于慧敏,工学博士,教授

清华大学化工系,生物化工研究所
电话: 8610-62795492
Email: yuhm@tsinghua.edu.cn


教育经历

  • 2001, 工学博士,生物化工,清华大学,北京
  • 1996, 工学学士,化学工程与技术,清华大学,北京

工作经历

  • 2012.12,教授,清华大学化工系,北京,中国
  • 2011.4,清华大学(化工系)-山东宝莫股份 生物化学品联合研究中心主任,北京
  • 2006.11-2005.9,访问学者,麻省理工学院化工系,波士顿,美国
  • 2003.12,副教授,清华大学化工系,北京,中国
  • 2001.9,讲师,清华大学化工系,北京

主要获奖

  • 2016,东营市科学技术合作奖,东营市科技局
  • 2013, 技术发明二等奖(第1完成人),中国石油和化学工业联合会
  • 2010, 青年科技突出贡献奖,中国石油和化学工业联合会
  • 2008, 新世纪优秀人才,教育部
  • 2007, 北京市科技新星(A类),北京市科学技术委员会
  • 2005, 华新杰出学者,清华大学
  • 2003, 全国百篇优秀博士学位论文奖
  • 2003, 教育部提名国家科学技术奖自然科学奖二等奖(第2完成人)
  • 2001, 清华大学优秀博士毕业生;第三届清华大学“学生十杰”
  • 2000, 清华大学特等奖学金;第五届航天海鹰杯学术新秀
  • 1996, 清华大学优秀毕业生

主要学术任职

  • 现任预研专家组专家;曾任国家自然科学基金委金属材料科学十二五规划专家;《化学与生物工程》编委;Metabolic Engineering,Bioresource Technology,Biotechnology and Bioengineering等20余种国际期刊审稿人;《化工学报》、《生物工程学报》、《微生物学通报》等10多种国内期刊审稿人。

主要研究方向

工业生物催化和生物纳米技术,尤其是:

  • 采用前沿生物技术和应用生物信息学,发现或改造生物催化剂(酶和细胞);
  • 通过生物-化学集成方法,强化生物过程;
  • 发展M13噬菌体介导的生物纳米技术及其应用。

主要研究内容和成果

  针对生物催化剂改造和生物过程强化的关键科学问题开展前沿研究,致力于发展生物催化剂构建技术与理论,构筑能够在工业环境中高效稳定发挥作用的生物催化剂,并以油田化学品(丙烯酰胺、表面活性剂)和医药中间体、可生物降解材料等的生物法生产新工艺为依托进行过程开发和产业化实践,为解决我国能源危机和环境问题,保障人类健康做出实际贡献。

基础研究:

1. 从细胞-酶协同改造理念出发,构造新型高效的生物催化剂和细胞工厂。在细胞层面,强调转录水平调控(启动子工程和转录因子工程)和分子伴侣网络改造强化抗逆性的基础研究。在酶分子层面,强调生物信息学工具指导下的盐桥和二硫键等强作用力在酶分子结构中的刚性强化作用,提高酶的活性和稳定性。相关成果发表在Metabolic Engineering, Bioresource Technology, Applied and Environmental Microbiology, Biotechnology & Bioengineering、Journal of Industrial Microbiology & Biotechnology等著名国际期刊上,并被PNAS、JBC等期刊引用。
2. 在生物纳米技术前沿研究方面,致力于以丝状M13噬菌体(大肠杆菌病毒,约6×880nm)为生物模板,辅助新型纳米金属晶体合成并加速氧化还原反应进程、开发新型检测器件的新方法,探索生物催化新形式以及生物和材料交叉研究的新方向。与材料系朱静院士合作,采用M13衣壳蛋白模板首次在温和条件下成功合成了自然界罕见的面心立方(FCC)铁纳米晶;制备了FCC铁二十面体/十面体纳米晶、五次孪晶纳米棒等特殊形貌,提出了可作重要半导体材料及催化剂的UO2纳米晶制备新途径,进一步在自然科学基金支持下,开发了M13介导的双金属纳米阵列微电解体系,可高效还原难降解污染物和重金属离子。部分成果已发表在Environmental Science: Nano、Nano Lett.、J Phys Chem C、Crystal Growth & Design以及Nanotechnol等著名期刊。

应用研究:

1. 基因工程红球菌生产油田化学品单体-丙烯酰胺:针对放线菌科赤红球菌基因组信息匮乏、基因操作困难、但工业生产对其性能改造提出迫切需求的难题,开发了红球菌染色体副产物基因敲除、外源基因导入和稳定遗传、细胞形态调控以及分子伴侣耦合酶工程强化抗逆性改造系列关键技术。通过了863验收和教育部科技成果鉴定,授权中国和美国专利,达到国际领先水平。成功实现基因工程红球菌TH3、TH7、TH8等系列菌株在5万吨/年规模的丙烯酰胺产业化生产。副产物丙烯酸下降了70-80%;精制离子交换过柱量提高55%,废水排放减少30%;细胞回用批次提高到6-10批,发酵成本下降40%;原料单耗(丙烯腈/丙烯酰胺)接近理论值;TH8高耐受性细胞可以实现约50%高浓丙烯酰胺的3批次水合生产。新增利润3.4亿以上,创收外汇7800多万美元。
2. 基因工程枯草芽孢杆菌制备油田化学品-表面活性素:建立了生物表面活性剂产生菌的定量可视化、高通量筛选新方法,获得了产表面活性素(脂肽类)的野生枯草芽孢杆菌,建立了枯草芽孢杆菌中外源基因高表达、染色体基因快速替换重组的方法,以表面活性素合成酶簇启动子和跨膜转运蛋白为核心,强化了表面活性素的生物合成途径和跨膜转运通道,开发了高产表面活性素的基因重组枯草芽孢杆菌,脂肽产量超过20 g/L。证实了表面活性素在洗油效率和乳化降粘等方面的突出性能,在油气开采领域的应用潜力巨大。正在致力于基因工程枯草芽孢杆菌的进一步高产改造、生物过程强化和放大生产以及应用探索。
3. 基因工程红球菌制备其它酰胺和羧酸产品、立普妥药物中间体:依托成功构建的基因工程红球菌平台,分别实现了腈水合酶和腈水解酶的高活性表达,酶活水平为国内外报道中的最高值。可以实现各种酰胺(如烟酰胺)和羧酸(如丙烯酸)产物、包括立普妥药物中间体等高附加值精细化学品的生物法高效合成。进一步以手性酶为对象,探索微反应器生物催化新工艺,致力于手性药物中间体的高效制备。
4. 基因工程谷氨酸棒杆菌安全高产透明质酸:成功实现了透明质酸合成代谢途径在食品安全级宿主—谷氨酸棒杆菌的高效表达,重组谷氨酸棒杆菌的透明质酸产量高于21.0 g/L,分子量100多万道尔顿和30万道尔顿,在医药、保健品、化妆品等领域应用前景广阔。
5. 基因工程大肠杆菌高产头孢菌素C酰化酶:进行了酶法催化生产国家战略性抗生素品种:头孢菌素半合抗中间体——7-氨基头孢烷酸(7-ACA) 的生产工艺及头孢菌素酰化酶的重组表达与改造研究,并取得重要进展。头孢菌素C酰化酶的酶活高达16000U/L国际单位。
6. 基因工程大肠杆菌高产可生物降解材料PHB通过聚-β-羟基丁酸酯(PHB)合成基因 (phbCAB)、λ噬菌体裂解基因(S-RRz)和透明颤菌血红蛋白基因(vgb)在重组大肠杆菌中的同时引入,成功实现了PHB的高密度、高表达生产并大幅度降低了生产成本。

授权发明专利

  • 2016,一种高表达脂肽类生物表面活性剂的工程菌及其应用. 专利号:CN20140124438.0
  • 2016,一种生产透明质酸的基因工程菌及其应用. 专利号:CN20140166015.5
  • 2016,一种M13噬菌体介导的纳米铁还原镉离子的方法. 专利号:CN200410090776.7
  • 2014,一种突变头孢菌素C酰化酶. 专利号:ZL 2012 1 04669788.
  • 2013,一种降低头孢菌素C分解的方法. 专利号:ZL 201110460235.5.
  • 2013,An engineered nitrile hydradase-producing bacterium with amidase gene knocked-out, the construction and the use thereof. 美国发明专利号:US 8518685.
  • 2013,一种突变腈水合酶. 专利号:ZL 201110415465.X.
  • 2012,一种高丙烯酰胺和丙烯腈耐受性产腈水合酶工程菌及应用. 专利号:ZL201010188495.7.
  • 2012,一种丙烯酰胺晶体的生产方法. 专利号:ZL 200810224258.5.
  • 2012,一种腈水合酶基因工程菌及应用. 专利号:ZL 200910210177.3.
  • 2011,敲除酰胺酶基因的腈水合酶工程菌及其构建方法和应用.专利号:ZL 200880000969.1.
  • 2011,一种腈水合酶基因簇及其应用. 专利号:200910076710.1.
  • 2011,一种融合蛋白及其编码基因和用途. 专利号:ZL 200710177396.7.
  • 2011, 一种D-氨基酸氧化酶融合蛋白及其载体和应用. 专利号:200810104198.2.
  • 2010,一种丙烯酰胺晶体的制备方法. 专利号:ZL 200710122048.x.
  • 2010,一种头孢菌素C酰化酶及其载体和应用. 专利号:ZL 200810102219.7.
  • 2010,一种腈水合酶基因工程菌的构建方法以及基因工程菌株和应用. 专利号:ZL 200710122047.5.
  • 2009,An engineered nitrile hydradase-producing bacterium with amidase gene knocked-out, the construction and the use thereof. 国际PCT专利,WO 2009/117843,PCT/CN2008/000572.
  • 2008,一种表达载体及其应用. 专利号:ZL 2004100836274.
  • 2008,一种组成型表达载体及其构建方法与应用. 专利号:ZL 200410083849.6.
  • 2008,一种戊二酰-7-氨基头孢烷酸酰化酶的固定化方法.专利号:ZL 200610011742.X.
  • 2007,可完全生物降解聚酯聚3-羟基丁酸酯的制备方法. 专利号:ZL 200410064809.7.
  • 2006,一种酶法生产7-氨基头孢烷酸的新工艺. 专利号:ZL 200410039573.1.
  • 2006,一种腈水合酶及其编码基因与应用. 专利号:ZL 200410042576.0.
  • 2006,一种生产7-氨基头孢烷酸的方法及其专用重组酶. 专利号:ZL 200310113563.3.
  • 2006,一种获取戊二酰-7-氨基头孢烷酸酰化酶基因的方法.专利号:ZL 03143198.4.
  • 2006,一种应用膜技术的微生物转化生产丙烯酰胺的方法.专利号:ZL 03109806.1.
  • 2002,构建多功能基因工程菌生产聚β-羟基丁酸酯的方法. 专利号:ZL 99 1 00577.5.

代表性文章

  • Song Jiao, Xu Li, Huimin Yu*, Huan Yang, Xue Li and Zhongyao Shen. In situ enhancement of surfactin biosynthesis in Bacillus subtilis using novel artificial inducible promoters. Biotechnology and Bioengineering 2017, 114(4): 832–842.
  • Shuai Zhang, Huimin Yu*, Ji Yang, Zhongyao Shen. Design of the nanoarray-pattern Fe-Ni bi-metal nanoparticles@M13 virus for enhanced reduction of p-chloronitrobenzene through micro-electrolysis effect. Environmental Science: Nano, 2017, 4, 876 - 885.
  • Fangyu Cheng, Qianying Gong, Huimin Yu*, Gregory Stephanopoulos*, High-titer biosynthesis of hyaluronic acid by recombinant Corynebacterium glutamicum. Biotechnology Journal, 2016, 11(4), 574-584.
  • Jizhe Sun, Huimin Yu*, Jie Chen, Hui Luo and Zhongyao Shen. Ammonium acrylate biomanufacturing by an engineered Rhodococcus ruber with nitrilase overexpression and double-knockout of nitrile hydratase and amidase. Journal of Industrial Microbiology & Biotechnology. 2016, 43(12):1631-1639.
  • Hui Luo*, Linlin Zhu, Yanhong Chang, Xiuhong Liu, Zijia Liu, Hongxu Sun, Xi Li, Huimin Yu, Zhongyao Shen. Microenvironmental pH changes in immobilized cephalosporin C acylase during a proton-producing reaction and regulation by a two-stage catalytic process. Bioresource Technology. 2016, 223:157-165.
  • Jiahui Li, Yang Chen, Mingzhao Guo, Yujun Wang*, Jianhong Xu, Guangsheng Luo, Huimin Yu. Using microchannels to visually investigate the formation and dissolution of acrylonitrile droplets in a bio-hydration system. Chemical Engineering Science, 2016, 152: 239-247.
  • Yuxuan Tian, Jie Chen, Huimin Yu* and Zhongyao Shen, Overexpression of the Escherichia coli chaperones GroEL-GroES in Rhodococcus ruber improves the activity and stability of cell catalysts harboring a nitrile hydratase, J Microbiol Biotechnol, 2016, 26(2): 337–346.
  • Yanmei Wei, Hui Luo*, Yanhong Chang, Huimin Yu and Zhongyao Shen. Reversible immobilization of cephalosporin C acylase on epoxy supports coated with polyethyleneimine. Biocatalysis and Biotransformation, 2016, 33(5-6): 250-259.
  • Huan Yang, Huimin Yu* and Zhongyao Shen, A Novel High-Throughput and Quantitative Method Based on Visible Color Shifts for Screening Bacillus subtilis THY-15 for Surfactin Production, Journal of Industrial Microbiology & Biotechnology, 2015, 42(8): 1139-1147
  • Huan Yang, Xu Li, Xue Li, Huimin Yu* and Zhongyao Shen. Identification of Lipopeptide Isoforms by Tandem MALDI-TOF-MS/MS Based on the Simultaneous Purification of Iturin, Fengycin and Surfactin by RP-HPLC. Analytical and Bioanalytical Chemistry. 2015, 407(9): 2529-2542.
  • Xu Li, Huan Yang, Donglai Zhang, Xue Li, Huimin Yu* & Zhongyao Shen. Overexpression of specific proton motive force-dependent transporters facilitate the export of surfactin in Bacillus subtilis. Journal of Industrial Microbiology & Biotechnology: 2015, 42(1), 93-103.
  • Shuai Zhang, Nakano Kazuhiko, Shu-liang Zhang and Hui-min Yu*. Synthesis of Dispersive Iron or Iron-silver Nanoparticles on Engineered Capsid pVIII of M13 Virus with Electronegative Terminal Peptides. J Nanopart Res (2015) 17(10):417.
  • Li, Jiahui; Chen, Jie; Wang, Yujun; Luo, Guangsheng, Yu Huimin. Hydration of acrylonitrile to produce acrylamide using biocatalyst in a membrane dispersion microreactor Bioresource Technology, 169, 2014, 416-420.
  • Chen Jie, Jia Xu, Yu Huimin*, Luo Hui, Shen Zhongyao. Catalytic kinetics of recombinant nitrile hydratase coupling terminal salt bridge and point-mutation. CIESC Journal. 2014, 65 (7): 2821-2828.
  • Jing Zhang, Huimin Yu*, Ying Wang, Hui Luo and Zhongyao Shen. Determination of the second autoproteolytic cleavage site of cephalosporin C acylase and the effect of deleting its flanking residues in the α-C-terminal region. Journal of Biotechnology 184 (2014) 138–145.
  • Shuai Zhang, Kazuhiko Nakano, Huimin Yu* and Zhongyao Shen. Bio-nano complexes of ZVFeNPs/Fe-s-M13 and Cd (II)/Cd-s-M13 accelerate Cd (II) reduction by FeNPs through dual dispersing and separate deposition. Materials Research Express. 1 (2014) 015043, 13 pages.
  • Jian Zhang, Zi-Ting Wang, Hui-Min Yu* and Yuchao Ma*. Paenibacillus catalpae sp. nov., isolated from the rhizosphere soil of Catalpa speciosa. Int J Syst Evol Microbiol 2013, 63:1776-1781.
  • Fangyu Cheng, Cheng Tang, Huan Yang, Huimin Yu*, Yu Chen and Zhongyao Shen. Characterization of a blend-biosurfactant of glycolipid and lipopeptide produced by Bacillus subtilis TU2 isolated from underground oil-extraction wastewater. J Microbiol Biotechnol. 2013; 23(3):390-396.
  • Jie Chen, Huimin Yu*, Changchun Liu, Jie Liu and Zhongyao Shen. Improving stability of nitrile hydratase by bridging the salt-bridges in specific thermal-sensitive regions. Journal of Biotechnology 164 (2012) 354–362
  • Yuchao Ma*, Huimin Yu* and Zhongyao Shen. Engineering Rhodococcus cell-catalysts for tolerance improvement by mutant sigma factor and plasmid active partition. Journal of Industrial Microbiology & Biotechnology. 2012, 39: 1421-1430.
  • Jian Zhang, Yuchao Ma* and Huimin Yu*. Arthrobacter cupressi sp. nov., a novel actinomycete isolated from the rhizosphere soil of Cupressus sempervirens. International Journal of Systematic and Evolutionary Microbiology, 2012, 62, 2731–2736.
  • Jian Zhang, Yuchao Ma* and Huimin Yu*. Nocardioides lianchengensis sp. nov., a novel actinomycete isolated from soil from Liancheng county, Fujian province, China. Int J Syst Evol Microbiol. 2012, 62, 2698–2702.
  • Ying Wang, Huimin Yu*, Jing Zhang, Hui Luo and Zhongyao Shen. Double knockout of β-lactamase and cephalosporin acetyl esterase genes from Escherichia coli reduces cephalosporin C decomposition. Journal of Bioscience and Bioengineering, 2012, 113(6), 737-741
  • Wang, Y., Yu, H., Song, W., An M., Zhang J., Luo, H., and Shen Z.: Overexpression of synthesized cephalosporin C acylase containing mutations in the substrate transport tunnel. Journal of Bioscience and Bioengineering, 2012, 113(1):36–41.
  • Luo Hui, Fan Lu, Chang Yanhong, Ma Jinwei, Yu Huimin, Shen Zhongyao. Gene cloning, overexpression, and characterization of the nitrilase from Rhodococcus rhodochrous tg1-A6 in E. coli. Applied Biochemistry and Biotechnology, 2010, 160(2): 393-400.
  • Yuchao Ma, Huimin Yu*, Wenyu Pan, Changchun Liu and Zhongyao Shen. Identification of nitrile hydratase-producing Rhodococcus ruber TH and characterization of the amiE-inactivation mutant. Bioresource technology, 2010, 101(1): 285-291.
  • Tao Ling, Jing Zhu, Huimin Yuand Lin Xie. Size Effect on Crystal Morphology of Faceted Face-Centered Cubic Fe Nanoparticles. Journal of Physical Chemistry C. 2009, 113(22): 9450-9453.
  • Daniel Klein-Marcuschamer, Christine Nicole S. Santos, Huimin Yu, and Gregory Stephanopoulos. Mutagenesis of the bacterial RNA polymerase alpha subunit for improving complex phenotypes. Appl. Environ. Microbiol. 2009, 75(9):2705-2711.
  • Tao Ling, Lin Xie, Jing Zhu, Huimin Yu, et al. Icosahedral Face-Centered Cubic Fe Nanoparticles: Facile Synthesis and Characterization with Aberration-Corrected TEM. Nano letters. 2009, 9 (4), pp 1572–1576.
  • Tao Ling, Huimin Yu, Xiaohua Liu, Zhongyao Shen, Jing Zhu. Fivefold Twinned Nanorods of FCC Fe: Synthesis and Characterization. Crystal Growth & Design, 2008, 8 (12), 4340–4342.
  • Jie Liu, Huimin Yu*, Zhongyao Shen. Insights into thermal stability of thermophilic nitrile hydratases by molecular dynamics simulation. Journal of Molecular Graphics and Modelling, 2008, 27(4): 529-535.
  • Huimin Yu*, Jie Liu, Zhongyao Shen. Modelling catalytic mechanism of nitrile hydratase by semi-empirical quantum mechanical calculation. Journal of Molecular Graphics and Modelling, 2008, 27(4): 522-528.
  • Huimin Yu, Keith Tyo, H. Alper, D. Marcuschamer, Gregory Stephanopoulos*. A High Throughput Screen for Hyaluronic Acid Accumulation in Recombinant Escherichia coli Transformed by Libraries of Engineered Sigma Factors.  Biotechnology and Bioengineering. 2008, 101 (4): 788-796.
  • Huimin Yu* and Gregory Stephanopoulos*. Metabolic Engineering of Escherichia coli for biosynthesis of hyaluronic acid. Metabolic Engineering. 2008, 10(1): 24-32.
  • Tao Ling, Huimin Yu, Zhongyao Shen, Hui Wang, Jing Zhu. Virus-mediated FCC Iron Nanoparticle Induced Synthesis of Uranium Dioxide Nanocrystal. Nanotechnology, 2008, 19(11):115608 (6pp).