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Stereoselective interaction of an azole antifungal agent with its target, lanosterol 14α‐demethylase (cytochrome p ‐450 14dm ): A model study with stereoisomers of triadimenol and purified cytochrome p ‐450 14dm from yeast
Author(s) -
Yoshida Yuzo,
Aoyama Yuri
Publication year - 1990
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530020103
Subject(s) - lanosterol , chemistry , azole , demethylase , stereochemistry , cytochrome , stereoselectivity , enzyme , cytochrome p450 , active site , yeast , antifungal , biochemistry , sterol , catalysis , microbiology and biotechnology , epigenetics , cholesterol , gene , biology
The effect of the four triadimenol stereoisomers on the purified yeast lanosterol 14α‐demethylase (cytochrome P ‐450 14DM ), the primary target of azole antifungal agents, was studied. (1S,2R)‐Triadimenol was the most potent demethylase inhibitor and bound quantitatively to the enzyme below 0.05 μM. This isomer also interfered with the chemical reduction of cytochrome P ‐450 14DM and the binding of CO to the cytochrome. The other isomers showed a lower inhibitory effect on the enzyme, and the order of activity was (1R,2R) > (1R,2S) ≧ (1S,2S). Based on these findings and the reported preferred conformations for the triadimenol stereoisomers (Anderson, N.H. et al., Pestic. Sci. 15:310–316, 1984), it is predicted that orientation of the hydrophobic tert ‐butyl and p ‐chlorophenyl groups relative to the azole nitrogen is important to fit the antifungal agent in the active site of the demethylase.