Nature头条:同步的时钟 编辑推荐: 许多的生物体呈现出昼夜节律——调控每日新陈代谢、生理学和行为改变的内部生物钟。但是从真菌、果蝇到人类,在物种间还没有发现有共同的生物钟基因或蛋白。在新研究中,研究人员首次鉴别出了在细菌、古细菌(archaea)和真核生物(eukaryotes)的昼夜节律中活跃的一个代谢蛋白。 研究人员鉴别出了跨越生命所有三个领域的首个保守的生物钟元件。 许多的生物体呈现出昼夜节律——调控每日新陈代谢、生理学和行为改变的内部生物钟。但是从真菌、果蝇到人类,在物种间还没有发现有共同的生物钟基因或蛋白。在新研究中,研究人员首次鉴别出了在细菌、古细菌(archaea)和真核生物(eukaryotes)的昼夜节律中活跃的一个代谢蛋白。 这一研究发现发布在5月16日的《自然》(Nature)杂志上,表明与此前的观点相反,昼夜时钟可能享有一个共同的祖先。此外,由于这一清除活性氧的代谢蛋白发生了周期性的改变,作者们认为在25亿年前对于大气中氧聚集的传感和反应有可能驱动了昼夜节律的进化。 “最厉害的是它表明不知何故所有这些生物体都具有从前不明显的代谢昼夜节律,”俄勒冈州立大学生物学家P. Andrew Karplus(没有参与这一研究)说。不过,他指出尽管鉴别的蛋白是代谢昼夜节律的一个有力标志物,但是没有证据表明它是这种节律的原因。最大的问题是这一节律的起源是什么?它是如何发生的? 在过去的20年里,研究人员主要通过研究果蝇确确定了大量的基因和蛋白质提供给共同模式:一个转录-翻译反馈回路,凭借它基因被转录然后翻译为蛋白质,然后累积直至它们达到能够触发转录关闭的阈值,所有都发生在大约24小时的周期内。这一模型已经成为了昼夜节律研究的基础。 然而在去年,英国剑桥大学的Akhilesh Reddy和同事们证实这一昼夜生物钟机器至少有一个组件与转录无关——一个称为过氧化物酶(peroxiredoxin)蛋白的抗氧化剂家族,它可以在与代谢相关的24小时氧化-还原循环中吸纳细胞中过量的过氧化氢。Reddy研究小组发现这一几乎存在于每一个生物体中的蛋白质在人类、小鼠和海藻细胞中均显示出了昼夜节律振荡(circadian oscillation)。 “我们似乎已经发现这些真核生物体具有这些节律,因此我们决定在细菌和古细菌中开展进一步研究,”Reddy说。在最近的研究中,他的研究团队在淡水蓝藻细长聚球藻(Synechococcus elongatus)和海洋有氧古菌嗜盐杆菌(Halobacterium salinarum)中检测了过氧化物酶的氧化节律。每个生物体均在48-72小时内维持在恒定的光线和温度中,在这期间研究人员定期检测样品的过氧化物酶氧化与否。果然,在这两个物种中,蛋白质随着24小时周期显示出强大的氧化振荡。 研究小组还检测了从前鉴别的生物钟机制与过氧化物酶之间的联系,发现当果蝇和拟南芥中的已知基因突变时,过氧化物酶周期仍持续不间断。这表明两个组件——传统的转录-翻译回路因子和过氧化物酶——相互独立运作生成了生物体的昼夜节律。 由于从前在生命的不同领域没有鉴别出共同的生物钟机制,科学家们认为昼夜节律是独立多次进化而来。“但是为何要多次推倒重来?它没有任何的意义,”Reddy说。Reddy早就怀疑昼夜节律可能享有一个共同的分子起源,而事实上生命的所有三个领域都享有过氧化物酶周期支持了这一观点。例如,昼夜节律有可能是随着细胞适应早期环境能源供应(阳光)循环和随后的氧化应激循环而进化的。 目前进化的证据还不能完全令人信服,Karplus说:“过氧化物酶蛋白似乎没有驱动任何或是大概与生物钟蛋白的互作。它们只是碰巧发生了成为了代谢活动的读值。” 但是由于新发现,过氧化物酶现在可用作一种标记物来在其他研究很少的物种中寻找昼夜节律。“第一次我们发现了可在所有生物体中观测昼夜节律的一个共同点,”Reddy说。 Reddy补充说研究结果也可能还有其他更多的实际应用。例如在未来,研究人员或可利用小分子靶向过氧化物酶来破坏致病细菌的昼夜节律,或是提高农作物的节律帮助它们更有效率地生长。 (生物通:何嫱) 原摘要:Peroxiredoxins are conserved markers of circadian rhythms Cellular life emerged ~3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth’s rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation–reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription–translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event ~2.5 billion years ago. · 创新参选:Western Blot中如何消除内源的过氧化物酶( 4-28) · 奥运新忧:Cell报道提高耐力药物问世( 8-4) · 日研究人员发现膀胱生物钟机制( 5-7) · 生物钟有助人体昼夜循环( 5-4) · Nature头条:调控我们的生物钟( 4-1) · 生物钟节奏对新陈代谢有重要影响( 3-26) · Science:植物内部的生物钟( 3-12) · 《自然》:科学家用大肠杆菌创造出“遗传时钟”
表观遗传是指DNA序列不发生变化但基因表达却发生了可遗传的改变。这种改变是胞内除遗传信息以外其他可遗传物质发生的改变,这种改变在发育和细胞增殖过程中能稳定传递。表观遗传学是上个世纪80年代兴起的一门学科,主要研究在细胞核DNA序列没有发生改变时,基因发生功能新的可逆的、可遗传的基因表达改变。进入21世纪以来,表观遗传学研究已成为当今生命科学研究的前沿和热点。 Cheryl H. Arrowsmith、Chas Bountra、Paul V. Fish、Kevin Lee和Matthieu Schapira在Nature Reviews Drug Discovery 11, 384-400 (May 2012)上发表题目“Epigenetic protein families: a new frontier for drug discovery”的综述。指出基因表达的表观遗传调控是一个不仅建立正常的细胞表型也有助于人类疾病的动态的和可逆的过程。在分子水平上,表观遗传调控涉及核酸和封装DNA的蛋白质如组蛋白的分层共价修饰。本文作者综述了通过组蛋白的乙酰化和甲基化诱导表观遗传信号转导的关键蛋白质家族,这一家族包括组蛋白去乙酰化酶、蛋白质甲基转移酶、赖氨酸脱甲基酶、溴结构域蛋白以及与甲基化组蛋白结合的蛋白。这些蛋白质家族作为新的成药类酶和成药类蛋白-蛋白相互作用域。作者还讨论了与疾病已知的关联,基础分子作用机制和每一类蛋白质药理调控的最新进展。
http://www.gopubmed.org/web/gopubmed/1?WEB0n4sl5oi4rmxuI1cI2mI0 2,012 documents semantically analyzed top author statistics 1 2 3 Top Years Publications 2009 228 2008 228 2007 215 2005 163 2006 159 2004 141 2003 97 2002 95 2001 64 2010 62 2000 57 1999 38 1998 33 1993 26 1995 24 1989 22 1996 21 1986 21 1990 20 1985 20 1 2 3 1 2 3 Top Countries Publications USA 895 United Kingdom 139 Japan 120 Germany 82 France 65 Italy 62 Canada 58 China 46 South Korea 29 Spain 29 India 24 Austria 21 Switzerland 20 Netherlands 18 Sweden 17 Australia 17 Taiwan 16 Belgium 13 Israel 13 Norway 12 1 2 3 1 2 3 ... 19 Top Cities Publications New York 63 Philadelphia 49 Boston 47 Bethesda 38 Houston 36 Cambridge 33 London 32 Los Angeles 31 Baltimore 29 Birmingham 23 San Francisco 21 Madison 21 Kyoto 20 Cambridge, USA 20 Tokyo 19 Rome 18 Columbus 18 Seoul 17 Montreal 17 Atlanta 16 1 2 3 ... 19 1 2 3 ... 23 Top Journals Publications J Biol Chem 240 Mol Cell Biol 121 Biochemistry-us 68 Mol Cell 59 P Natl Acad Sci Usa 55 Biochim Biophys Acta 44 Nature 30 Cancer Res 30 J Mol Biol 28 Embo J 28 Biochem J 28 Oncogene 27 Nucleic Acids Res 27 Cell 27 Science 27 Biochem Bioph Res Co 25 Eur J Biochem 22 Cell Cycle 21 Febs Lett 18 Anal Biochem 18 1 2 3 ... 23 1 2 3 ... 449 Top Terms Publications Acetylation 1,979 Lysine 1,855 cytolysis 1,547 Histones 1,318 Proteins 1,045 Animals 949 Humans 901 Genes 834 histone acetylation 801 Chromatin 743 chromatin 684 DNA 534 Methylation 527 histone h3 505 Acetyltransferases 492 methylation 467 Histone Deacetylases 444 Histone Acetyltransferases 437 Amino Acid Sequence 435 Protein Processing, Post-Translational 390 1 2 3 ... 449 1 2 3 ... 413 Top Authors Publications Allis C 36 Turner B 31 Grunstein M 17 Marmorstein R 13 Pestell R 13 Berger S 12 Erdjument-Bromage H 11 Tempst P 11 Parthun M 11 Perham R 11 Bosshard H 11 O'Neill L 10 Straehl B 10 Belyaev N 10 Allfrey V 10 Seto E 9 Cole P 9 Zhou M 9 Workman J 9 Kouzarides T 9 最新研究报道 http://news.sciencenet.cn/htmlnews/2010/2/228483.shtm 《科学》聚焦中国生物医学新成果 研究在一个全新的层面上呈现出广阔前景 美国当地时间2月19日,最新出版的《科学》杂志,罕见地同时发表两篇复旦大学生物医学研究院的最新成果。其中关于蛋白质向能量转化过程中乙酰化修饰的重要发现,对肝病、肿瘤等代谢疾病的药物研发提供了开拓性的思路,生物医学研究在一个全新的层面上呈现出广阔的前景。 2月19日,该项目的课题组负责人介绍了此项研究在药物研发等方面的意义。两篇分别题为《代谢酶的乙酰化协调碳源的利用和代谢流》和《蛋白赖氨酸的乙酰化调控》的文章,分别研究了乙酰化对蛋白质进行修饰以及对代谢通路进行调控的问题。 据介绍,人体好比一个战场,细胞就是士兵,维持着人体的基本功能;赤手空拳的蛋白质被乙酰武装起来后,才可以变成为人体作战的士兵。嫁接上一个乙酰基分子,修饰后的蛋白质就可以对细胞内的各类通路进行精确调节与控制。 乙酰调控蛋白质活性变化,使其中活跃、不活跃的部分相互平衡。而当平衡出现问题,就会导致代谢疾病。据了解,人类疾病中与代谢相关的占80%,包括肝病、肿瘤等。如果研制出一种药物能使乙酰改邪归正,对细胞进行正确调控,将成为一种全新的治疗方案。 教科书中关于代谢调控内容将有可能被改写,乙酰化修饰的概念将可能成为代谢调控新内容,相关负责人赵世民介绍说,细胞蛋白、代谢酶等大量非细胞核蛋白的乙酰化修饰,都是在研究中首次得到确认。 《科学》杂志以如此大的篇幅聚焦一个科研成果,实为罕见,充分显示了该研究的开拓性意义。《科学》的评论文章称:了解赖氨酸乙酰化是如何调控,以及改变蛋白质乙酰化对特定细胞通路的影响,对人类疾病的意义不言而喻。 更多阅读 《科学》杂志发表《蛋白赖氨酸的乙酰化调控》论文摘要(英文) 《科学》杂志发表《代谢酶的乙酰化协调碳源的利用和代谢流》论文摘要(英文) http://www.sciencemag.org/cgi/content/abstract/327/5968/1000 Science 19 February 2010: Vol. 327. no. 5968, pp. 1000 - 1004 DOI: 10.1126/science.1179689 Prev | Table of Contents | Next Reports Regulation of Cellular Metabolism by Protein Lysine Acetylation Shimin Zhao, 1 ,2 Wei Xu, 1 ,2 ,* Wenqing Jiang, 1 ,2 ,* Wei Yu, 1 ,2 Yan Lin, 2 Tengfei Zhang, 1 ,2 Jun Yao, 3 Li Zhou, 4 Yaxue Zeng, 4 Hong Li, 5 Yixue Li, 6 Jiong Shi, 6 Wenlin An, 7 Susan M. Hancock, 7 Fuchu He, 3 Lunxiu Qin, 5 Jason Chin, 7 Pengyuan Yang, 3 Xian Chen, 3 ,4 Qunying Lei, 1 ,2 ,8 Yue Xiong, 1 ,2 ,4 , Kun-Liang Guan 1 ,2 ,8 ,9 , Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation, in particular through the modification of histones and nuclear transcription regulators. We show that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoylcoenzyme A hydratase/3-hydroxyacylcoenzyme A dehydrogenase in fatty acid oxidation and malate dehydrogenase in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase in gluconeogenesis. Our study reveals that acetylation plays a major role in metabolic regulation. 1 School of Life Sciences, Fudan University, Shanghai 20032, China. 2 Molecular and Cell Biology Lab, Fudan University, Shanghai 20032, China. 3 Center of Proteomics, Institute of Biomedical Sciences, Fudan University, Shanghai 20032, China. 4 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. 5 Affiliated Zhongshan Hospital, Fudan University, Shanghai 20032, China. 6 Bioinformatics Center, Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. 7 Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, UK. 8 Department of Biological Chemistry, Fudan University, Shanghai 20032, China. 9 Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Science 19 February 2010: Vol. 327. no. 5968, pp. 1004 - 1007 DOI: 10.1126/science.1179687 Prev | Table of Contents | Next Reports Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux Qijun Wang, 1 Yakun Zhang, 2 Chen Yang, 3 Hui Xiong, 1 ,2 Yan Lin, 4 Jun Yao, 4 Hong Li, 3 Lu Xie, 3 Wei Zhao, 3 Yufeng Yao, 5 Zhi-Bin Ning, 3 Rong Zeng, 3 Yue Xiong, 4 ,6 Kun-Liang Guan, 4 ,7 Shimin Zhao, 1 ,4 ,* Guo-Ping Zhao 1 ,2 ,3 ,8 ,* Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated extensively and differentially in response to different carbon sources, concomitantly with changes in cell growth and metabolic flux. The relative activities of key enzymes controlling the direction of glycolysis versus gluconeogenesis and the branching between citrate cycle and glyoxylate bypass were all regulated by acetylation. This modulation is mainly controlled by a pair of lysine acetyltransferase and deacetylase, whose expressions are coordinated with growth status. Reversible acetylation of metabolic enzymes ensure that cells respond environmental changes via promptly sensing cellular energy status and flexibly altering reaction rates or directions. It represents a metabolic regulatory mechanism conserved from bacteria to mammals. 1 State Key Laboratory of Genetic Engineering, Department of Microbiology, School of Life Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. 2 MOST-Shanghai Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China. 3 Key Laboratory of Synthetic Biology, Bioinformatics Center and Laboratory of Systems Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China. 4 Molecular Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. 5 Laboratory of Human Bacterial Pathogenesis, Department of Medical Microbiology and Parasitology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. 6 Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. 7 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. 8 Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China. * To whom correspondence should be addressed. E-mail: zhaosm@fudan.edu.cn