Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지

Chemical Genomics with Natural Products

  • Jung, Hye-Jin (Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University) ;
  • Ho, Jeong-Kwon (Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University)
  • Published : 2006.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Natural products are a rich source of biologically active small molecules and a fertile area for lead discovery of new drugs [10, 52]. For instance, 5% of the 1,031 new chemical entities approved as drugs by the US Food and Drug Administration (FDA) were natural products between 1981 and 2002, and another 23% were natural product-derived molecules [53]. These molecules have evolved through millions of years of natural selection to interact with biomolecules in the cells or organisms and offer unrivaled chemical and structural diversity [14, 37]. Nonetheless, a large percentage of nature remains unexplored, in particular, in the marine and microbial environments. Therefore, natural products are still major valuable sources of innovative therapeutic agents for human diseases. However, even when a natural product is found to exhibit biological activity, the cellular target and mode of action of the compound are mostly mysterious. This is also true of many natural products that are currently under clinical trials or have already been approved as clinical drugs [11]. The lack of information on a definitive cellular target for a biologically active natural product prevents the rational design and development of more potent therapeutics. Therefore, there is a great need for new techniques to expedite the rapid identification and validation of cellular targets for biologically active natural products. Chemical genomics is a new integrated research engine toward functional studies of genome and drug discovery [40, 69]. The identification and validation of cellular receptors of biologically active small molecules is one of the key goals of the discipline. This eventually facilitates subsequent rational drug design, and provides valuable information on the receptors in cellular processes. Indeed, several biologically crucial proteins have already been identified as targets for natural products using chemical genomics approach (Table 1). Herein, the representative case studies of chemical genomics using natural products derived from microbes, marine sources, and plants will be introduced.

Keywords

References

  1. Abe, J., W. Zhou, N. Takuwa, J. Taguchi, K. Kurokawa, M. Kumada, and Y. Takuwa. 1994. A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclindependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells. Cancer Res. 54: 3407-3412
  2. Adam, G. C., C. D. Vanderwal, E. J. Sorensen, and B. F. Cravatt. 2003. (-)-FR182877 is a potent and selective inhibitor of carboxylesterase-1. Angew. Chem. Int. Ed. Engl. 42: 5480-5484 https://doi.org/10.1002/anie.200352576
  3. Altmann, K. H. 2001. Microtubule-stabilizing agents: A growing class of important anticancer drugs. Curr. Opin. Chem. Biol. 5: 424-431 https://doi.org/10.1016/S1367-5931(00)00225-8
  4. Arbiser, J. L., N. Klauber, R. Rohan, R. van Leeuwen, M. T. Huang, C. Fisher, E. Flynn, and H. R. Byers. 1998. Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med. 4: 376-383
  5. Bae, M. A., K. Yamada, D. Uemura, J. H. Seu, and Y. H. Kim. 1998. Aburatubolactam C, a novel apoptosis-inducing substance produced by marine Streptomyces sp. SCRC A-20. J. Microbiol. Biotechnol. 8: 455-460
  6. Bierer, B. E., P. K. Somers, T. J. Wandless, S. J. Burakoff, and S. L. Schreiber. 1990. Probing immunosuppressant action with a nonnatural immunophilin ligand. Science 250: 556-559 https://doi.org/10.1126/science.1700475
  7. Borel, J. F., C. Feurer, C. Magnee, and H. Stahelin. 1977. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology 32: 1017-1025
  8. Borisy, G. G. and E. W. Taylor. 1967. The mechanism of action of colchicine. Binding of colchicine-3H to cellular protein. J. Cell Biol. 34:525-533 https://doi.org/10.1083/jcb.34.2.525
  9. Buchnicek J. 1950. Colchicine in ripening seeds of the wild saffron (Colchicum autumnale L). Pharm. Acta Helv. 25: 389-401
  10. Butler, M. S. 2004. The role of natural product chemistry in drug discovery. J. Nat. Prod. 67: 2141-2153 https://doi.org/10.1021/np040106y
  11. Butler, M. S. 2005. Natural products to drugs: natural product derived compounds in clinical trials. Nat. Prod. Rep. 22: 162-195 https://doi.org/10.1039/b402985m
  12. Chen, J. K., W. S. Lane, and S. L. Schreiber. 1999. The identification of myriocin-binding proteins. Chem. Biol. 6: 221-235 https://doi.org/10.1016/S1074-5521(99)80038-6
  13. Cheung, W. Y. 1980. Calmodulin plays a pivotal role in cellular regulation. Science 207: 19-27 https://doi.org/10.1126/science.6243188
  14. Clardy, J. and C. Walsh. 2004. Lessons from natural molecules. Nature 432: 829-837 https://doi.org/10.1038/nature03194
  15. Clipstone, N. A. and G. R. Crabtree. 1992. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357: 695-697 https://doi.org/10.1038/357695a0
  16. Crews, C. M., W. S. Lane, and S. L. Schreiber. 1996. Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis. Proc. Natl. Acad. Sci. 93: 4316-4319
  17. Fenteany, G., R. F. Standaert, W. S. Lane, S. Choi, E. J. Corey, and S. L. Schreiber. 1995. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 5: 726-731
  18. Fujii, H., M. Nakajima, I. Saiki, J. Yoneda, I. Azuma, and T. Tsuruo. 1995. Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/ CD13. Clin. Exp. Metastasis 13: 337-344
  19. Gingras, A. C., B. Raught, and N. Sonenberg. 1999. eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68: 913- 963 https://doi.org/10.1146/annurev.biochem.68.1.913
  20. Griffith, E. C., Z. Su, B. E. Turk, S. Chen, Y. H. Chang, Z. Wu, K. Biemann, and J. O. Liu. 1997. Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem. Biol. 4: 461-471 https://doi.org/10.1016/S1074-5521(97)90198-8
  21. Hait, W. N. 1987. Targeting calmodulin for the development of novel cancer chemotherapeutic agents. Anticancer Drug Des. 2: 139-149
  22. Handschumacher, R. E., M. W. Harding, J. Rice, R. J. Drugge, and D. W. Speicher. 1984. Cyclophilin: A specific cytosolic binding protein for cyclosporin A. Science 226: 544-547 https://doi.org/10.1126/science.6238408
  23. Harding, M. W., A. Galat, D. E. Uehling, and S. L. Schreiber. 1989. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341: 758-760 https://doi.org/10.1038/341758a0
  24. He, L., G. A. Orr, and S. B. Horwitz. 2001. Novel molecules that interact with microtubules and have functional activity similar to taxol. Drug Discov. Today 6: 1153-1164 https://doi.org/10.1016/S1359-6446(01)02038-4
  25. Heitman, J., N. R. Movva, and M. N. Hall. 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 23: 905-909
  26. Heitman, J., N. R. Movva, P. C. Hiestand, and M. N. Hall. 1991. FK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. 88: 1948-1952
  27. Hou, T. and X. Xu. 2004. Recent development and application of virtual screening in drug discovery: An overview. Curr. Pharm. Des. 10: 1011-1033 https://doi.org/10.2174/1381612043452721
  28. Ingber, D., T. Fujita, S. Kishimoto, K. Sudo, T. Kanamaru, H. Brem, and J. Folkman. 1990. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348: 555-557 https://doi.org/10.1038/348555a0
  29. Itazaki, H., K. Nagashima, K. Sugita, H. Yoshida, Y. Kawamura, Y. Yasuda, K. Matsumoto, K. Ishii, N. Uotani, and H. Nakai. 1990. Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J. Antibiot. 43: 1524-1532 https://doi.org/10.7164/antibiotics.43.1524
  30. Jin, Y., J. Yu, and Y. G. Yu. 2002. Identification of hNopp140 as a binding partner for doxorubicin with a phage display cloning method. Chem. Biol. 9: 157-162 https://doi.org/10.1016/S1074-5521(02)00096-0
  31. Jordan, M. A. and L. Wilson. 1998. Microtubules and actin filaments: Dyanmic targets for cancer chemotherapy. Curr. Opin. Cell Biol. 10:123-131 https://doi.org/10.1016/S0955-0674(98)80095-1
  32. Kelloff, G. J., J. A. Crowell, E. T. Hawk, V. E. Steele, R. A. Lubet, C. W. Boone, J. M. Covey, L. A. Doody, G. S. Omenn, and P. Greenwald. 1996. Strategy and planning for chemopreventive drug development: Clinical development plans II. J. Cell Biochem. 26: 54-71
  33. Kijima, M., M. Yoshida, K. Sugita, S. Horinouchi, and T. Beppu. 1993. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J. Biol. Chem. 268: 22429-22435
  34. Kim, H. J., J. H. Kim, C. H. Lee, and H. J. Kwon. 2006. Gentisyl alcohol, an antioxidant from microbial metabolite, induces angiogenesis in vitro. J. Microbiol. Biotechnol. 16: 475-479
  35. Kino, T., H. Hatanaka, S. Miyata, N. Inamura, M. Nishiyama, T. Yajima, T. Goto, M. Okuhara, M. Kohsaka, H. Aoki, and H. Imanaka. 1987. FK-506, a novel immunosuppressant isolated from a Streptomyces. J. Antibiot. 40: 1256-1265 https://doi.org/10.7164/antibiotics.40.1256
  36. Ko, H. R. 2002. PC-766B' and PC-766B, 16-membered macrolide angiogenesis inhibitors produced by Nocardia sp. RK97-56. J. Microbiol. Biotechnol. 12: 829-833
  37. Koehn, F. E. and G. T. Carter. 2005. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4: 206-220 https://doi.org/10.1038/nrd1657
  38. Kwok, B. H., B. Koh, M. I. Ndubuisi, M. Elofsson, and C. M. Crews. 2001. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem. Biol. 8: 759- 766 https://doi.org/10.1016/S1074-5521(01)00049-7
  39. Kwon, H. J. 2003. Chemical genomics-based target identification and validation of anti-angiogenic agents. Curr. Med. Chem. 10: 717-736 https://doi.org/10.2174/0929867033457755
  40. Kwon, H. J. 2006. Discovery of new small molecules and targets towards angiogenesis via chemical genomics approach. Curr. Drug Targets 7: 397-405 https://doi.org/10.2174/138945006776359377
  41. Kwon, H. J., J. H. Kim, H. J. Jung, Y. G. Kwon, M. Y. Kim, J. R. Rho, and J. H. Shin. 2001. Anti-angiogenic activity of Acalycixenolide E, a novel marine natural product from Acalycigorgia inermis. J. Microbiol. Biotechnol. 11: 656- 662
  42. Levine, M. 1951. The action of colchicine of cell division in human cancer, animal, and plant tissues. Ann. N. Y. Acad. Sci. 51:1365-1408 https://doi.org/10.1111/j.1749-6632.1951.tb30070.x
  43. Liu, J., J. D. Jr. Farmer, W. S. Lane, J. Friedman, I. Weissman, and S. L. Schreiber. 1991. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66: 807-815 https://doi.org/10.1016/0092-8674(91)90124-H
  44. Liu, S., J. Widom, C. W. Kemp. C. M. Crews, and J. Clardy. 1998. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 282: 1324-1327 https://doi.org/10.1126/science.282.5392.1324
  45. Look, A. T., R. A. Ashmun, L. H. Shapiro, and S. C. Peiper. 1989. Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N. J. Clin. Invest. 83: 1299-1307 https://doi.org/10.1172/JCI114015
  46. Low, W. K., Y. Dang, T. Schneider-Poetsch, Z. Shi, N. S. Choi, W. C. Merrick, D. Romo, and J. O. Liu. 2005. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell 20: 709-722 https://doi.org/10.1016/j.molcel.2005.10.008
  47. Lowther, W. T., D. A. McMillen, A. M. Orville, and B. W. Matthews. 1998. The anti-angiogenic agent fumagillin covalently modifies a conserved active-sith histidine in the Escherichia coli methionine aminopeptidase. Proc. Natl. Acad. Sci. USA 95: 12153-12157
  48. Luibrand, R. T., T. R. Erdman, J. J. Vollmer, P. J. Scheuer, J. Finer, and J. Clardy. 1979. Ilimaquinone, a sesquiterpenoid quinone from a marine sponge. Tetrahedron 35: 609-612 https://doi.org/10.1016/0040-4020(79)87004-0
  49. Macarron, R. 2006. Critical review of the role of HTS in drug discovery. Drug Discov. Today 11: 277-279 https://doi.org/10.1016/j.drudis.2006.02.001
  50. Meng, L., B. H. Kwok, N. Sin, and C. M. Crews. 1999. Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Res. 59: 2798- 2801
  51. Mohri, H. 1968 Amino-acid composition of 'Tubulin' constitution microtubules of sperm flagella. Nature 217: 1053-1054 https://doi.org/10.1038/2171053a0
  52. Newman, D. J., G. M. Cragg, and K. M. Snader. 2000. The influence of natural products upon drug discovery. Nat. Prod. Rep. 17: 215-234 https://doi.org/10.1039/a902202c
  53. Newman, D. J., G. M. Cragg, and K. M. Snader. 2003. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66: 1022-1037 https://doi.org/10.1021/np030096l
  54. Nishi, K., M. Yoshida, D. Fujiwara, M. Nishikawa, S. Horinouchi, and T. Beppu. 1994. Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J. Biol. Chem. 269: 6320-6324
  55. Northcote, P. T., J. W. Blunt, and M. H. G. Munro. 1991. Pateamine: A potent cytotoxin from the New Zealand marine sponge, Mycale sp. Tetrahedron Lett. 32: 6411-6414 https://doi.org/10.1016/0040-4039(91)80182-6
  56. Osawa, M, M. B. Swindells, J. Tanikawa, T. Tanaka, T. Mase, T. Furuya, and M. Ikura. 1998. Solution structure of calmodulin-W-7 complex: The basis of diversity in molecular recognition. J. Mol. Biol. 276: 165-176 https://doi.org/10.1006/jmbi.1997.1524
  57. Paterson, I. and E. A. Anderson. 2005. The renaissance of natural products as drug candidates. Science 21: 451-453
  58. Peterson, J. R. and T. J. Mitchison. 2002. Small molecules, big impact: A history of chemical inhibitors and the cytoskeleton. Chem. Biol. 9: 1275-1285 https://doi.org/10.1016/S1074-5521(02)00284-3
  59. Piggott, A. M. and P. Karuso. 2004. Quality, not quantity: The role of natural products and chemical proteomics in modern drug discovery. Comb. Chem. High Throughput Screen 7: 607-630
  60. Radeke, H. S., C. A. Digits, R. L. Casaubon, and M. L. Snapper. 1999. Interactions of (-)-ilimaquinone with methylation enzymes: Implications for vesicular-mediated secretion. Chem. Biol. 6: 639-647 https://doi.org/10.1016/S1074-5521(99)80115-X
  61. Radeke, H. S. and M. L. Snapper. 1998. Photoaffinity study of the cellular interactions of ilimaquinone. Bioorg. Med. Chem. 6: 1227-1232 https://doi.org/10.1016/S0968-0896(98)00100-X
  62. Rodeschini, V., J. G. Boiteau, P. Van de Weghe, C. Tarnus, and J. Eustache. 2004. MetAP-2 inhibitors based on the fumagillin structure. Side-chain modification and ringsubstituted analogues. J. Org. Chem. 69: 357-373 https://doi.org/10.1021/jo035065+
  63. Rosato, R. R. and S. Grant. 2004. Histone deacetylase inhibitors in clinical development. Expert Opin. Investig. Drugs 13: 21-38 https://doi.org/10.1517/13543784.13.1.21
  64. Rozen, F., I. Edery, K. Meerovitch, T. E. Dever, W. C. Merrick, and N. Sonenberg. 1990. Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol. Cell Biol. 10: 1134-1144 https://doi.org/10.1128/MCB.10.3.1134
  65. Ruegger, A., M. Kuhn, H. Lichti, H. R. Loosli, R. Huguenin, C. Quiquerez, and A. von Wartburg. 1976. Cyclosporin A, a peptide metabolite from Trichoderma polysporum Rifai, with a remarkable immunosuppressive activity. Helv. Chim. Acta. 59: 1075-1092 https://doi.org/10.1002/hlca.19760590412
  66. Saiki, I., H. Fujii, J. Yoneda, F. Abe, M. Nakajima, T. Tsuruo, and I. Azuma. 1993. Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation. Int. J. Cancer 54: 137-143 https://doi.org/10.1002/ijc.2910540122
  67. Sato, Y. 2003. Aminopeptidases and angiogenesis. Endothelium 10: 287-290 https://doi.org/10.1080/714007543
  68. Sawada, S., G. Suzuki, Y. Kawase, and F. Takaku. 1987. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J. Immunol. 139: 1797-1803
  69. Schreiber, S. L. 1998. Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg. Med. Chem. 6: 1127-1152 https://doi.org/10.1016/S0968-0896(98)00126-6
  70. Sharma, S. V., T. Agatsuma, and H. Nakano. 1998. Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol. Oncogene 16: 2639-2645 https://doi.org/10.1038/sj.onc.1201790
  71. Shim, J. S., D. H. Kim, H. J. Jung, J. H. Kim, D. Lim, S. K. Lee, K. W. Kim, J. W. Ahn, J. S. Yoo, J. R. Rho, and H. J. Kwon. 2002. Hydrazinocurcumin, a novel synthetic curcumin derivative, is a potent inhibitor of endothelial cell proliferation. Bioorg. Med. Chem. 10: 2987-2992 https://doi.org/10.1016/S0968-0896(02)00129-3
  72. Shim, J. S. and H. J. Kwon. 2004. Chemical genetics for therapeutic target mining. Expert Opin. Ther. Targets 8: 653-661 https://doi.org/10.1517/14728222.8.6.653
  73. Shim, J. S., J. H. Kim, H. Y. Cho, Y. N. Yum, S. H. Kim, H. J. Park, B. S. Shim, S. H. Choi, and H. J. Kwon. 2003. Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin. Chem. Biol. 10: 695-704 https://doi.org/10.1016/S1074-5521(03)00169-8
  74. Shim, J. S., J. Lee, H. J. Park, S. J. Park, and H. J. Kwon. 2004. A new curcumin derivative, HBC, interferes with the cell cycle progression of colon cancer cells via antagonization of the Ca2+/calmodulin function. Chem. Biol. 11: 1455- 1463 https://doi.org/10.1016/j.chembiol.2004.08.015
  75. Siekierka, J. J., S. H. Hung, M. Poe, C. S. Lin, and N. H. Sigal. 1989. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341: 755-757 https://doi.org/10.1038/341755a0
  76. Sigg, H. P. and H. P. Weber. 1968. Isolation and structure elucidation of ovalicin. Helv. Chim. Acta. 51: 1395-1408 https://doi.org/10.1002/hlca.19680510624
  77. Sin, N., L. Meng, M. Q. Wang, J. J. Wen, W. G. Bornmann, and C. M. Crews. 1997. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc. Natl. Acad. Sci. 94: 6099-6103
  78. Sternson, S. M., J. C. Wong, C. M. Grozinger, and S. L. Schreiber. 2001. Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. Org. Lett. 3: 4239-4242 https://doi.org/10.1021/ol016915f
  79. Takizawa, P. A., J. K. Yucel, B. Veit, D. J. Faulkner, T. Deerinck, G. Soto, M. Ellisman, and V. Malhotra. 1993. complete vesiculation of Golgi membranes and inhibition of protein transport by a novel sea sponge metabolite, ilimaquinone. Cell 73: 1079-1090 https://doi.org/10.1016/0092-8674(93)90638-7
  80. Taunton, J., C. A. Hassig, and S. L. Schreiber. 1996. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272: 408-411 https://doi.org/10.1126/science.272.5260.408
  81. Thaloor, D., A. K. Singh, G. S. Sidhu, P. V. Prasad, H. K. Kleinman, and R. K. Maheshwari. 1998. Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin. Cell Growth Differ. 9: 305-312
  82. Tong, J. K., C. A. Hassig, G. R. Schinitzler, R. E. Kingston, and S. L. Schreiber. 1998. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395: 917-921 https://doi.org/10.1038/27699
  83. Towbin, H., K. W. Bair, J. A. DeCaprio, M. J. Eck, S. Kim, F. R. Kinder, A. Morollo, D. R. Mueller, P. Schindler, H. K. Song, J. van Oostrum, R. W. Versace, H. Voshol, J. Wood, S. Zabludoff, and P. E. Phillips. 2003. Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J. Biol. Chem. 278: 52964- 52971 https://doi.org/10.1074/jbc.M309039200
  84. Towle, M. J., K. A. Salvato, J. Budrow, B. F. Wels, G. Kuznetsov, K. K. Aalfs, S. Welsh, W. Zheng, B. M. Seletsk, M. H. Palme, G. J. Habgood, L. A. Singer, L. V. Dipietro, Y. Wang, J. J. Chen, D. A. Quincy, A. Davis, K. Yoshimatsu, Y. Kishi, M. J. Yu, and B. A. Littlefield. 2001. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 61: 1013-1021
  85. Vandonselaar, M., R. A. Hickie, J. W. Quail, and L. T. Delbaere. (1994) Trifluoperazine-induced conformational change in Ca(2+)-calmodulin. Nat. Struct. Biol. 1: 795-801 https://doi.org/10.1038/nsb1194-795
  86. Veigl, M. L., T. C. Vanaman, and W. D. Sedwick. 1984. Calcium and calmodulin in cell growth and transformation. Biochim. Biophys. Acta 738: 21-48
  87. Weisenberg, R. C., G. G. Borisy, and E. W. Taylor. 1968. The colchicine-binding protein of mammalian brain and its relation to microtubules. Biochemistry 7: 4466-4479 https://doi.org/10.1021/bi00852a043
  88. Wong, D. L., R. J. Hayashi, and R. D. Ciaranello. 1985. Regulation of biogenic amine methyltransferases by glucocorticoids via S-adenosylmethionine and its metabolizing enzymes, methionine adenosyltransferase and S-sdenosylhomocysteine hydrolase. Brain Res. 330:209-216 https://doi.org/10.1016/0006-8993(85)90679-1
  89. Yoshida, M., M. Kijima, M. Akita, and T. Beppu. 1990. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265: 17174-17179