创新团队《Cancer Res》发封面文章

【字体: 时间:2009年09月18日 来源:生物通

编辑推荐:

  生物通报道,癌症研究方面的著名期刊《癌症研究》(Cancer Research)以封面文章的形式发表了中科院生物物理研究所刘志杰课题组在肝脏疾病相关蛋白质结构与功能研究方面的最新成果。该论文的标题为Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues。

  

生物通报道,癌症研究方面的著名期刊《癌症研究》(Cancer Research)以封面文章的形式发表了中科院生物物理研究所刘志杰课题组在肝脏疾病相关蛋白质结构与功能研究方面的最新成果。该论文的标题为Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues

 

刘志杰是中国科学院生物物理研究所创新队伍研究组组长,主要从事人体内信号转录调控和激活相关蛋白质及蛋白质复合体的结构与功能研究;与人类肝脏疾病相关蛋白质的结构与发病机理的研究。结构蛋白质组学新技术和新方法的研究。

 

该项工作主要由博士后武栋完成,张荣光研究员亦参与了部分研究工作。该研究课题得到了国家自然科学基金委、科技部、卫生部和中国科学院的资助。

 

据悉,叶酸依赖型单碳代谢途径与一些重要的生命活动密切相关,如嘌呤、胸苷和氨基酸代谢等,对细胞的增殖和分化有着重要的调控作用。该代谢途径中的许多催化酶是癌症化疗和其它代谢类疾病的重要靶标,目前市场上已有多种以该代谢途径中的催化酶为靶标的药物用于临床。人源5,10-次甲基四氢叶酸合成酶(Homo sapiens 5,10-methenyltetrahydrofolate synthetase 简称hMTHFS,酶学分类名:EC 6.3.3.2)位于单碳代谢途径的起始点,对代谢途径下游单碳代谢的调控非常重要。针对癌症引起的基因组甲基化异常、DNARNA的完整性、DNA的修复能力等,hMTHFS都是一个非常关键的调控位点。因此,hMTHFS也是一个极具潜力的药物靶点。

 

由于长期以来缺乏hMTHFS的三维结构,人们对其催化和调控的分子机制缺乏深入的了解,以hMTHFS为靶标的药物研发也进展缓慢。刘志杰课题组的该项研究工作报道了该催化酶的四种不同的复合物模型,其中包括hMTHFS-ATP-底物的反应中间态和产物的结构,首次向人们揭示了hMTHFS催化反应活性位点的组成、参与催化反应的重要氨基酸以及催化反应的详细过程。该项研究成果为后续的基于结构的药物设计提供了宝贵的结构信息,为癌症化疗和代谢疾病治疗的新药研制奠定了基础。

生物通推荐原文检索

Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues

Dong Wu1, Yang Li1, Gaojie Song1, Chongyun Cheng1, Rongguang Zhang2, Andrzej Joachimiak2, Neil Shaw1 and Zhi-Jie Liu1

1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China and 2 Structural Biology Center, Argonne National Laboratory, Argonne, Illinois

 

Requests for reprints: Zhi-Jie Liu or Neil Shaw, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Phone: 86-10-64857988; Fax: 86-10-64888426; E-mail: zjliu@ibp.ac.cn or neilshaw@moon.ibp.ac.cn.

 

Key Words: antifolate • cancer • 5,10-methenyltetrahydrofolate synthetase • one-carbon metabolic network • X-ray crystallography

 

5,10-Methenyltetrahydrofolate synthetase (MTHFS) regulates the flow of carbon through the one-carbon metabolic network, which supplies essential components for the growth and proliferation of cells. Inhibition of MTHFS in human MCF-7 breast cancer cells has been shown to arrest the growth of cells. Absence of the three-dimensional structure of human MTHFS (hMTHFS) has hampered the rational design and optimization of drug candidates. Here, we report the structures of native hMTHFS, a binary complex of hMTHFS with ADP, hMTHFS bound with the N5-iminium phosphate reaction intermediate, and an enzyme-product complex of hMTHFS. The N5-iminium phosphate captured for the first time in our crystal structure unravels a unique strategy used by hMTHFS for recognition of the substrate and provides structural basis for the regulation of enzyme activity. Binding of N10-substituted folate analogues places Y152 in the middle of the channel connecting ATP binding site with the substrate binding pocket, precluding the positioning of -phosphate for a nucleophilic attack. Using the structures of hMTHFS as a guide, we have probed the role of residues surrounding the active site in catalysis by mutagenesis. The ensemble of hMTHFS structures and the mutagenesis data yield a coherent picture of the MTHFS active site, determinants of substrate specificity, and new insights into the mechanism of inhibition of hMTHFS. [Cancer Res 2009;69(18):7294–301]

 

刘志杰研究员

1991年-1995 中国科学院生物物理研究所,获博士学位

1995 University of Pittsburgh,博士后

1995年-2005 University of Georgia,博士后, 助理研究员,副研究员

2006年- 中国科学院生物物理研究所,"****"研究员

 

 

 

代表性论文:

Song, G., Li, Y., Cheng, C., Zhao, Y., Gao, A., Zhang, R., Joachimiak, A., Shaw, N., & Liu, Z. J. (2008) Structural insight into acute intermittent porphyria. Faseb J., in press.(Correspondence) 

 

Shaw, N., Tempel, W., Chang, J., Yang, H., Cheng, C., Ng, J., Rose, J., Rao, Z., Wang, B. C. & Liu, Z. J. (2008) Crystal structure solution of a parb-like nuclease at atomic resolution. Proteins, 70(1), 263-267. (Correspondence) 

 

Shaw, N., Zhao, M., Cheng, C., Xu, H., Saarikettu, J., Li, Y., Da, Y., Yao, Z., Silvennoinen, O., Yang, J., Liu, Z.J, Wang, B. C. & Rao, Z. (2007) The multifunctional human p100 protein 'hooks' methylated ligands. Nat Struct Mol Biol, 14(8), 779-84.(Correspondence) 

 

Shimada, A., Niwa, H., Tsujita, K., Suetsugu, S. Kyoko, H.S., Akasaka, R.,Nishino, Y., Toyama, M., Chen, L., Liu, Z.J, Wang, B.C., Yamamoto, M., Terada, T., Miyazawa, A., Shirouzu, M., Tanaka, A., Sugano, S., Takenawa, T., and Yokoyama, S. (2007). Curved EFC/F-BAR domain dimers are joined end to end into a filament for membrane invagination in endocytosis. Cell, 129, 747-759.

 

Liu, Z.J., Stepanyuk, G.A., Vysotski, E.S., Lee, J., Markova, S.V., Malikova, N.P., and Wang, B.C. (2006). Crystal structure of obelin after Ca2+-triggered bioluminescence suggests neutral coelenteramide as the primary excited state. Proc Natl Acad Sci 103, 2570-2575.

相关新闻
生物通微信公众号
微信
新浪微博
  • 搜索
  • 国际
  • 国内
  • 人物
  • 产业
  • 热点
  • 科普
  • 急聘职位
  • 高薪职位

知名企业招聘

热点排行

    今日动态 | 人才市场 | 新技术专栏 | 中国科学人 | 云展台 | BioHot | 云讲堂直播 | 会展中心 | 特价专栏 | 技术快讯 | 免费试用

    版权所有 生物通

    Copyright© eBiotrade.com, All Rights Reserved

    联系信箱:

    粤ICP备09063491号