結論

生物感應器-BIAcore 是以 SPR 原理為基礎的一種生物分子分 析系統，近年來引人注目，發展快速及具有潛力的生物技術。

BIAcore 不但使用上相當的快速、省時、也免除了需要標示的麻 煩以及較少的污染問題，此外其感應晶片更能重複的循環使用減 少耗材。配合一整套設計完善之數據分析與即時偵測顯示的功 能，相較於其它技術更具推廣之潛力。此系統的應用範圍相當廣 泛，除了本篇論文所探討之應用，包括:成功的利用 BIA 的技術 輔助傳統測試藥理方法進行 MAT 抑制物及 Grb2 SH2 抑制物篩 選；另外，可提供蛋白質與分子間相互作用的動態訊息，對生物 分子的結構研究與反應機制提供一個極有價值之研究方法，此 外，也能應用於免疫分析、核酸研究、抗體定性、蛋白工程、神 經生物學等方面。因此，生物分子交互作用分析- BIA 將是未來 應用於生化分析發展上之一個重要技術。

參考文獻

1. C. S. Mayo and R. B. Hallock. Immunoassay based on surface plasmon oscillations,

Journal of Immunological Methods, 120 (1989) 105-114

2. Esa Stenberg, Bjorn Persson, Hakan Root and Csaba Urbanuczky. Quantitative determination of surface concentraction of protein with Surface Plasmon Resonance using radiolabeled proteins, Journal of colloid and Interface Science. 143. 2. (1991) 513-526

3.P. B. Daniels, J. K. Deacon, M. J. Eddowes and D. G. Pedley. Surgace Plasmon Resonance applied to immunosensing, Sensors and Actuators. 15 (1988) 11-18

4. U. Jonsson, L. Fagerstam, B. Ivarsson, B. Johnsson, and M. Malmqvist. Real-time biospecific interaction analysis using Surface Plasmon Resonance and a sensor chip technology, Biotechniques. 11. 5. (1991) 620-626

5. Liedberg, B., Nylander, C. and Lundstrom, l. Sensors Actuators. 4. (1983) 299-304

6. 吳宗正, 生物技術, 18. (1993) 247-262

7. 陳治誠, 科儀新知, 15(2). (1982) 71-81

8. Berit Johne, Margaretha Gadnell and Kari Hansen. Epitope mapping and binding of monoclonal antibodies studied by real time biospecific interaction analysis using surface plasmon resonance, Journal of Immunological Methods. 160 (1993) 191-198

9. Melen J. Watts, Debra Yeung, and Helen Parkes. Real- time detection and quantification of DNA hybridization by an optical biosensor, Journal. Chem. 67, (1995) 4283-4289

10. Daniele Volpi and Dario Ballinari. BIA technology for new anticancer drug discovery, BIA iournal (1997) 15-16

11. Brian C. Cunningham and James A. Wells. Comparison of structural and a functional epitope, J. Mol. Biol. 234 (1993) 554-563

12. Timothy D. Bartley, Robert W. Hunt and Gary M. Fox. B61 is a ligand for the

ECK receptor protein-tyrosine kinase, Nature. 368. 7. (1994) 558-560

13. Karin Stenhag, Peter Nilsson, Anita Larsson and Mathias Uhlen. Detections of oligonucleotide probe affinities using Surface Plasmon Resonance:A means for Mutational Scanning, Biochemistry 246 (1997) 34-44

14. Robert Karlsson, Lars Fagerstam, Helena Nilshans and Bjorn Persson. Analysis of active antibody concentration. Separation of affinity and concentration parameters,

Journal of Immunological Methods, 166 (1993) 75-84

15. Maguns Malmqvist. Biospecific interaction analysis using biosensor technology,

Nature. 361. 14. (1993) 186-187

16. .Stefan Lofas and Bo Johnsson. A Novel Hydrogel Matrix on gold surfaces in Surface Plasmon Resonance sensors for fast and efficient covalent immobilization of ligands, J. CHEM. SOC., CHEM. COMMUN., (1990) 1526-1528

17. BIA Applications Handbook, edition June (1994)

18. .BIA Technology Handbook, edition June (1994)

19. Lars G. Fagerstam, Asa Frostell-Karlesson, Robert Karlesson, Bjorn Persson and Inger Ronnberg. Biospecific interaction analysis using surface plasmon resonance detection applied to kinetic, binding site and concentration analysis, Journal of

Chromatography, 597 (1992) 397-410

20. Bo Johnsson, Stefan Lofas and Gabrielle Lindquist. Immobilization of proteins to a carboxymethyldextran- modified gold surface for biospecific interaction analysis in Surface Plasmon Resonance sensors, Analytical Biochemistry 198 (1991) 268-277

21. Peter End, Ivan Gout, Michael J. Fry, George Panayotou, Ritu Dhand, Kazuyoshi Yonezawa and Michael D. Waterfield. A biosensor approach to probe the structure and function of the p85α subunit of the phosphatidylinositol 3-kinase complex,

The Journal Of Biological Chemistry 268, 14, (1993) 10066-10075

22. Patericia C. Weber, D. H. Ohlendorf, J. J. Wendoloski and F. R. Salemme.

Structural origins of high-affinity biotin binding to streptavidin, Science 243

(1989) 85-88

23. Robert Karlsson and Ralph Stahlberg. Surface Plasmon Resonance detection and multispot sensing for direct monitoring of interactions involving

low-molecular-weight analytes and for determination of low affinities, Analytical

Biochemistry 228, (1995) 274-280

24. .Liau MC, Chang CF and Giovanella BC. Demonstration of an altered S-adenosylmethionine synthetase in human malignant tumors xenografted into athymic nude mice, J. Natl. Cancer Inst. 64. (1980) 1071

25. Liau MC, Chang CF, Saunders GF and Tsai TH. S- adenosylhomocysteine hydrolases as the primary target enzymrs in androgen regulation of methylation complexes, Arch Biochem Biophys. 208. (1981) 261

26. De La Rosa J, Geller AM, LeGros HL Jr and Kotb M. Induction of interleukin 2 production but not methionine adenosyltransferase activity or

S-adenosylmethionine turnover in Jurkat T-cells, Cancer Res. 15. 52(12). (1992) 3361-3366

27. Hoffman RM. Methioninase: a therapeutic for diseases related to altered

methionine metabolism and transmethylation: cancer, heart disease, obesity, aging, and Parkinsons disease, Hum Cell. 10(1). (1997) 69-80

28. Cheng H, Gomes-Trolin C, Aquilonius SM, Steinberg A, Lofberg C, Ekblom J and Oreland L. Levels of L-methionine S-adenosylhomocysteine in whole blood of patients with Parkinsons disease, Exp Neurol. 145. (1997) 580-585

29. Lavrador, K., Guillerm, D. and Guillerm G.A new series of cyclic amino acids as inhibitors of S-adenosyl L-Methionine synthetase, Bioorg. Med. Chem. Lett.

8(13) (1998) 1629-1634

30. Liau MC and Burzynski SR. Altered methylation complex isozymes as selective targets for cancer chemotherapy, Drugs Exp Clin Res. 12. Suppl1. (1986) 77-86

31. Paukovits, J. B., Paukovits, W.R. and Laerum, O. D. Identification of a regulatory peptide distinct from Normal Granulocyte-derived Hemoregulatory peptide produced by human promyelocytic HL-60 Leukemia cells after differentiation

induction with Retinoic Acid, Cancer Research. 46. (1986) 4444-4448

32. Yuan-Shan Tu, Li-Jiau Huang, Mei-Hua Has, Sheng-Horng Wang, Jem-Min Lai, Chiu-Chang Yeh, Feng-Di T. Lung and Sheng-Chu Kuo. Synthesis of

Hemoregulatory peptide derivatives as Inhibitors of the interaction between Methionine Adenosyl Transferase and its binding partner, The Chinese Pharmacentical Journal. 52. (2000) 139-149

33. Lai, J. M., L. T., Chung, J. G., Huang, L. J., Liau, M. C.and Kuo, S. C.

All-trans-retinoic acid and Indole-3-acetic acid inhibit Methionine Adenosyl Transferase activity in human tumor Cells, Clin Pharm. J. 49(2). (1997). 61-76

34. Feng-Di T. Lung, C. Richter King and Peter P. Roller. Development of

non-phosphorylated cyclic thioether peptide binding to the Grb2 SH2 domain,

Peptide Science. 6. (1999) 45-49

35. Hermann GRAM, Rita SCHMITZ, Jean Francosis ZUBER and Gotz BAUMANN.

Identification of phosphopeptide ligands for the Src-homology 2 (SH2) domain of Grb2 by phage display, Eur. J. Biochem. 246. (1997) 633-637

36. Wang-Qing Liu, Michel Vidal, Nohad Gresh, Bernard P. Roques and Christiane Garbay. Small peptide containing phosphotyrosine and adjacent α

Me-phosphotyrosine or its mimetics as highly potent inhibitors of Grb2 SH2 domain. J. Med. Chem. 42. (1999) 3737-3741

37. Yang Gao, Juliet Luo, Zhu-JunYao, Ribo Guo, Hong Zou, James Kelley, johannes H. Vo igt, Dajun Yang and Terrence R. Burke, Jr. Inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. 2. 4-(2-Malonyl) phenylalanine as a potent phosphotyrosyl mimetic. J. Med. Chem. 43. (2000) 911-920

38. Ya-Qiu Long, Zhu-Jun Yao, Johannes H. Voigt, Feng-Di t. Lung, Juliet H. Luo, Terrence R. Burke, Jr., C. Richter King, Dajun Yang and Peter P. Roller. Structure requirements for Tyr in the consensus sequence Y-E-N of a novel

nonphosphorylated inhibitor to the Grb2 SH2 domain, Biochemical and Biophysical Research Communications. 264. (1999) 902-908

39. Mayer, B. J. and Baltimore, D. Signalling through SH2 and SH3 domain, Trends

Cell Biol. 14. (1993) 6926-6935

40. Ya-Qiu Long, Johannes H. Voigt, Feng-Di T. Lung, C. Richter King and Peter P.

Roller, Bioorganic &Medicinal Chemistry Letters. 9. (1999) 2267-2272

41. Schlessinger, J. and Bar-Sagi, D. Activation of Ras and other signaling pathways by receptor tyrosine kinase, Glod Spring Harbor Symp Quant Biol. 59.

(1994) 173-179

42. Sastry, L., Cao, T. and King, R. Multiple Grb2-protein complexes in human cancer cells, Int J. Cancer. 70. (1997) 208-213

43. Furet, P., Gay, B., Garcia-Echeverria, C., rahuels, J., Fretz, H., Schoepter, J. and Caravatti. Discovery of 3-amino-benzyloxycarbonyl as N-terminal group

conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2 SH2 domain, J. Med. Chem. 40. (1997) 3551-3556

44. Lyn Oligino, Feng-Di T. Lung, Lakshmi Sastry, James Bigelow, Tin Cao, Michael Currant, Terrence R. Burke, Jr., Shaomeng Wang, David Krag, Peter P. Roller and C. Richter King. Nonphosphorylated peptide ligands for the Grb2 Src Homology 2 domain, The Journal of Biological Chemistry. 272. 46. (1997) 29046-29052

45. Maignan, S., Guilloteau, J.-P., Fromage, N., Arnoux, B., Becquart, J. and Ducruix, A., Nature. 268. (1995) 291-293

46. Songyarg, Z., Shoelson, S. E., Mc glade, J., Olivier, P., Pawson, T., Bustelo, X. R., Barbacid, M., Sabe, H. and Cantly, L. C., et al (1993)

47. Joseph Rahuel, Carlos Garcia-Echeverria, Pascal Furet Andre Strauss, Giorgio Caravatti, Heinz Fretz, Joseph Schoepfer and Brigitte Gay. Structure basis for the high affinity of amino-aromatic SH2 phosphopeptide ligands, J. Med. Biol. 279.

(1998) 1013-1022

48. M. Bellanda, E. Peggion, R. Burgi, W. van Gunsteren, S. Mammi. Conformational study of an Aib-rich peptide in DMSO by NMR, J. Peptide Res. 57. (2001) 97-106

49. Salcini, A. E., McGlade, J., Pelicci, G., Nicoletti, I., Pawson, T. and Pelicci, P.

Fromation of Shc-Grb2 complex is necessary to induce neoplastic trans for mation by overepression of Shc proteins, Oncogene. 9. (1994) 2827-2836

50. .Martha L. Ludwig and Rowena G. Matthews. Structure-based perspectives on B

12

51. Daniel E. Holloway and E. Neil G. Marsh. Adenosylcobalamin-dependent

glutamate mutase from Clostridium tetanomorphum, The Journal of Biological

Chemistry. 269. 32. (1994) 20425-20430

52. Filippo Mancia, Nicholas H Keep, Atsushi Nakagawa, Peter F Leadlay, sean McSweeney, Bjarne Rasmussen, Peter Bosecke, Olivier Diat and Philip R Evans.

How coenzyme B

12

methylmalonyl-coenzyme A mutase at 2 A resolution, Structure. 4. 3. (1996) 339-350

53. Oskar Zelder, Birgitta Beatrix, Friedrich Kroll, Wolfgang Buckel. Coordination of a histidine residue of the protein-component S to the cobalt atom in coenzyme B

12

369. (1995) 252-254

54. E. Neil G. Marsh and Daniel E. Holloway. Clonong and sequencing of glutamate mutase component S from Clostridium tetanomorphum, FEBS. 310. 2. (1992) 167-170

55. Daniel E. Holloway and E. Neil G. Marsh. Cloning and sequencing of glutamate mutase component E from Clostridium tetanomorphum, FEBS. 371. 1. (1993) 44-48

56. E. Neil G. Marsh. Tritium isotope effects in Adenosylcobalamin-dependent glutamate mutase: Implications for the mechanism, Biochemistry. 34. (1995) 7542-7547

57. Mohan Amaratunga, Kerry Fluhr, Joseph T. Jarrett, Catherine L. Drennan, Martha L. Ludwig, Rowena G. Matthews and Jeffrey D. scholten. A synthetic module for the metH gene permits Facile Mutagenensis of the cobalamin-binding region of Escherichia coli Methionine synthase: Initial characterization of seven mutase proteins. Biochemistry. 35. (1996) 2453-2463

58. Joseph T. Jarrett, Mohan Amaratunga, Catherine L. Drennan, Jeffrey D. Scholten,

Richard H. Sands, Martha L. Ludwig and Rowena G. Matthews. Mutations in the B

12

Methylcobalamin reactivity, Biochemistry. 35. (1996) 2464-2475

59. Catherine Luschinsky Drennan, Sha Huang, James t. Drummond, Rowena G.

Mattews and Martha L. Ludwig. How a protein binds B

12

12

1669-1674

60. Hao-Ping Chen and E. Neil G. Marsh. How enzymes control the reactivity of adenosylcobalamin: Effect on coenzyme binding and catalysis of Mutations in the consrved Histidine-Aspartate pair of glutamate mutase, Biochemistry. 36. (1997) 7884-7889

61. Iodice, A. A. J. Biol. Chem. 239. (1964) 3260-3266