在3月23日召開的上海市科學技術大會上,，生化與細胞所戚正武院士領銜的“活性多肽毒素結構與功能的研究”榮獲上海市科學技術進步一等獎,。
該項目從東亞馬氏鉗蝎及我國南海各種芋螺中獲得多種新的神經毒素，并深入研究了它們的蛋白質與基因結構,、生理功能及其構效關系,。
在對東亞馬氏鉗蝎神經毒素的研究中，研究者闡明了鈉通道毒素B－mKM1的蛋白與基因結構,，利用蛋白質工程獲得15個突變體,，深入研究其構效關系。發(fā)現(xiàn)新的鉀通道毒素,，具有高度選擇性,。發(fā)現(xiàn)具有雙功能的BmTx3，既可阻斷A型鉀電流,，也可抑制HERG鉀通道。提出毒素阻斷離子通道的新機理,。闡明了全蝎作為重要抗癲癇及鎮(zhèn)痛的物質基礎,。
在芋螺毒素研究方面，研究者從桶形芋螺中純化并克隆了■－BtX,，它代表芋螺毒素中一新的超家族,，是首次報道的鉀通道開放劑。從線紋芋螺中克隆了μ－SIIIA,，可作為先導化合物用于新的鎮(zhèn)痛藥物的開發(fā),。從多種芋螺中純化及克隆了M超家族中新一類芋螺毒素，提出了芋螺毒素超家族分類的新原則,。從6種芋螺中純化,、鑒定了新的多肽毒素40個左右，克隆鑒定的新基因超過60個,，涵蓋了各種超家族,。
該成果共發(fā)表SCI論文27篇，被他人引用197次,，論文總影響因子為94.4,，單篇最高影響因子為13.3。該成果不僅對神經學科的研究,，而且對開發(fā)治療多種神經性疾病的新藥具有重要意義,。
戚正武院士簡介
生物化學家。1932年4月出生于寧波,。1952年畢業(yè)于同濟大學化學系,，
1959年獲蘇聯(lián)莫斯科醫(yī)學科學院生物與醫(yī)學研究所副博士學位,。
1981-1982年以及1987年、1995年分別于美國Purdue 及Notre Dame大學進行學術交流,。曾擔任數(shù)屆國際《血栓研究》雜志的編委,，現(xiàn)任《中國科學》,《生物化學與生物物理學報》及其他國內多種學術期刊的編委。現(xiàn)兼同濟大學蛋白質研究所所長及化學系主任,。
1999年被評為中國科學院院士,，
2001年被評為第三世界科學院院士。
長期從事蛋白質,，活性多肽,，尤其是蛋白酶及其抑制劑的研究。其中慈菇蛋白酶抑制劑為國內首先發(fā)現(xiàn)的新的抑制劑家族,，有明顯的中國特色,，還克隆了凝血因子FVIII及vWF的全cDNA基因，并在CHO和BHK細胞中進行了表達,。近年來又解析了中華馬氏鉗蝎毒素中多種Na+通道毒素的氨基酸序列及其基因結構,，通過基因突變研究其結構與功能的關系，并開展了其它K+,Ca++及Cl-通道神經毒素的研究,，近來又找到了新的神經毒素,，從而開辟了新的研究領域。
發(fā)表論文百余篇,，大多數(shù)刊登在國外主要學術期刊及英文版"中國科學"上,，培養(yǎng)博士生及碩士生各20名。曾獲得中國科學院自然科學獎二等獎3次,，一等獎1次,，獲國家自然科學獎三等獎2次，1981年慕尼黑國際激肽會議上獲優(yōu)秀論文獎,。
長期以來從事活性多肽及酶蛋白結構與功能的研究,，利用蛋白質工程技術研究結構與功能的關系。有關蛋白酶抑制劑,，蝎及芋螺多肽神經毒素以及與凝血纖溶有關的蛋白質的研究居國際前沿,。曾從不同植物中分離純化了三種不同類型的蛋白酶抑制劑，闡明了它們的蛋白質,、基因及晶體結構,，確定了活性中心位置，其中多功能雙頭慈菇蛋白酶抑制劑是屬于新的抑制劑家族,。利用多肽合成,，蛋白酶限止性降解及蛋白質工程等手段研究了它們的結構與功能的關系。在基因水平上闡明了異常人血清白蛋白及血小板無力癥遺傳性疾病的基因缺陷,。對凝血因子Ⅷ及vWF因子進行了基因克隆,，并在哺乳動物細胞中獲得表達,，申請了生產重組凝血因子Ⅷ的專利。90年代以來又開展研究蝎及芋螺毒腺中各種離子通道及神經遞質受體的神經毒素,發(fā)現(xiàn)了多種結構全新的神經毒素,。此外在豬肝中分離純化了與體內重要生理功能相關的天然蛋白質前體加工酶的抑制劑,。
典型論文列表:
1. Hui-ling Yang, Rong-shu Luo, Li-xiu Wang, De-xu Zhu and Cheng-wu Chi Primary Structure and Disulfide Bridge Location of Arrowhead Double-headed Proteinase Inhibitors. J. Biochem. (Tokyo) 111, 537, 1992.
2. Xiao-ming Chen, Yue-wei Qian, Ke-da Gan and Cheng-wu Chi Chemical Synthesis, Molecular Cloning, and Expression of the Gene Coding for the Trichosanthes Trypsin Inhibitor -a Squash family Inhibitor. J. Biochem. (Tokyo) 112, 45, 1992.
3. Wen-feng Xu, Wei-kang Tao, Zhen-zhen Gong and Cheng-wu Chi cDNA and Genomic Structures of Arrowhead Proteinase Inhibitors J. Biochem. (Tokyo) 113, 153, 1993.
4. Min-hua Ling, Hai-yan Qi and Cheng-wu Chi Protein, cDNA, and Genomic DNA Sequences of the Towel Gourd Trypsin Inhibitor -- a Squash Family Inhibitor. J. Biol. Chem. (US) 268, 810, 1993.
5. Wei-chang Zan, Wen-feng Xu and Cheng-wu Chi Protein and Gene Structure Analysis of an Albumin Genetic Variant: Proalbumin Wu Yang (-2 Arg--His). Int. J. Peptide Protein Res. 41, 441, 1993.
6. Jian-ming Gu, Wen-feng Xu, Xiao-dong Wang, Cheng-wu Chi and Chang-geng Ruan Identification of a Nonsense Mutation at Amino Acid 584-Arg of Platelet Glycoprotein Iib in Patients with TypeI Glanzmann Thrombasthenia. British J. Hematology 83, 442, 1993.
7. Ling Wang, Xiao-hong Lin, Da-fu Cui, Zhen-yi Wang and Cheng-wu Chi★ Assignment of the Binding Site for Tissue Plasminogen Activator on Human Fibronectin J. Biol. Chem. (US) 269, 4332,1993.
8. Guang-da Lin, Wolfram Bode, Robert Huber, Cheng-wu Chi and Richard A. Engn The 0.25 nm X-ray Structure of the Bowman-Birk Type Inhibitor from Mung Bean in Ternary Complex with Porcine Trypsin. Eur. J. Biochem. 212, 549, 1993.
9. Yi-li Li, Qi-chen Huang, Shi-wei Zhang, Cheng-wu Chi and You-qi Tang Studies on anArtificial Trypsin Inhibitor Peptide Derived from the Mung Bean Trypsin Inhibitor: Chemical Synthesis, Refolding, and Crystallographic Analysis of its Complex with Trypsin. J. Biochem. (Tokyo) 116, 18, 1994.
10. Zhi-wei Xie, Ming-juan Luo, Wen-feng Xu and Cheng-wu Chi Two Reactive Site Location and Structure-Function Study of the Arrowhead Protease Inhibitors,A and B, Using Mutagenesis. Biochemistry (US) 36, 5846, 1997.
11. Ming-juan Luo, Wu-yuan Lu and Cheng-wu Chi Clarification of an Uncertain Intron within the cDNA Sequences of Arrowhead Proteinase Inhibitor A and B. J. Biochem. (Tokyo) 121, 991, 1997.
12. Ming-juan Luo, Yu-mei Xiong, Miao Wang, Da-cheng Wang and Cheng-wu Chi Purification and Sequence Determination of a New Neutral Mammalian Neurotoxin from Scorpion Buthus martensii Karsch. Toxicon 35, 723, 1997.
13. Yu-mei Xiong, Min-hua Ling, Da-cheng Wang and Cheng-wu Chi The cDNA and Genomic DNA Sequences of a Mammalian Neurotoxin from the Scorpion Buthus martensii Karsch. Toxicon 35, 1025, 1997.
14. Yu-mei Xiong, Min-hua Ling, Zheng-dao Lan, Da-cheng Wang and Cheng-wu Chi The cDNA Sequence of an Excitatory Insect Selective Neurotoxin from the Scorpion Buthus martinsi Karsch. Toxicon 37, 335, 1999.
15. Zheng-dao Lan, Li Dai, Xiao-liang Zhuo, Ke Xu, Jun-Cai Feng and Cheng-wu Chi Gene Cloning and Sequencing of BmK AS and BmK As-1, Two Novel Neurotoxins from the Scorpion Buthus martinsi Karsch. Toxicon 37, 815, 1999.
16. Yu-mei Xiong, Zheng-dao Lan, Miao Wang. Bo Liu, Xin-qi Liu, Hao Fei, Lai-gen Xu, Qi-Chang Xia, Chung-guang Wang, Da-cheng Wang and Cheng-wu Chi Molecular Characterization of a New Excitatory Insect Neurotoxin with an Analgesic Effect on Mice from the Scorpion Buthus martinsi Karsch. Toxicon 37, 1165, 1999.
17. Jing-jiang Wu, Li Dai, Zheng-dao Lan and Cheng-wu Chi Genomic Organization of Three Neurotoxins Active on Small Conductance Ca++-activated Potassium Channels from the Scorpion Buthus martinsi Karsch. FEBS Letters 452, 360, 1999.
18. Chun Chen, Xiao-dong Fang, Jiang Zhu, Xiang-fu Wu, Zu-chuan Zhang, Zheng-yi Wang and Cheng-wu Chi The Gene Expression of Coagulation Factor VIII in Mammalian Cell Lines. Thrombosis Res. 95, 105, 1999.
19. Yan-shi Zhu, Qi-chen Huang and Cheng-wu Chi Crystal Structure of Mung Bean Inhibitor Lysine Active Fragment Complex with Bovine ?-trypsin at 1.8 ? Resolution. J. Biomolecular Structure and Dynamics 16, 1219, 1999.
20. Feng Shao, Yu-mei Xiong, Rong-huan Zhu, Min-hua Ling, Cheng-wu Chi & Da-cheng Wang Expression and Purification of the BmK M1 Neurotoxin from the Buthus martinsi Karsch. Protein Expression and Purification 17, 358, 1999.
21. Jing-jiang Wu, Li Dai, Zheng-dao Lan and Cheng-wu Chi The Gene Cloning and Sequencing of Bm-12, a Chlorotoxin-like Peptide from the Scorpion Buthus martinsi Karsch. Toxicon 38, 661, 2000.
22. Li Dai, Jing-jiang Wu, Yi-hua Gu, Zheng-dao Lan, Min-hua Ling and Cheng-wu Chi Genomic organization of three novel toxins from the scorpion Buthus martinsi Karsch that are active on potassium channels. Biochem. J. 346, 805, 2000.
23. Hao Fei, Yan LI, Li-Xiu Wang, Ming-Juan Luo, Min-Hua Ling, Cheng-Wu Chi Purified nonhistone protein from porcine kidney acts as a suicide substrate inhibitor on furin-like enzyme. Acta Pharmacol. Sin. 21, 265, 2000.
24. Xiang-Dong Fang, Chun Chen, Qi Wang, Jian-Xin Gu, Cheng-Wu Chi The Interaction of the Calcium and Integrin Binding Protein (CIBP) with the Coagulation Factor VIII Thromb. Res. 102, 177, 2001.
25. Chun-Guang Wang, Xiao-Lin He, Feng Shao, Wei Liu, Min-Hua Ling, Da-Cheng Wang, Cheng-Wu Chi Molecular characterization of an anti-epilepsy peptide from the scorpio Buthus martensi Karsch. Eur. J. Biochem. 268, 2480, 2001.
26. Guang-yu Zhu, Qi-chen Huang, Yan-shi Zhu, Cheng-wu Chi, You-qi Tang X-ray study on an artificial mung bean inhibitor complex with bovine ?-trypsin in neat cyclohexane. Biochim. Biophys. Acta 1546, 98, 2001.
27. Chun Chen, Qi Wang, Xiang-dong Fang, Qin Xu, Cheng-wu Chi and Jian-xin Gu Roles of the phytanoyl CoA ?-hydroxylase in mediating the expression of human coagulation factor VIII. J. Biol. Chem. 276, 46340, 2001.
28. Jing-Jiang Wu, Lin-Lin He, Zhuan Zhou and Cheng-Wu Chi Gene expression, mutation and structure-function relationship of scorpion toxin BmP05 active on SKCa channels.Biochemistry 41, 2844, 2002.
29. Jiong Li, Cheng-wu Chi, Kang-cheng Ruan Conformation nearby Trp residues of APIA and APIB modulates the inhibitory specificity of the protease. Acta Biochi. Biophys. Sinica 34, 494, 2002.
30. Jiong Li, Kang-cheng Ruan, Cheng-wu Chi The assignment of the reactive sites of the double-headed arrowhead proteinase inhibitor A and B. Acta Biochi. Biophys. Sinica 34, 662, 2002.
31. C. Goudet, Cheng-wu Chi, J.Tytgat An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch. Toxicon. 40(9), 1239, 2002
32. Wang CG, Stankiewicz M, Ling MH, Pelhate M, Wang DC and Chi CW★. Purification of two depressant insect neurotoxins and their gene cloning from the scorpion Buthus martensi Karsch. J. Pept. Res. 61(1): 7-16, 2003.
33. Wang CG, Gilles N, Hamon A, Le Gall F, Stankiewicz M, Pelhate M, Xiong YM, Wang DC and Chi CW Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis. Biochemistry 42 (16), 4699-4708, 2003
34. Fan CX, Chen XK, Zhang C, Wang LX, Duan KL, He LL, Cao Y, Liu SY, Zhong MN, Ulens C, Tytgat J, Chen JS, Chi CW, and Zhou Z. A novel conotoxin from conus betulinus, k-BtX, unique in cysteine pattern and in function as a specific BK channel modulator.J Biol Chem. 278(15), 12624-12633, 2003
35. Chen-Qi Xu, Shun-Yi Zhu, Cheng-Wu Chi and Jan Tytgat Turret and pore block of K+Channels: what is the different? Trends Pharmac. Sci. 24(9): 446-449, 2003
