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个人信息

博士生导师
研究员

Email: ylxiao@sibs.ac.cn
个人网页: http://sippe.ac.cn/ylxiao

研究方向

化学生物学与酶学研究

肖友利

个人简介

1996-2000年 山东大学化学学院,理学学士;
2000-2005年 中科院上海有机化学研究所, 理学博士;
2005年 通用电气全球研发中心(上海),主任工程师;
2006-2011 美国波士顿大学化学系,Postdoctoral Research Associate;
2011-2012 美国Biogen,Scientist;
2012年 美国哈佛大学医学院,Research Fellow;
2012年 中科院上海生命科学研究院植物生理生态研究所合成生物学重点实验室,研究员。

研究工作

课题组主要从事生物学与化学方面的交叉学科研究,旨在利用化学生物学的策略探索蛋白质与化学小分子或者代谢物的相互作用、以及天然产物转化(分解和合成)的代谢途径和分子酶学反应机制和药用天然产物合成生物学研究。主要课题研究方向包括:
1) 基于多组学方法的天然产物合成生物学研究;
2) 酶催化反应机制研究;
3) 活性天然产物等小分子的化学蛋白质组学研究。

主要成果

1) 石杉碱甲生物合成途径的解析-石杉碱甲合成的关键基因的挖掘
蛇足石杉 (Huperzia serrata) 作为蕨类中石松类石松科石杉属的一个物种,是迄今报道含有包括石杉碱甲 (Huperzine A, HupA) 等重要石松类生物碱最丰富的药用植物, 在中药使用中有悠久的历史。为解析石杉碱甲的生物合成途径, 对植物蛇足石杉全组织 (根、茎、叶和孢子) 的转录组和代谢组深入分析, 筛选到蛇足石杉中石杉碱甲生物合成相关候选基因, 部分工作已在线发表于BMC Genomics (2017) 和Synthetic & Systems Biotechnology (2017); 同时利用体外生化表达系统、烟草瞬时表达系统和体外代谢组学策略, 对克隆到的HsLDC和HsCAO基因进行体外和体内功能验证, 该工作已在线发表于Phytochemistry (2017), 并申请了专利。

2) 核苷类抗生素多碳糖双环骨架的生物合成反应机制研究
核苷类抗生素是一类有200多种不同结构的天然产物,作为药物广泛应用于抗菌、抗病毒等方面。这一家族的天然产物通常以核苷母核作为起始代谢物,通过一连串的代谢反应、生化修饰,形成复杂多样的结构。我们根据必需蛋白酶的生信预测功能,结合代谢物之间转化的酶学方面的要求,阐明了该类蛋白催化对新颖自由基引发的碳碳键形成中的重要作用及催化反应机制。相关成果发表在Chemical Science (2017)上。

3) 活性天然产物的化学蛋白质组学研究
基于活性蛋白谱 (Activity-based Protein Profiling, ABPP) 策略利用化学手段将天然产物探针化,利用分子探针研究天然产物与活性蛋白质的相互作用, 为解决天然产物的分子机制提供新的研究思路。我们通过设计合成的以青蒿素为骨架的小分子探针, 利用化学蛋白质组学策略, 阐释了青蒿素的抗癌新机制, 相关工作已经发表在ACS Chemical Biology (2016) 上。在此基础上, 我们进一步发展并优化探针策略, 借助探针对肽段的富集作用和高分辨质谱发现了青蒿素与翻译调节肿瘤蛋白 (TCTP) 的特异结合肽段及作用氨基酸位点。相关工作发表在Bioconjugate Chemistry (2016)上。
通过结合研究组新近发展的定量蛋白质组学技术和ABPP策略,深入开展了针对具有抗癌抗炎活性的复杂天然产物藤黄酸、雷公藤红素和土荆皮乙酸的分子活性方面的研究。相关成果分别发表于Chemical Communications (2016,2017)和Molecular BioSystems (2017)上,同时相关部分工作也已综述的形式整理在化学学报期刊(2017)。

    1. 周怡青,肖友利* (Yiqing Zhou, Youli Xiao*). 活性天然产物靶标蛋白的鉴定(Target Identification of Bioactive Natural Products). 化学学报(Acta Chimica Sinica), 2017, in revision.

    2. Shiwen Wu, Zhen Fan, and Youli Xiao*. Comprehensive relative quantitative metabolomics analysis of lycopodium alkaloids in different tissues of Huperzia serrata. Synthetic and Systems Biotechnology, 2017, in press.

    3. Yiqing Zhou, Zhengao Di, Xiaoming Li, Yuanhong Shan, Weichao Li, Haibing Zhang, Youli Xiao*. Chemical proteomics reveal CD147 as a functional target of pseudolaric acid B in human cancer cells. Chem Commun. 2017, 53, 8671-8674.

    4. Xin Fang, Jianxu Li, Jinquan Huang, Youli Xiao, Peng Zhang, Xiaoya Chen*. Systematic identification of functional residues of Artemisia annua amorpha-4,11-diene synthase. Biochemical Journal. 2017, 474, 2191-2202.

    5. Wenbo Li, Randy F. Lacey, Yajin Ye, Juan Lu, Kuo-Chen Yeh, Youli Xiao, Laigeng Li, Chi-Kuang Wen, Brad M. Binder*, Yang Zhao*. Triplin, a small molecule, reveals copper ion transport in ethylene signaling from ATX1 to RAN1. PLoS Genet. 2017, 13, e1006703.

    6. Mengquan Yang, Wenjing You, Shiwen Wu, Zhen Fan, Baofu Xu, Mulan Zhu, Xuan Li, Youli Xiao*. Global transcriptome analysis of Huperzia serrata and identification of critical genes involved in the biosynthesis of huperzine A. BMC Genomics. 2017, 18, 245.

    7. Baofu Xu, Lei Lei, Xiaocen Zhu, Yiqing Zhou, Youli Xiao*. Identification and characterization of L-lysine decarboxylase from Huperzia serrata and its role in the metabolic pathway of lycopodium alkaloid. Phytochemistry. 2017, 136, 23-30.

    8. Yiqing Zhou, Weichao Li, Mingli Wang, Xixi Zhang, Haibing Zhang, Xiaofeng Tong, Youli Xiao*. Competitive profiling of celastrol targets in human cervical cancer HeLa cells via quantitative chemical proteomics. Mol. BioSyst. 2017, 13, 83-91.

    9. Nisha He#, Pan Wu#, Yongxing Lei, Baofu Xu, Xiaochen Zhu, Gudan Xu, Yaojie Gao, Jianzhao Qi, Zixin Deng, Gongli Tang, Weqing Chen*, Youli Xiao*. Construction of the octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics. Chem. Sci. 2017, 8, 444-451.

    10. Weichao Li#, Yiqing Zhou#, Guanghui Tang, Youli Xiao*. Characterization of the artemisinin binding site for translationally controlled tumor protein (TCTP) by bioorthogonal click chemistry. Bioconjugate Chem. 2016, 12, 2828-2833.

    11. Yiqing Zhou, Weichao Li, Xixi Zhang, Haibing Zhang, Youli Xiao*. Global profiling of cellular targets of gambogic acid by quantitative chemical proteomics. Chem. Commun. 2016, 97,14035-14038.

    12. Xiang Gao#,Hui Hong#, Wei-Chao Li, Lili Yang, Jirong Huang, Youli Xiao, Xiaoya Chen*, Genyun Chen*. Down-regulation of Rubisco Activity by Non-enzymatic Acetylation of RbcL. Mol. Plant. 2016, 9, 1018-1027.

    13. Xiaofeng Qi,Wei Lin,Miaolian Ma,Chengyuan Wang, Yang He, Nisha He, Jin Gao, Hu Zhou,Youli Xiao, Yong Wang, Peng Zhang*. Structural basis of rifampin inactivation by rifampin phosphotransferase. PNAS 2016, 113, 3803-3808.

    14. Yiqing Zhou, Weichao Li, and Youli Xiao*. Profiling of Multiple Targets of Artemisinin Activated by Hemin in Cancer Cell Proteome. ACS Chem. Biol. 2016, 11, 882-888.

    15. Lishan Zhao*, Wei-chen Chang*, Youli Xiao*, Hung-wen Liu*, Pinghua Liu*. Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis. Annual Review of Biochemistry 2013, 82,497-530.

    16. Kelly Daughtry, Youli Xiao, Deborah Stoner-Ma, Eunsun Cho, Allen M. Orville*, Pinghua Liu*, Karen N. Allen*. Quaternary Ammonium Oxidative Demethylation: X-ray Crystallographic, Resonance Raman and UV-visible Spectroscopic Analysis of a Rieske-type Demethylase. J. Am. Chem. Soc. 2012, 134, 2823-2834.

    17. Youli Xiao, Wei-chen Chang, Hung-wen Liu*, Pinghua Liu*. Study of IspH, A Key Enzyme in the Methylerythritol Phosphate Pathway Using Fluoro-substituted Substrate Analogues. Organic Letter 2011, 13, 5912–5915.

    18. Wei-chen Chang#, Youli Xiao#, Hung-wen Liu*, Pinghua Liu*. Mechanistic Studies of IspH-catalyzed Reaction Using Substrate Analogue: Implications for Substrate Binding and Protonation. Angewandte Chemie International Edition 2011, 50, 12304–12307.

    19. Youli Xiao, Debra Rooker, Quincy You, Caren L. Freel Meyers, Pinghua Liu*. IspG-catalyzed Positional Isotopic Exchange in Methylerythritol Cyclodiphosphate of the Deoxyxylulose Phosphate Pathway: Mechanistic Implications. ChemBioChem 2011, 12, 527–530 (selected as Cover Paper).

    20. Youli Xiao, Rodney L. Nyland II, Caren L. Freel Meyers, Pinghua Liu*. Methylerythritol Cyclodiphosphate (MEcPP) in Deoxyxylulose Phosphate Pathway: Synthesis from an Epoxide and Mechanisms. Chemical Communications, 2010, 46, 7220-7222.

    21. Rodney L. Nyland II, Youli Xiao, Pinghua Liu,* Caren L. Freel Meyers*. IspG converts an epoxide substrate analog to (E)-4-hydroxy-3-methylbut-2-enyl diphosphate: implications for IspG catalysis in isoprenoid biosynthesis J. Am. Chem. Soc., 2009, 131, 17734-17735.

    22. Youli Xiao, Georgia Zahariou, Yiannis Sanakis, Pinghua Liu*. IspG Enzyme Activity in the Deoxyxylulose Phosphate Pathway: Roles of the Iron-Cluster Biochemistry, 2009, 48, 10483-10485.

    23. Youli Xiao, Lisa Chu, Yiannis Sanakis, Pinghua Liu*. Revisiting the IspH Catalytic System in the Deoxyxylulose Phosphate Pathway: Achieving High Activity. J. Am. Chem. Soc., 2009, 131,9931-9933.

    24. Youli Xiao, Miranda Machacek, Kent Lee, Tomohisha Kuzuyama, Pinghua Liu*. Prenyltransferase Substrate Binding Pocket Flexibility and Its Application in Isoprenoid Profiling. Molecular BioSystems 2009, 5, 913-917.

    25. Youli Xiao, Pinghua Liu*. Synthesis of [1-13C] and Stereo-specifically [1-2H] Labeled Fluorinated Substrate Analogues of IspH Enzyme in the Deoxyxylulose Phosphate Pathway. Tetrahedron Letter, 2009, 50, 309-311.

    26. Youli Xiao, Kent Lee, Pinghua Liu*. Synthesis of P-metlylase Substrates of the Bialaphos Biosynthetic Pathway. Organic Letter. 2008, 10, 5521-5524.

    27. Youli Xiao, Pinghua Liu*. IspH Protein of the Deoxyxylulose Phosphate Pathway: Mechanistic Studies with C1 Deuterium Labeled Substrate and Fluorinated Analogue. Angew. Chem. Int. Ed., 2008, 47, 9722-9725.

    28. Youli Xiao, Zongbao K. Zhao, Pinghua Liu*. Mechanistic Studies of IspH in the Deoxyxylulose Phosphate Pathway: Heterolytic C-O Bond Cleavage at C4 Position. J. Am. Chem. Soc., 2008, 130, 2164-2165.

    29. Youli Xiao, Zheng Wang, Kuiling Ding*. Intramolecularly Dinuclear Magnesium Complex Catalyzed Copolymerization of Cyclohexene Oxide with CO2 under Ambient CO2 Pressure: Kinetics and Mechanism. Macromolecules, 2006, 39, 128-137.

    30. Youli Xiao, Zheng Wang, Kuiling Ding*. Copolymerization of Cyclohexene Oxide with CO2 Using Intramolecularly Dinuclear Zinc Catalysts. Chem.-Eur. J. 2005, 11, 3668-3678.
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