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The general transcription factors (GTFs) of RNA polymerase II and their roles in plant development and stress responses. RNA 聚合酶 II 的一般转录因子 (GTFs) 及其在植物发育和胁迫反应中的作用。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-03 DOI: 10.1080/10409238.2024.2408562
Shivam Sharma, Sanjay Kapoor, Athar Ansari, Akhilesh Kumar Tyagi

In eukaryotes, general transcription factors (GTFs) enable recruitment of RNA polymerase II (RNA Pol II) to core promoters to facilitate initiation of transcription. Extensive research in mammals and yeast has unveiled their significance in basal transcription as well as in diverse biological processes. Unlike mammals and yeast, plant GTFs exhibit remarkable degree of variability and flexibility. This is because plant GTFs and GTF subunits are often encoded by multigene families, introducing complexity to transcriptional regulation at both cellular and biological levels. This review provides insights into the general transcription mechanism, GTF composition, and their cellular functions. It further highlights the involvement of RNA Pol II-related GTFs in plant development and stress responses. Studies reveal that GTFs act as important regulators of gene expression in specific developmental processes and help equip plants with resilience against adverse environmental conditions. Their functions may be direct or mediated through their cofactor nature. The versatility of GTFs in controlling gene expression, and thereby influencing specific traits, adds to the intricate complexity inherent in the plant system.

在真核生物中,一般转录因子(GTFs)能将 RNA 聚合酶 II(RNA Pol II)招募到核心启动子上,从而促进转录的启动。对哺乳动物和酵母的广泛研究揭示了它们在基础转录和各种生物过程中的重要作用。与哺乳动物和酵母不同,植物 GTFs 具有显著的变异性和灵活性。这是因为植物 GTFs 和 GTF 亚基通常由多基因家族编码,从而在细胞和生物水平上给转录调控带来了复杂性。本综述深入探讨了一般转录机制、GTF 的组成及其细胞功能。它进一步强调了与 RNA Pol II 相关的 GTFs 在植物发育和胁迫响应中的参与。研究表明,GTFs 是特定发育过程中基因表达的重要调控因子,有助于增强植物抵御不利环境条件的能力。它们的功能可能是直接的,也可能是通过其辅助因子介导的。GTFs 在控制基因表达从而影响特定性状方面的多功能性增加了植物系统固有的复杂性。
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引用次数: 0
Methanogens and what they tell us about how life might survive on Mars. 甲烷菌及其对火星生命生存方式的启示。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-11-03 DOI: 10.1080/10409238.2024.2418639
Chellapandi Paulchamy, Sreekutty Vakkattuthundi Premji, Saranya Shanmugam

Space exploration and research are uncovering the potential for terrestrial life to survive in outer space, as well as the environmental factors that affect life during interplanetary transfer. The presence of methane in the Martian atmosphere suggests the possibility of methanogens, either extant or extinct, on Mars. Understanding how methanogens survive and adapt under space-exposed conditions is crucial for understanding the implications of extraterrestrial life. In this article, we discuss methanogens as model organisms for obtaining energy transducers and producing methane in a simulated Martian environment. We also explore the chemical evolution of cellular composition and growth maintenance to support survival in extraterrestrial environments. Neutral selective pressure is imposed on the chemical composition of cellular components to increase cell survival and reduce growth under physiological conditions. Energy limitation is an evolutionary driver of macromolecular polymerization, growth maintenance, and survival fitness of methanogens. Methanogens grown in a Martian environment may exhibit global alterations in their metabolic function and gene expression at the system scale. A space systems biology approach would further elucidate molecular survival mechanisms and adaptation to a drastic outer space environment. Therefore, identifying a genetically stable methanogenic community is essential for biomethane production from waste recycling to achieve sustainable space-life support functions.

太空探索和研究正在揭示地球生命在外太空生存的潜力,以及在星际转移过程中影响生命的环境因素。火星大气中存在甲烷,这表明火星上可能存在现存或已灭绝的甲烷菌。了解甲烷菌如何在太空暴露条件下生存和适应,对于了解地外生命的影响至关重要。在本文中,我们将讨论甲烷菌作为在模拟火星环境中获取能量转换器和生产甲烷的模式生物。我们还探讨了细胞组成和生长维持的化学进化,以支持在地外环境中的生存。在生理条件下,细胞成分的化学组成受到中性选择压力,以提高细胞存活率并降低生长速度。能量限制是甲烷菌大分子聚合、生长维持和生存能力的进化驱动力。在火星环境中生长的甲烷菌可能会在系统尺度上表现出代谢功能和基因表达的全面改变。空间系统生物学方法将进一步阐明分子生存机制和对恶劣外太空环境的适应性。因此,确定一个基因稳定的甲烷菌群落对于利用废物循环生产生物甲烷以实现可持续的太空生命支持功能至关重要。
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引用次数: 0
Mechanisms of immune evasion by Mycobacterium tuberculosis: the impact of T7SS and cell wall lipids on host defenses. 结核分枝杆菌逃避免疫的机制:T7SS 和细胞壁脂质对宿主防御的影响。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-08 DOI: 10.1080/10409238.2024.2411264
Asrar Ahmad Malik, Mohd Shariq, Javaid Ahmad Sheikh, Udyeshita Jaiswal, Haleema Fayaz, Gauri Shrivastava, Nasreen Z Ehtesham, Seyed E Hasnain

Mycobacterium tuberculosis (M. tb) is one of the most successful human pathogens, causing a severe and widespread infectious disease. The frequent emergence of multidrug-resistant (MDR) strains has exacerbated this public health crisis, particularly in underdeveloped regions. M. tb employs a sophisticated array of virulence factors to subvert host immune responses, both innate and adaptive. It utilizes the early secretory antigenic target (ESAT6) secretion system 1 (ESX-1) type VII secretion system (T7SS) and cell wall lipids to disrupt phagosomal integrity, inhibiting phagosome maturation, and fusion with lysosomes. Although host cells activate mechanisms such as ubiquitin (Ub), Ub-ligase, and cyclic GMP-AMP synthase-stimulator of interferon genes 1 (CGAS-STING1)-mediated autophagy to inhibit M. tb survival within macrophages, the pathogen counteracts these defenses with its own virulence factors, thereby inhibiting autophagy and dampening host-directed responses. T7SSs are critical for transporting proteins across the complex mycobacterial cell envelope, performing essential functions, including metabolite uptake, immune evasion, and conjugation. T7SS substrates fall into two main families: ESAT-6 system proteins, which are found in both Firmicutes and Actinobacteria, and proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) proteins, which are unique to mycobacteria. Recent studies have highlighted the significance of T7SSs in mycobacterial growth, virulence, and pathogenesis. Understanding the mechanisms governing T7SSs could pave the way for novel therapeutic strategies to combat mycobacterial diseases, including tuberculosis (TB).

结核分枝杆菌(M. tb)是最成功的人类病原体之一,可引起严重而广泛的传染病。耐多药(MDR)菌株的频繁出现加剧了这一公共卫生危机,尤其是在欠发达地区。结核杆菌利用一系列复杂的毒力因子来破坏宿主的先天性和适应性免疫反应。它利用早期分泌抗原靶标(ESAT6)分泌系统 1(ESX-1)VII 型分泌系统(T7SS)和细胞壁脂质破坏吞噬体的完整性,抑制吞噬体的成熟以及与溶酶体的融合。虽然宿主细胞会激活泛素(Ub)、Ub 连接酶和环 GMP-AMP 合成酶-干扰素基因 1(CGAS-STING1)介导的自噬等机制来抑制 M. tb 在巨噬细胞内的存活,但病原体会用自身的毒力因子来抵消这些防御措施,从而抑制自噬并抑制宿主定向反应。T7SS 对于在复杂的分枝杆菌细胞包膜上转运蛋白质至关重要,可发挥重要功能,包括代谢物吸收、免疫逃避和连接。T7SS 底物分为两大类:ESAT-6 系统蛋白存在于固氮菌和放线菌中,而脯氨酸-谷氨酸(PE)和脯氨酸-脯氨酸-谷氨酸(PPE)蛋白则是分枝杆菌所特有的。最近的研究强调了 T7SS 在分枝杆菌生长、毒力和致病过程中的重要作用。了解 T7SSs 的作用机制可为制定新型治疗策略以防治包括结核病在内的分枝杆菌疾病铺平道路。
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引用次数: 0
Evolution, classification, and mechanisms of transport, activity regulation, and substrate specificity of ZIP metal transporters. ZIP 金属转运体的进化、分类和转运机制、活性调节和底物特异性。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1080/10409238.2024.2405476
Jian Hu, Yuhan Jiang

The Zrt/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent d-block metal transporters that play central roles in the uptake, secretion, excretion, and distribution of several essential and toxic metals in living organisms. The past few years has witnessed rapid progress in the molecular basis of these membrane transport proteins. In this critical review, we summarize the research progress at the molecular level of the ZIP family and discuss the future prospects. Furthermore, an evolutionary path for the unique ZIP fold and a new classification of the ZIP family are proposed based on the presented structural and sequence analyses.

Zrt/Irt-like蛋白(ZIP)家族由普遍表达的二价d-受体金属转运体组成,在生物体内几种必需金属和有毒金属的摄取、分泌、排泄和分布过程中发挥着核心作用。过去几年,这些膜转运蛋白的分子基础研究进展迅速。在这篇重要综述中,我们总结了 ZIP 家族分子水平的研究进展,并讨论了未来的前景。此外,我们还根据所提供的结构和序列分析,提出了独特 ZIP 折叠的进化路径以及 ZIP 家族的新分类。
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引用次数: 0
Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics". 运动训练与骨骼肌线粒体蛋白质的变化:从印迹到 "omics"。
IF 6.5 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1080/10409238.2024.2383408
Elizabeth G Reisman,Nikeisha J Caruana,David J Bishop
Mitochondria are essential, membrane-enclosed organelles that consist of ∼1100 different proteins, which allow for many diverse functions critical to maintaining metabolism. Highly metabolic tissues, such as skeletal muscle, have a high mitochondrial content that increases with exercise training. The classic western blot technique has revealed training-induced increases in the relatively small number of individual mitochondrial proteins studied (∼5% of the >1100 proteins in MitoCarta), with some of these changes dependent on the training stimulus. Proteomic approaches have identified hundreds of additional mitochondrial proteins that respond to exercise training. There is, however, surprisingly little crossover in the mitochondrial proteins identified in the published human training studies. This suggests that to better understand the link between training-induced changes in mitochondrial proteins and metabolism, future studies need to move beyond maximizing protein detection to adopting methods that will increase the reliability of the changes in protein abundance observed.
线粒体是一种重要的膜封闭细胞器,由 1100 多种不同的蛋白质组成,可发挥对维持新陈代谢至关重要的多种功能。新陈代谢旺盛的组织,如骨骼肌,线粒体含量很高,并随着运动训练而增加。经典的 Western 印迹技术显示,训练诱导了所研究的相对较少的线粒体蛋白质(占 MitoCarta 中超过 1100 种蛋白质的 5%)的增加,其中一些变化取决于训练刺激。蛋白质组学方法还发现了数百种对运动训练有反应的线粒体蛋白质。然而,在已发表的人体训练研究中,所发现的线粒体蛋白质几乎没有交叉,这令人惊讶。这表明,要想更好地了解训练诱导的线粒体蛋白质变化与新陈代谢之间的联系,未来的研究不仅需要最大限度地检测蛋白质,还需要采用能提高所观察到的蛋白质丰度变化可靠性的方法。
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引用次数: 0
The biogenesis of potassium transporters: implications of disease-associated mutations. 钾转运体的生物生成:疾病相关突变的影响。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-07-01 DOI: 10.1080/10409238.2024.2369986
Morgan Kok, Jeffrey L Brodsky

The concentration of intracellular and extracellular potassium is tightly regulated due to the action of various ion transporters, channels, and pumps, which reside primarily in the kidney. Yet, potassium transporters and cotransporters play vital roles in all organs and cell types. Perhaps not surprisingly, defects in the biogenesis, function, and/or regulation of these proteins are linked to range of catastrophic human diseases, but to date, few drugs have been approved to treat these maladies. In this review, we discuss the structure, function, and activity of a group of potassium-chloride cotransporters, the KCCs, as well as the related sodium-potassium-chloride cotransporters, the NKCCs. Diseases associated with each of the four KCCs and two NKCCs are also discussed. Particular emphasis is placed on how these complex membrane proteins fold and mature in the endoplasmic reticulum, how non-native forms of the cotransporters are destroyed in the cell, and which cellular factors oversee their maturation and transport to the cell surface. When known, we also outline how the levels and activities of each cotransporter are regulated. Open questions in the field and avenues for future investigations are further outlined.

由于各种离子转运体、通道和泵的作用,细胞内和细胞外钾的浓度受到严格调节,而这些离子转运体、通道和泵主要位于肾脏。然而,钾转运体和共转运体在所有器官和细胞类型中都发挥着重要作用。也许不足为奇的是,这些蛋白质的生物发生、功能和/或调节缺陷与一系列灾难性人类疾病有关,但迄今为止,治疗这些疾病的药物很少获得批准。在这篇综述中,我们将讨论一组钾-氯共转运体(KCCs)以及相关的钠-钾-氯共转运体(NKCCs)的结构、功能和活性。此外,还讨论了与四种 KCC 和两种 NKCC 相关的疾病。我们特别强调了这些复杂的膜蛋白如何在内质网中折叠和成熟,非原生形式的共转运体如何在细胞中被破坏,以及哪些细胞因素会监督它们的成熟和向细胞表面的转运。如果已知,我们还将概述如何调节每种共转运体的水平和活性。我们还进一步概述了该领域的未决问题和未来的研究方向。
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引用次数: 0
Pioneer factors: nature or nurture? 先驱因素:天性还是后天培养?
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-05-22 DOI: 10.1080/10409238.2024.2355885
Shane Stoeber, Holly Godin, Cheng Xu, Lu Bai

Chromatin is densely packed with nucleosomes, which limits the accessibility of many chromatin-associated proteins. Pioneer factors (PFs) are usually viewed as a special group of sequence-specific transcription factors (TFs) that can recognize nucleosome-embedded motifs, invade compact chromatin, and generate open chromatin regions. Through this process, PFs initiate a cascade of events that play key roles in gene regulation and cell differentiation. A current debate in the field is if PFs belong to a unique subset of TFs with intrinsic "pioneering activity", or if all TFs have the potential to function as PFs within certain cellular contexts. There are also different views regarding the key feature(s) that define pioneering activity. In this review, we present evidence from the literature related to these alternative views and discuss how to potentially reconcile them. It is possible that both intrinsic properties, like tight nucleosome binding and structural compatibility, and cellular conditions, like concentration and co-factor availability, are important for PF function.

染色质中核糖体密集,这限制了许多染色质相关蛋白的可及性。先驱因子(PFs)通常被视为一组特殊的序列特异性转录因子(TFs),它们能识别核糖体嵌入的基序,侵入紧密的染色质并产生开放的染色质区域。通过这一过程,PFs 启动了一系列在基因调控和细胞分化中发挥关键作用的事件。该领域目前存在的一个争论是,PFs 是否属于具有内在 "先驱活性 "的独特 TFs 子集,或者是否所有 TFs 都有可能在特定细胞环境中发挥 PFs 的功能。对于定义先锋活性的关键特征也存在不同观点。在这篇综述中,我们将介绍与这些不同观点相关的文献证据,并讨论如何调和这些观点。核糖体紧密结合和结构相容性等内在特性和细胞条件(如浓度和辅助因子的可用性)可能对 PF 的功能都很重要。
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引用次数: 0
Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism. 线粒体 sirtuin 3 和天然化合物的作用:翻译后修饰对细胞代谢的影响。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-07-11 DOI: 10.1080/10409238.2024.2377094
Francesca Oppedisano, Salvatore Nesci, Anna Spagnoletta

Sirtuins (SIRTs) are a family of proteins with enzymatic activity. In particular, they are a family of class III NAD+-dependent histone deacetylases and ADP-ribosyltransferases. NAD+-dependent deac(et)ylase activities catalyzed by sirtuin include ac(et)ylation, propionylation, butyrylation, crotonylation, manylation, and succinylation. Specifically, human SIRT3 is a 399 amino acid protein with two functional domains: a large Rossmann folding motif and NAD+ binding, and a small complex helix and zinc-binding motif. SIRT3 is widely expressed in mitochondria-rich tissues and is involved in maintaining mitochondrial integrity, homeostasis, and function. Moreover, SIRT3 regulates related diseases, such as aging, hepatic, kidney, neurodegenerative and cardiovascular disease, metabolic diseases, and cancer development. In particular, one of the most significant and damaging post-translational modifications is irreversible protein oxidation, i.e. carbonylation. This process is induced explicitly by increased ROS production due to mitochondrial dysfunction. SIRT3 is carbonylated by 4-hydroxynonenal at the level of Cys280. The carbonylation induces conformational changes in the active site, resulting in allosteric inhibition of SIRT3 activity and loss of the ability to deacetylate and regulate antioxidant enzyme activity. Phytochemicals and, in particular, polyphenols, thanks to their strong antioxidant activity, are natural compounds with a positive regulatory action on SIRT3 in various pathologies. Indeed, the enzymatic SIRT3 activity is modulated, for example, by different natural polyphenol classes, including resveratrol and the bergamot polyphenolic fraction. Thus, this review aims to elucidate the mechanisms by which phytochemicals can interact with SIRT3, resulting in post-translational modifications that regulate cellular metabolism.

Sirtuins(SIRTs)是一个具有酶活性的蛋白质家族。特别是,它们是第三类 NAD+依赖性组蛋白去乙酰化酶和 ADP-核糖基转移酶家族。由 sirtuin 催化的 NAD+ 依赖性脱乙酰酶活性包括乙酰化、丙酰化、丁酰化、巴豆酰化、马尼酰化和琥珀酰化。具体来说,人类 SIRT3 是一种 399 个氨基酸的蛋白质,具有两个功能域:一个大的 Rossmann 折叠基序和 NAD+ 结合基序,以及一个小的复合螺旋和锌结合基序。SIRT3 在线粒体丰富的组织中广泛表达,参与维持线粒体的完整性、平衡和功能。此外,SIRT3 还能调节相关疾病,如衰老、肝脏、肾脏、神经退行性疾病、心血管疾病、代谢性疾病和癌症的发生。特别是,最重要和最具破坏性的翻译后修饰之一是不可逆的蛋白质氧化,即羰基化。线粒体功能障碍导致的 ROS 生成增加明确诱发了这一过程。SIRT3 在 Cys280 水平被 4-hydroxynenal 羰基化。羰基化引起活性位点构象的改变,导致 SIRT3 活性受到异位抑制,失去去乙酰化和调节抗氧化酶活性的能力。植物化学物质,特别是多酚,具有很强的抗氧化活性,是对各种病症中的 SIRT3 起积极调节作用的天然化合物。事实上,SIRT3 的酶活性受到不同天然多酚类别(包括白藜芦醇和佛手柑多酚成分)的调节。因此,本综述旨在阐明植物化学物质与 SIRT3 相互作用的机制,从而导致翻译后修饰,调节细胞代谢。
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引用次数: 0
Molecular insights into the prototypical single-stranded DNA-binding protein from E. coli. 大肠杆菌单链 DNA 结合蛋白原型的分子研究。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-05-21 DOI: 10.1080/10409238.2024.2330372
Nina J Bonde, Alexander G Kozlov, Michael M Cox, Timothy M Lohman, James L Keck

The SSB protein of Escherichia coli functions to bind single-stranded DNA wherever it occurs during DNA metabolism. Depending upon conditions, SSB occurs in several different binding modes. In the course of its function, SSB diffuses on ssDNA and transfers rapidly between different segments of ssDNA. SSB interacts with many other proteins involved in DNA metabolism, with 22 such SSB-interacting proteins, or SIPs, defined to date. These interactions chiefly involve the disordered and conserved C-terminal residues of SSB. When not bound to ssDNA, SSB can aggregate to form a phase-separated biomolecular condensate. Current understanding of the properties of SSB and the functional significance of its many intermolecular interactions are summarized in this review.

大肠杆菌的 SSB 蛋白可在 DNA 代谢过程中的任何地方与单链 DNA 结合。根据条件的不同,SSB 有几种不同的结合模式。在发挥作用的过程中,SSB 会在 ssDNA 上扩散,并在 ssDNA 的不同区段之间快速转移。SSB 与许多其他参与 DNA 代谢的蛋白质相互作用,迄今已定义了 22 种这样的 SSB 相互作用蛋白质或 SIP。这些相互作用主要涉及 SSB 的无序和保守的 C 端残基。当 SSB 未与 ssDNA 结合时,可聚集形成相分离的生物分子凝聚物。本综述概述了目前对 SSB 特性及其多种分子间相互作用功能意义的理解。
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引用次数: 0
Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques. 利用生化和模拟技术探究蛋白质赖氨酸甲基转移酶的催化机理。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-02-01 Epub Date: 2024-03-07 DOI: 10.1080/10409238.2024.2318547
Philipp Schnee, Jürgen Pleiss, Albert Jeltsch

Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2. Biochemical experiments have unraveled many mechanistic features of PKMTs concerning their substrate and product specificity, processivity and the effects of somatic mutations observed in PKMTs in cancer cells. Structural data additionally provided information about the substrate recognition, enzyme-substrate complex formation, and allowed for simulations of the substrate peptide interaction and mechanism of PKMTs with atomistic resolution by molecular dynamics and hybrid quantum mechanics/molecular mechanics methods. These simulation technologies uncovered important mechanistic details of the PKMT reaction mechanism including the processes responsible for the deprotonation of the target lysine residue, essential conformational changes of the PKMT upon substrate binding, but also rationalized regulatory principles like PKMT autoinhibition. Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.

蛋白质赖氨酸甲基转移酶(PKMTs)可将多达三个甲基转移到蛋白质中赖氨酸残基的侧链上,并通过控制蛋白质的稳定性、定位和蛋白质/蛋白质相互作用来实现重要的调控功能。甲基化反应受到高度调控,蛋白质的异常甲基化与多种疾病有关,包括神经系统疾病、心血管疾病和各种癌症。这篇综述介绍了过去几年中通过生化实验和模拟方法的综合应用对各种 PKMT 催化机制的新见解,重点是与临床相关且研究较多的该组酶,如 DOT1L、SMYD1-3、SET7/9、G9a/GLP、SETD2、SUV420H2、NSD1/2、不同的 MLL 和 EZH2。生化实验揭示了 PKMTs 在底物和产物特异性、过程性以及体细胞突变对癌细胞的影响等方面的许多机理特征。结构数据还提供了有关底物识别、酶-底物复合物形成的信息,并通过分子动力学和量子力学/分子力学混合方法,以原子分辨率模拟了 PKMTs 的底物肽相互作用和机理。这些模拟技术揭示了 PKMT 反应机制的重要机理细节,包括目标赖氨酸残基的去质子化过程、PKMT 与底物结合后的基本构象变化,以及 PKMT 自动抑制等调控原理的合理性。本文讨论了进一步的研究进展,这些进展可能会在不久的将来使我们更接近于从机理上理解这一类重要酶的催化作用。本文描述的结果说明了通过生化实验和模拟技术的结合应用来研究酶机理的威力。
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引用次数: 0
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