An oxidosqualene cyclase makes numerous products by diverse mechanisms: A challenge to prevailing concepts of triterpene biosynthesis

Journal of the American Chemical Society

Volumn 129, Issue 36, 2007, Pages 11213-11222

  Lodeiro, Silvia ^a   Xiong, Quanbo ^a,b   Wilson, William K ^a   Kolesnikova, Mariya D ^a   Onak, Carl S ^a   Matsuda, Seiichi P T ^a  

^a RICE UNIVERSITY   (United States)

^b TEXAS SOUTHERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARABIDOPSIS CYCLASES; MECHANISTIC PATHWAYS; PROTON ACCEPTORS; TRITERPENE;

BIOSYNTHESIS; CHARACTERIZATION; DEPROTONATION; GENES; HYDROPHOBIC CHROMATOGRAPHY; PLANTS (BOTANY);

ENZYMES;

BARS1 ENZYME; OXIDOSQUALENE CYCLASE; SQUALENE DERIVATIVE; SYNTHETASE; TRITERPENE; UNCLASSIFIED DRUG;

ACCURACY; ANIMAL CELL; ARABIDOPSIS; ARTICLE; BIOSYNTHESIS; CONTROLLED STUDY; CYCLIZATION; ENZYME STRUCTURE; GENE INTERACTION; GENE STRUCTURE; GENETIC VARIABILITY; HYDROPHOBICITY; NONHUMAN;

ARABIDOPSIS; ARABIDOPSIS PROTEINS; INTRAMOLECULAR TRANSFERASES; MOLECULAR STRUCTURE; N-GLYCOSYL HYDROLASES; TRITERPENES;

EID: 34548757971     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja073133u     Document Type: Article

References (116)

1. Reviews: (a) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int. Ed. 2000, 39, 2812-2833.
2. (b) Wendt, K. U. Angew. Chem., Int. Ed. 2005, 44, 3966-3971.
3. (c) Xu, R.; Fazio, G. C.; Matsuda, S. P. T. Phytochemistry 2004, 65, 261-291.
4. (d) Hoshino, T.; Sato, T. Chem. Commun. 2002, 291-301.
5. (e) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730-4756.
6. (f) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93, 2189-2206.
7. (g) Segura, M. J. R.; Jackson, B. E.; Matsuda, S. P. T. Nat. Prod. Rep. 2003, 20, 304-317.
8. (h) Cattel, L.; Ceruti, M. Crit. Rev. Biochem. Mol. Biol. 1998, 33, 353-373.
9. (a) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. Helv. Chim. Acta 1955, 38, 1890-1904.
10. (b) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068-5077.
11. (c) Eschenmoser, A.; Arigoni, D. Helv. Chim. Acta 2005, 88, 3011-3050.
12. Husselstein-Muller, T.; Schaller, H.; Benveniste, P. Plant Mol. Biol. 2001, 45, 75-92.
13. Review: Phillips, D. R.; Rasbery, J. M.; Battel, B.; Matsuda, S. P. T. Curr. Opin. Plant Biol. 2006, 9, 305-314.
14. Arabidopsis cyclases: CAS1: (a) Corey, E. J.; Matsuda, S. P. T.; Battel, B. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 11628-11632.
15. LSS1: (b) Kolesnikova, M. D.; Xiong, Q.; Lodeiro, S.; Hua, L.; Matsuda, S. P. T. Arch. Biochem. Biophys. 2006, 447, 87-95.
16. (c) Suzuki, M.; Xiang, T.; Ohyama, K.; Seki, H.; Saito, K.; Muranaka, T.; Hayashi, H.; Katsube, Y.; Kushiro, T.; Shibuya, M.; Ebizuka, Y. Plant Cell Physiol. 2006, 47, 565-571.
17. LUP1: (d) Herrera, J. B. R.; Bartel, B.; Wilson, W. K.; Matsuda, S. P. T. Phytochemistry 1998, 49, 1905-1911.
18. (e) Segura, M. J. R.; Meyer, M. M.; Matsuda, S. P. T. Org. Lett. 2000, 2, 2257-2259.
19. LUP2: ref 3 and (f) Kushiro, T.; Shibuya, M.; Masuda, K.; Ebizuka, Y. Tetrahedron Lett. 2000, 41, 7705-7710.
20. LUP5: (g) Ebizuka, Y.; Katsube, Y.; Tsutsumi, T.; Kushiro, T.; Shibuya, M. Pure Appl. Chem. 2003, 75, 369-374.
21. PEN6: ref 5g and (h) Shibuya, M.; Xiang, T.; Katsube, Y.; Otsuka, M.; Zhang, H.; Ebizuka, Y. J. Am. Chem. Soc. 2007, 129, 1450-1455.
22. PEN4 (THAS1): (i) Fazio, G. C.; Xu, R.; Matsuda, S. P. T. J. Am. Chem. Soc. 2004, 126, 5678-5679.
23. PEN5 (MRN1): (j) Xiong, Q.; Wilson, W. K.; Matsuda, S. P. T. Angew. Chem., Int. Ed. 2006, 45, 1285-1288.
24. PEN1: (k) Xiang, T.; Shibuya, M.; Katsube, Y.; Tsutsumi, T.; Otsuka, M.; Zhang, H.; Masuda, K.; Ebizuka, Y. Org. Lett. 2006, 8, 2835-2838.
25. (m) Kolesnikova, M. D.; Obermeyer, A. C.; Wilson, W. K.; Lynch, D. A.; Xiong, Q.; Matsuda, S. P. T. Org. Lett. 2007, 9, 2183-2186.
26. (a) Thoma, R.; Schulz-Gasch, T.; D'Arcy, B.; Benz, J.; Aebi, J.; Dehmlow, H.; Hennig, M.; Stihle, M.; Ruf, A. Nature 2004, 432, 118-122.
27. (b) Lenhart, A.; Weihofen, W. A.; Pleschke, A. E. W.; Schulz, G. E. Chem. Biol. 2002, 9, 639-645.
28. (c) Lenhart, A.; Reinert, D. J.; Aebi, J. D.; Dehmlow, H.; Morand, O. H.; Schulz, G. E. J. Med. Chem. 2003, 46, 2083-2092.
29. (a) Wu, T.-K.; Griffin, J.-H. Biochemistry 2002, 41, 8238-8244.
30. (b) Lodeiro, S.; Segura, M. J. R.; Stahl, M.; Schulz-Gasch, T.; Matsuda, S. P. T. ChemBioChem 2004, 5, 1581-1585.
31. (c) Schulz-Gasch, T.; Stahl, M. J. Comput. Chem. 2003, 24, 741-753.
32. (d) Wu, T.-K.; Chang, C.-H. ChemBioChem 2004, 5, 1712-1715.
33. (e) Oliaro-Bosso, S.; Schulz-Gasch, T.; Taramino, S.; Scaldaferri, M.; Viola, F.; Balliano, G. Biochem. Soc. Trans. 2005, 33, 1202-1205.
34. (f) Lodeiro, S.; Schulz-Gasch, T.; Matsuda, S. P. T. J. Am. Chem. Soc. 2005, 127, 14132-14133.
35. (a) Morikubo, N.; Fukuda, Y.; Ohtake, K.; Shinya, N.; Kiga, D.; Sakamoto, K.; Asanuma, M.; Hirota, H.; Yokoyama, S.; Hoshino, T. J. Am. Chem. Soc. 2006, 128, 13184-13194.
36. (b) Wu, T.-K.; Liu, Y.-T.; Chiu, F.-H.; Chang, C.-H. Org. Lett. 2006, 8, 4691-4694.
37. (c) Xiang, T.; Shibuya, M.; Katsube, Y.; Tsutsumi, T.; Otsuka, M.; Zhang, H.; Masuda, K.; Ebizuka, Y. Org. Lett. 2006, 8, 2835-2838.
38. (d) Kushiro, T.; Shibuya, M.; Masuda, K.; Ebizuka, Y. J. Am. Chem. Soc 2000, 122, 6816-6824.
39. (e) Morita, M.; Shibuya, M.; Kushiro, T.; Masada, K.; Ebizuka, Y. Eur. J. Biochem. 2000, 267, 3453-3460.
40. (f) Wu, T.-K.; Liu, Y.-T.; Yu, M.-T.; Wang, H.-J. J. Am. Chem. Soc. 2006, 128, 6414-6419.
41. Reviews: (a) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303-1324.
42. (b) Zacharias, N.; Dougherty, D. A. Trends Pharmacol. Sci. 2002, 23, 281-287.
43. Early application to triterpene synthesis: (c) ref 1f.
44. (d) Poralla, K.; Hewelt, A.; Prestwich, G. D.; Abe, I.; Reipen, I.; Sprenger, G. Trends Biochem. Sci. 1994, 19, 157-158.
45. Herrera, J. B. R.; Wilson, W. K.; Matsuda, S. P. T. J. Am. Chem. Soc. 2000, 122, 6765-6766.
46. For citations to the accurate cyclases, see ref 4.
47. 3,5c α-Amyrin and β-amyrin were found in leaf wax: (a) Jenks, M. A.; Tuttle, H. A.; Eigenbrode, S. D.; Feldmann, K. A. Plant Phys. 1995, 108, 359-377.
48. 5c Oxidized triterpenoid secondary metabolites are known in Brassicaceae but not in Arabidopsis: (b) D'Auria, J. C.; Gershenzon, J. Curr. Opin. Plant Biol. 2005, 8, 308-316.
49. 3 phylogenetic analyses in refs 4 and 5b indicate that LSS is in neither the PEN nor LUP clade.
50. (a) Hart, E. A.; Hua, L.; Darr, L. B.; Wilson, W. K.; Pang, J.; Matsuda, S. P. T. J. Am. Chem. Soc. 1999, 121, 9887-9888.
51. For details, see: (b) Hua, L. Ph.D. thesis, Rice University, 2000, p. 76.
52. Corey, E. J.; Matsuda, S. P. T.; Baker, C. H.; Ting, A. Y.; Cheng, H. Biochem. Biophys. Res. Commun. 1996, 219, 327-331.
53. Lodeiro, S.; Wilson, W. K.; Shan, H.; Matsuda, S. P. T. Org. Lett. 2006, 8, 439-442.
54. Joubert, B. M.; Hua, L.; Matsuda, S. P. T. Org. Lett. 2000, 2, 339-341.
55. Nadeau, R. G.; Hanzlik, R. P. Methods Enzymol. 1969, 15, 346-351.
56. Nunez, M. J.; Lopez, M. R.; Jimenez, I. A.; Moujir, L. M.; Ravelo, A. G.; Bazzocchi, I. L. Tetrahedron Lett. 2004, 45, 7367-7370.
57. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R. Tetrahedron Lett. 1989, 30, 3351-3352.
58. Akihisa, T.; Arai, K.; Kimura, Y.; Koike, K.; Kokke, W. C. M. C.; Shibata, T.; Nikaido, T. J. Nat. Prod. 1999, 62, 265-268.
59. Justicia, J.; Rosales, A.; Buñuel, E.; Oller-López, J. L.; Valdivia, M.; Haidour, A.; Oltra, J. E.; Barrero, A. F.; Cárdenas, D. J.; Cuerva, J. M. Chem. Eur. J. 2004, 10, 1778-1788.
60. Leong, Y.-W.; Harrison, L. J. Phytochemistry 1999, 50, 849-857.
61. (a) Kitahara, Y.; Kato, T.; Kishi, M. Chem. Pharm. Bull. 1968, 16, 2216-2222.
62. (b) Arai, Y.; Hirohara, M.; Ageta, H. Tetrahedron Lett. 1989, 30, 7209-7212.
63. (c) Hoshino, T.; Kouda, M.; Abe, T.; Sato, T. Chem. Commun. 2000, 1485-1486.
64. Itoh, T.; Tamura, T.; Matsumoto, T. Lipids 1976, 11, 434-441.
65. Polonsky, J.; Varon, Z.; Rabanal, R. M.; Jacquemin, H. Isr. J. Chem. 1977, 16, 16-19.
66. Akihisa, T.; Yasukawa, K.; Kimura, Y.; Takase, S.-I.; Yamanouchi, S.; Tamura, T. Chem. Pharm. Bull. 1997, 45, 2016-2023.
67. Goad, L. J.; Akihisa, T. Analysis of sterols; Blackie (Chapman & Hall): London 1997, appendix 3, sections g and h.
68. Bates, R. B.; Jacobsen, N. E.; Setzer, W. N.; Stessman, C. C. Magn. Reson. Chem. 1998, 36, 539-541.
69. Bauer, S. Ph.D. dissertation, Westfälischen Wilhelms- Universität Münster, 2002.
70. Tanaka, R.; Matsunaga, S. Phytochemistry 1988, 27, 3579-3584.
71. Honda, C.; Suwa, K.; Takeyama, S.; Kamisako, W. Chem. Pharm. Bull. 2002, 50, 467-474.
72. Akihisa, T.; Yasukawa, K.; Kimura, Y.; Yamanouchi, S.; Tamura, T. Phytochemistry 1998, 48, 301-305.
73. Sasanqual has not been isolated but has implicitly been proposed as the precursor of sasanquol: Akihisa, T.; Koike, K.; Kimura, Y.; Sashida, N.; Matsumoto, T.; Ukiya, M.; Nikaido, T. Lipids 1999, 34, 1151-1157.
74. The amount of sasanqual was estimated from the level of sasanquol from the in vivo experiment; 19 was also quantified from in vivo results. Although in vivo product profiles may be distorted through further metabolism, selective loss to the medium, and other factors, these effects were modest for BARS1. Nevertheless, our in vivo experiments were used mainly for obtaining standards and determining their structures rather than for quantifying product ratios.
75. 5m and we have reexamined the MRN1 fraction containing 8, 11, and 28 and confirmed the absence of isocamelliol.
76. Although we are unaware of reports of oxidosqualene cyclization on silica gel, Sen et al. have described cyclization of epoxypolyenes on zeolites: (a) Sen, S. E.; Zhang, Y. z.; Roach, S. L. J. Org. Chem. 1996, 61, 9534-9537.
77. (b) Sen, S. E.; Zhang, Y. z.; Smith, S. M.; Huffman, J. C. J. Org. Chem. 1998, 63, 4459-4465. Reaction on silica gel gave products of epoxide ring opening but no cyclization.
78. (a) Abe, I.; Rohmer, M. J. Chem. Soc. Perkin Trans. 1 1994, 783-791.
79. (b) 30 has different chromatographic behavior from the other triterpenes and was usually excluded from the analyses.
80. van Tamelen, E. E. Pure Appl. Chem. 1981, 53, 1259-1270.
81. Pale-Grosdemange, C.; Feil, C.; Rohmer, M.; Poralla, K. Angew. Chem., Int. Ed. 1998, 37, 2237-2240.
82. 41b we continue to use these established terms. (a) Copley, S. D. Curr. Opin. Chem. Biol. 2003, 7, 265-272.
83. (b) Wassif, C. A.; Brownson, K. E.; Sterner, A. L.; Forlino, A.; Zerfas, P. M.; Wilson, W. K.; Starost, M. F.; Porter, A. F. Hum. Mol. Genet. 2007, 16, 1176-1187.
84. Steele, C. L.; Crock, J.; Bohlmann, J.; Croteau, R. J. Biol. Chem. 1998, 273, 2078-2089.
85. Review: Porter, F. D. Curr. Opin. Pediatr. 2003, 15, 607-613.
86. Ruan, B.; Wilson, W. K.; Pang, J.; Gerst, N.; Pinkerton, F. D.; Tsai, J.; Kelley, R. I.; Whitby, F. G.; Milewicz, D. M.; Garbern, J.; Schroepfer, G. J., Jr. J. Lipid Res. 2001, 42, 799-812.
87. Firn and Jones have noted the compromises inherent in categorizing enzymes by the structure of the dominant product when minor products are likely to be the catalytic distinction: Firn, R. D.; Jones, C. G. Nat. Prod. Rep. 2003, 20, 382-391.
88. Xiong, Q.; Rocco, F.; Wilson, W. K.; Xu, R.; Ceruti, M.; Matsuda, S. P. T. J. Org. Chem. 2005, 70, 5362-5375.
89. Matsuda, S. P. T.; Wilson, W. K.; Xiong, Q. Org. Biomol. Chem. 2006, 4, 530-543.
90. Cyclase active sites exclude cytosolic water and are clearly hydrophobic from the viewpoint of protein folding. However, hydrophobic active sites of enzymes commonly contain a number of polar residues and bound waters linked by hydrogen bond networks. About 30-40% of the putative BARS1 active site residues (derived from LSS sequence alignments) have neutral polar side chains, many of which could quench a carbocationic intermediate. This environment is not hydrophobic from the viewpoint of an organic chemist.
91. The magnitude of electrostatic stabilization is rather insensitive to the orientation and distance of the cation from the aromatic residue: (a) Matsuda, S. P. T.; Wilson, W. K.; Xiong, Q. Unpublished results.
92. Jenson, C.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 10846-10854.
93. Greenhagen, B. T.; O'Maille, P. E.; Noel, J. P.; Chappell, J. Proc Natl. Acad. Sci. U.S.A. 2006, 103, 9826-9833.
94. (a) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 429-431.
95. For similar nonenzymatic rearrangements to dihydroparkeol, see: (b) van Tamelen, E. E.; Anderson, R. J. J. Am. Chem. Soc. 1972, 94, 8225-8228 and references therein.
96. PEN6, the only characterized PEN cyclase that makes pentacycles, differs from BARS1 in seven putative active-site residues, four of which appear to be in the side-chain/D-ring region.
97. Shan, H.; Segura, M. J. R.; Wilson, W. K.; Lodeiro, S.; Matsuda, S. P. T. J. Am. Chem. Soc. 2005, 127, 18008-18009.
98. Hyatt, D. C.; Croteau, R. Arch. Biochem. Biophys. 2005, 439, 222-233.
99. (a) Khersonsky, O.; Roodveldt, C.; Tawfik, D. S. Curr. Opin. Chem. Biol. 2006, 10, 498-508.
100. (b) O' Loughlin, T. L.; Patrick, W. M.; Matsumura, I. Protein Eng. Des. Sel. 2006, 19, 439-442.
101. (c) Glasner, M. E.; Gerlt, J. A.; Babbitt, P. C. Curr. Opin. Chem. Biol. 2006, 10, 492-497.
102. (a) Corey, E. J.; Russey, W. E.; Ortiz de Montellano, P. R. J. Am. Chem. Soc. 1966, 88, 4750-4751.
103. (b) van Tamelen, E. E.; Willett, J. D.; Clayton, R. B.; Lord, K. E. J. Am. Chem. Soc. 1966, 88, 4752-4754.
104. Being the sole cyclase in most animals and fungi, LSS could be studied by incubating crude preparations with oxidosqualene or an analogue. In contrast, plants contain multiple cyclases, whose individual study requires protein purification or cloning/heterologous expression.
105. (a) Seminal review: Jensen, R. A. Annu. Rev. Microbiol. 1976, 30, 409-425.
106. (b) We use "catalysis" in the broad sense of facilitating a reaction rather than the strict sense of lowering an activation energy barrier.
107. Joyce, C. M.; Benkovic, S. J. Biochemistry 2004, 43, 14317-14324.
108. Cochella, L.; Green, R. Curr. Biol. 2005, 15, R536-R540.
109. Kazlauskas, R. J. Curr. Opin. Chem. Biol. 2005, 9, 195-201.
110. Our enhanced NMR sensitivity derived from a cold probe. Alternatively, capillary NMR offers comparable sensitivity: (a) Olson, D. L.; Norcross, J. A.; O'Neil-Johnson, M.; Molitor, P. F.; Detlefsen, D. J.; Wilson, A. G.; Peck, T. L. Anal. Chem. 2004, 76, 2966-2974.
111. (b) Schroeder, F. C.; Gronquist, M. Angew. Chem., Int. Ed. 2006, 45, 7122-7131.
112. Wilson, W. K.; Sumpter, R. M.; Warren, J. J.; Rogers, P. S.; Ruan, B.; Schroepfer, G. J.; Jr. J. Lipid Res. 1996, 37, 1529-1555.
113. (a) This idea was expressed almost 50 years ago by Robert Robinson: Wolstenholme, G. E. W.; O'Connor, M., Eds. Ciba Foundation symposium on the biosynthesis ofterpenes and sterols; Little, Brown, and Co.: Boston, 1959; pp 299-300.
114. (b) See also: Christianson, D. W. Chem. Rev. 2006, 106, 3412-3443.
115. Rétey, J. Angew. Chem., Int. Ed. 1990, 29, 355-361.
116. Schiestl, R. H.; Gietz, R. D. Curr. Genet. 1989, 16, 339-346.