人体80%疾病与代谢有关，揭开代谢的奥秘就等于找到了制服疾病的密钥。2月19日出版的国际权威刊物《科学》同时刊发了两篇复旦大学科研人员对生命新陈代谢乙酰化作用新机制的最新研究成果。两篇题为《代谢酶的乙酰化协调碳源的利用和代谢》和《蛋白赖氨酸的乙酰化调控》文章，以蛋白质向能量转化过程中“乙酰化修饰”的重要发现，为肝病、肿瘤等代谢疾病的药物研发提供了开拓性的思路。
最新的研究成果来自于复旦大学生物医学研究院分子细胞生物学研究室赵世民和雷群英团队。据介绍，构成人体最基本结构与功能的单位是细胞,细胞主要通过蛋白质执行复杂的调控和信息传递功能。而在执行前，往往需要先在蛋白质分子链上接上某种分子或分子团，称为蛋白质的修饰。“乙酰化修饰”——即在蛋白质分子链上嫁接上一个乙酰基分子是蛋白质最主要的修饰方式之一。修饰后的蛋白质可以对细胞内的各类通路进行精确的调节与控制，完成对基因所发出的“指令”的执行过程。揭开蛋白质“乙酰化修饰”的机理之谜，将为破解蛋白质修饰规律的生命之谜打下重要基础。
科学界早期一般认为，乙酰化修饰功能主要集中在对细胞染色体结构的影响以及对核内转录调控因子的激活方面。但是，复旦科研人员通过通量化的蛋白质组研究和不同物种的代谢通路研究发现，在生理状况下，存在着大量非细胞核的蛋白被乙酰化修饰，而且在从低等原核生物到包括人在内的高等哺乳动物，乙酰化对代谢的调控，不仅普遍存在着，而且在生命进化过程中一直保存下来。
鉴于现在人体80%疾病与代谢有关，《科学》杂志的评论认为：该研究为开发调控代谢的药物提供了新的思路，为包括肿瘤在内的新的治疗手段的发展提供了可能。（生物谷Bioon.com）
生物谷推荐原文阅读：
Science 19 February 2010 | DOI: 10.1126/science.1179689
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 Guan1,2,8,9,
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 enoyl–coenzyme A hydratase/3-hydroxyacyl–coenzyme 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 | DOI: 10.1126/science.1179687
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 Zhao1,2,3,8,*
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.
