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  • Title: Substrate-based inhibitors of lanosterol 14 alpha-methyl demethylase: II. Time-dependent enzyme inactivation by selected oxylanosterol analogs.
    Author: Trzaskos JM, Fischer RT, Ko SS, Magolda RL, Stam S, Johnson P, Gaylor JL.
    Journal: Biochemistry; 1995 Aug 01; 34(30):9677-81. PubMed ID: 7626637.
    Abstract:
    Selected 15-, 32-, and 15,32-substituted lanosterol analogs are shown here to display time-dependent inactivation and lanosterol 14 alpha-methyl demethylase. These molecules are competitive with respect to substrate and require NADPH and O2 in order to display time dependence, thus supporting the premise that they are mechanism-based inactivators. Structural features required for lanosterol demethylation by the lanosterol demethylase such as nuclear double bond location and availability of an abstractable 15 alpha-proton are also essential elements for time-dependent inactivation. 32-(S)-Vinyllanost-8-en-3 beta,32-diol is a potent time-dependent inactivator (Kinact/Ki = 0.36 min-1 microM-1), while the 32-(R)-vinyllanost-8-en-3 beta,32-diol functions solely as a competitive demethylase inhibitor. These results support the premise that stereoselective oxidation occurs during lanosterol demethylation and that the 32-pro-S proton is abstracted during the demethylation reaction.
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