荧光传感器
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.002

Synthetic-based fluorescent chemosensors and protein-based fluorescent biosensors are two well-established classes of tools for visualizing and monitoring biological processes in living tissues. Chemigenetic sensors, created using a combination of both synthetic parts and protein parts, are an emerging class of tools that aims to combine the strengths, and overcome the drawbacks, of traditional chemosensors and biosensors. This review will survey the landscape of strategies used for fluorescent chemigenetic sensor design. These strategies include: attachment of synthetic elements to proteins using in vitro protein conjugation; attachment of synthetic elements to proteins using autonomous protein labeling; and translational incorporation of unnatural amino acids.

基于合成的荧光化学传感器和基于蛋白质的荧光生物传感器是可视化和监测活体组织中生物过程的两类成熟工具。化学基因传感器由合成部分和蛋白质部分组合而成,是一类新兴的工具,旨在结合传统化学传感器和生物传感器的优点并克服其缺点。本综述将对用于荧光化学基因传感器设计的策略进行概述。这些策略包括:利用体外蛋白质共轭将合成元素附着到蛋白质上;利用自主蛋白质标记将合成元素附着到蛋白质上;以及非天然氨基酸的转化结合。
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引用次数: 0
Prephenate decarboxylase: An unexplored branchpoint to unusual natural products Prephenate decarboxylase:通向不寻常天然产物的一个尚未探索的分支点
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.06.015

Prephenate decarboxylases are a small family of enzymes which initiate a specialized divergence from the shikimate pathway, where prephenate (2) is decarboxylated without aromatization. In addition to effecting a challenging chemical transformation, prephenate decarboxylases have been implicated in the production of rare specialized metabolites, sometimes directly constructing bioactive warheads. Many of the biosynthetic steps to natural products derived from prephenate decarboxylases remain elusive. Here, we review prephenate decarboxylase research thus far and highlight natural products that may be derived from biosynthetic pathways involving prephenate decarboxylases. We also highlight commonly encountered challenges in the structure elucidation of these natural products. Prephenate decarboxylases are a gateway into understudied biosynthetic pathways which present a high potential for the discovery of novel and bioactive natural products, as well as new biosynthetic enzymes.

预铼酸脱羧酶是一个小的酶家族,它启动了莽草酸途径的专门分化,在该途径中,预铼酸(2)被脱羧而不芳香化。除了进行具有挑战性的化学转化外,预苯甲酸脱羧酶还参与生产罕见的特殊代谢物,有时直接构建具有生物活性的弹头。由前铼酸盐脱羧酶衍生出的天然产物的许多生物合成步骤仍然难以捉摸。在此,我们回顾了迄今为止的预苯甲酸脱羧酶研究,并重点介绍了可能从涉及预苯甲酸脱羧酶的生物合成途径中提取的天然产物。我们还重点介绍了在这些天然产物的结构阐释过程中通常会遇到的挑战。预铼酸脱羧酶是进入未被充分研究的生物合成途径的一个通道,它为发现新型和具有生物活性的天然产物以及新的生物合成酶提供了巨大的潜力。
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引用次数: 0
The physiological and pathological roles of RNA modifications in T cells T 细胞中 RNA 修饰的生理和病理作用
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.06.003

RNA molecules undergo dynamic chemical modifications in response to various external or cellular stimuli. Some of those modifications have been demonstrated to post-transcriptionally modulate the RNA transcription, localization, stability, translation, and degradation, ultimately tuning the fate decisions and function of mammalian cells, particularly T cells. As a crucial part of adaptive immunity, T cells play fundamental roles in defending against infections and tumor cells. Recent findings have illuminated the importance of RNA modifications in modulating T cell survival, proliferation, differentiation, and functional activities. Therefore, understanding the epi-transcriptomic control of T cell biology enables a potential avenue for manipulating T cell immunity. This review aims to elucidate the physiological and pathological roles of internal RNA modifications in T cell development, differentiation, and functionality drawn from current literature, with the goal of inspiring new insights for future investigations and providing novel prospects for T cell-based immunotherapy.

RNA 分子在各种外部或细胞刺激下会发生动态化学修饰。其中一些修饰已被证明能在转录后调节 RNA 的转录、定位、稳定性、翻译和降解,最终调整哺乳动物细胞(尤其是 T 细胞)的命运决定和功能。作为适应性免疫的重要组成部分,T 细胞在抵御感染和肿瘤细胞方面发挥着重要作用。最近的研究结果表明,RNA 修饰在调节 T 细胞存活、增殖、分化和功能活动方面非常重要。因此,了解 T 细胞生物学的表转录组控制是操纵 T 细胞免疫的潜在途径。本综述旨在从现有文献中阐明内部 RNA 修饰在 T 细胞发育、分化和功能中的生理和病理作用,目的是为未来的研究提供新的见解,并为基于 T 细胞的免疫疗法提供新的前景。
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引用次数: 0
RNA and condensates: Disease implications and therapeutic opportunities RNA 和凝结物:疾病影响和治疗机会
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.009

Biomolecular condensates are dynamic membraneless organelles that compartmentalize proteins and RNA molecules to regulate key cellular processes. Diverse RNA species exert their effects on the cell by their roles in condensate formation and function. RNA abnormalities such as overexpression, modification, and mislocalization can lead to pathological condensate behaviors that drive various diseases, including cancer, neurological disorders, and infections. Here, we review RNA’s role in condensate biology, describe the mechanisms of RNA-induced condensate dysregulation, note the implications for disease pathogenesis, and discuss novel therapeutic strategies. Emerging approaches to targeting RNA within condensates, including small molecules and RNA-based therapies that leverage the unique properties of condensates, may revolutionize treatment for complex diseases.

生物分子凝聚体是一种动态的无膜细胞器,可将蛋白质和 RNA 分子分隔开来,从而调节关键的细胞过程。各种 RNA 在凝聚体的形成和功能中发挥作用,从而对细胞产生影响。RNA 的异常,如过度表达、修饰和错误定位,可导致病理凝聚态行为,从而引发各种疾病,包括癌症、神经系统疾病和感染。在此,我们将回顾 RNA 在凝集素生物学中的作用,描述 RNA 诱导的凝集素失调机制,指出其对疾病发病机制的影响,并讨论新的治疗策略。针对凝集物中 RNA 的新方法,包括利用凝集物独特性质的小分子和基于 RNA 的疗法,可能会彻底改变复杂疾病的治疗方法。
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引用次数: 0
What is chemical biology? 什么是化学生物学?
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.011

Since its inception, the chemical biology field has undergone significant evolution, with its definition varying greatly based on individual perspectives. For the September 30th anniversary special issue of Cell Chemical Biology, we asked our readers from a range of backgrounds, what is chemical biology?

自诞生以来,化学生物学领域经历了重大演变,其定义也因个人观点的不同而大相径庭。在 9 月 30 日的《细胞化学生物学》周年特刊上,我们向来自不同背景的读者提问:什么是化学生物学?
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引用次数: 0
Ligand discovery by activity-based protein profiling 通过基于活性的蛋白质分析发现配体
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.006

Genomic technologies have led to massive gains in our understanding of human gene function and disease relevance. Chemical biologists are a primary beneficiary of this information, which can guide the prioritization of proteins for chemical probe and drug development. The vast functional and structural diversity of disease-relevant proteins, however, presents challenges for conventional small molecule screening libraries and assay development that in turn raise questions about the broader “druggability” of the human proteome. Here, we posit that activity-based protein profiling (ABPP), by generating global maps of small molecule-protein interactions in native biological systems, is well positioned to address major obstacles in human biology-guided chemical probe and drug discovery. We will support this viewpoint with case studies highlighting a range of small molecule mechanisms illuminated by ABPP that include the disruption and stabilization of biomolecular (protein-protein/nucleic acid) interactions and underscore allostery as a rich source of chemical tools for historically “undruggable” protein classes.

基因组技术使我们对人类基因功能和疾病相关性的了解大为提高。化学生物学家是这些信息的主要受益者,这些信息可以指导我们优先选择蛋白质进行化学探针和药物开发。然而,与疾病相关的蛋白质在功能和结构上具有巨大的多样性,这给传统的小分子筛选库和检测开发带来了挑战,反过来又对人类蛋白质组更广泛的 "可药用性 "提出了质疑。在这里,我们认为基于活性的蛋白质分析(ABPP)通过生成原生生物系统中小分子与蛋白质相互作用的全局图,可以很好地解决以人类生物学为指导的化学探针和药物发现中的主要障碍。我们将通过案例研究来支持这一观点,重点介绍 ABPP 所揭示的一系列小分子机制,包括生物分子(蛋白质-蛋白质/核酸)相互作用的破坏和稳定,并强调异构体是化学工具的丰富来源,可用于历史上 "不可药用 "的蛋白质类别。
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引用次数: 0
Reflections from advisory board members and associate editors 顾问委员会成员和副主编的思考
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.015

For the celebration of the 30th anniversary of Cell Chemical Biology, in the September special issue, we asked former and current advisory board members and former editors to reflect on the advancements in chemical biology, changes in the field, and their insights into Cell Chemical Biology (originally Chemistry & Biology).

为庆祝《细胞化学生物学》创刊 30 周年,我们在 9 月特刊中请前任和现任顾问委员会成员以及前任编辑回顾了化学生物学的进步、该领域的变化以及他们对《细胞化学生物学》(原名《化学与生物学》)的见解。
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引用次数: 0
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Cell Chemical Biology
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