Plant sterol biosynthesis: novel potent and selective inhibitors of cytochrome P450-dependent obtusifoliol 14 alpha-methyl demethylase.
The R-(-) isomer of methyl 1-(2,2-dimethylindan-1-yl)imidazole-5-carboxylate (CGA 214372; 2) strongly inhibited P450-dependent obtusifoliol 14 alpha-demethylase (P450OBT.14DM) (I50 = 8 x 10(-9) M, I50/Km = 5 x 10(-5) in a maize (Zea mays) microsomal preparation. Kinetic studies indicated uncompetitive inhibition with respect to obtusifoliol. The corresponding S-(+) isomer was a 20-fold weaker inhibitor for P450OBT.14DM. The molecular features of a variety of analogues of 2 were related to their potency as inhibitors of P450OBT.14DM in vitro, allowing delineation of the key structural requirements governing inhibition of the demethylase. CGA 214372 proved to have a high degree of selectivity for P450OBT.14DM. This allowed easy distinction of this activity from other P450-dependent activities present in the maize microsomal preparation and gave strong evidence that P450OBT.14DM is a herbicidal target. Microsomal maize P450OBT.14DM and yeast P450LAN.14DM, the only known examples of P450-dependent enzymes carrying out an identical metabolic function in different eukaryotes, showed distinct inhibition patterns with CGA 214372 and ketoconazole, a substituted imidazole anti-mycotic.
Salmon
F
F
Département d'Enzymologie Cellulaire et Moléculaire, CNRS-UPR 406, Strasbourg, France.
Taton
M
M
Benveniste
P
P
Rahier
A
A
D001393:Azoles / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000378:metabolism*; D013329:Structure-Activity Relationship; D003313:Zea mays / Q000201:enzymology*
D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D013261:Sterols; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase