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Volumn 118, Issue 38, 1996, Pages 9180-9181

Mechanism-based active site modification of oxidosqualene cyclase by tritium-labeled 18-thia-2,3-oxidosqualene

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME; LANOSTEROL SYNTHASE; SQUALENE DERIVATIVE; TRITIUM;

EID: 0029801927     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja961643a     Document Type: Article
Times cited : (26)

References (40)
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    • For recent work on the cloning and functional expression of lanosterol synthases, see: (a) Abe, I.; Prestwich, G. D. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9274-9278 (rat), (b) Kusano, M.; Shibuya, M.; Sankawa, U.; Ebizuka, Y. Biol. Pharm. Bull. 1995, 18, 195-197 (rat), (c) Baker, C. H.; Matsuda, S. P. T.; Liu, D. R.; Corey, E. J. Biochem. Biophys. Res. Commun. 1995, 213, 154-160 (human). (d) Corey, E. J.; Matsuda, S. P. T.; Bartel, B. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2211-2215 (S. cerevisiae). (e) Shi, Z.; Buntel, C. J.; Griffin, J. H. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7370-7374 (S. cerevisiae). (f) Buntel, C. J.; Griffin, J. H. J. Am. Chem. Soc. 1992, 114, 9711-9713 (Candida albicans). (g) Corey, E. J.; Matsuda, S. P. T.; Baker, C. H.; Ting, A. Y.; Cheng, H. Biochem. Biophys. Res. Commun. 1996, 219, 327-331 (Schizosaccharomyces pombe). (h) Sung, C. H.; Shibuya, M.; Sankawa, U.; Ebizuka, Y. Biol. Pharm. Bull. 1995, 18, 1459-1461 (human).
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    • For synthesis and biological activities of sulfur-containing analogues of 1, see: (a) Zheng, Y. F.; Oehlschlager, A. C.; Georgopapadakou, N. H.; Hartman, P. G.; Scheliga, P. J. Am. Chem. Soc. 1995, 117, 670-680 (S-6, S-10, S-14, and S-19). (b) Zheng, Y. F.; Oehlschlager, A. C.; Hartman, P. G. J. Org. Chem. 1994, 59, 5803-5809 (S-8 and S-13). (c) Zheng, Y. F.; Dodd, D. S.; Oehlschlager, A. C.; Hartman, P. G. Tetrahedron 1995, 51, 5255-5276 (S-5, S-9, S-16, and S-20). (e) Stach, D.; Zheng, Y. F.; Perez, A. L.; Oehlschlager, A. C.; Abe, I.; Prestwich, G. D.; Hartman, P. G. J. Med. Chem., submitted (S-11, S-15, S-18, and S-19).
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    • J. Med. Chem.
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    • For recent reviews on OSC inhibitors, see: (a) Abe, I.; Tomesch, J. C.; Wattanasin, S.; Prestwich, G. D. Nat. Prod. Rep. 1994, 11, 279-302. (b) Oehlschlager, A. C.; Czyzewska, E. In Emerging Targets in Antibacterial and Antifungal Chemotherapy; Sutcliffe, J., Georgopapadakou, N. H., Eds.; Routledge, Chapman & Hall: New York, 1992.
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    • note
    • 6a for 29-MOS, i.e., by extrapolating (to infinite dilution) the linear range of a plot of remaining OSC activity vs the ratio of [8] to [pure OSC activity]. The data was generated by adding increasing amounts of 8 to a constant amount of enzyme solution (0.125 μM).
  • 35
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    • note
    • 4 and treatment with TBDMSC1 gave 9.
  • 37
    • 10244242096 scopus 로고    scopus 로고
    • note
    • 50 concentration, while 15 gave quantitative recovery of OSC activity. In addition, with rat OSC, nearly 100% activity was recovered for 8 as well as for 15.
  • 38
    • 10244239639 scopus 로고    scopus 로고
    • note
    • 3H]-8 at 37°C for 1 h, a 15 μL aliquot of the assay mixture was diluted with 300 μL of buffer A, added to 50 μL of preequilibrated DEAE-Sepahacel. After incubation for 1 h at rt, the 10000g supernatant was removed, the DEAE resin was washed (5 × 1 mL of buffer A) and resuspended in 1 mL buffer, and bound radioactivity was assessed by LSC.
  • 39
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    • note
    • f values for 8, 1, 3, and the polar product were 0.39, 0.48, 0.26, and 0.06, respectively. As a control experiment, boiled-enzyme preparation was employed.


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