Plant sterol biosynthesis: 7-oxo-obtusifoliol analogues as potential selective inhibitors of cytochrome P-450 dependent obtusifoliol 14 alpha-demethylase.
A series of 7-oxo-obtusifoliol analogues have been synthetized and investigated as potential inhibitors of cytochrome P-450 dependent obtusifoliol 14 alpha-demethylase (P-450OBT.14DM) from higher plant microsomes. 7-Oxo-24 xi(24')-dihydro-obtusifoliol and 7-oxo-24(25)-dihydro-29-nor-lanosterol were potent competitive inhibitors for P-450OBT.14DM, binding 125-200 times more tightly than the substrates obtusifoliol and 24(25)-dihydro-29-nor-lanosterol. Inhibition of P-450OBT.14DM by these analogues showed strict structural requirements including the 8-en-7-one system which was compulsory for binding. 7-Oxo-24(25)-dihydro-lanosterol possessing an additional 4 beta-methyl substituent, did not have such inhibitory effects. Treatment of cultures of suspended bramble cells with 7-oxo-24(25)-dihydro-29-nor-lanosterol resulted in a strong decrease of [14C]acetate incorporation into the demethylsterols fraction and in an accumulation of [14C]obtusifoliol. This confirms that P-450OBT.14DM is the main in vivo target of 7-oxo-24(25)-dihydro-29-nor-lanosterol in the sterol-biosynthetic pathway.
Rahier
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A
Institut de Biologie Moléculaire des Plantes, Département d'Enzymologie Cellulaire et Moléculaire, Strasbourg, France.
Taton
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M
D002478:Cells, Cultured; D002775:Cholestadienols / Q000138:chemical synthesis / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D005052:Eucalyptus / Q000737:chemistry; D001467:Hordeum / Q000737:chemistry; D007810:Lanosterol / Q000031:analogs & derivatives / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010840:Phytosterols / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010946:Plants, Medicinal; D058886:Sterol 14-Demethylase; D013535:Suspensions; D003313:Zea mays / Q000737:chemistry / Q000201:enzymology
D002775:Cholestadienols; D065607:Cytochrome P-450 Enzyme Inhibitors; D010840:Phytosterols; D013535:Suspensions; D007810:Lanosterol; C008693:obtusifoliol; C032444:lanosten-3-ol-32-al; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase