Inhibition of 2,3-oxidosqualene cyclases.
Monocyclic and tricyclic compounds possessing a nitrogen atom situated at a position corresponding to the carbenium ion of high energy intermediates or transition states involved during cyclization of 2,3-oxidosqualene to tetra- and pentacyclic triterpenes have been synthesized. These compounds were tested as inhibitors of 2,3-oxidosqualene cycloartenol, lanosterol-, and beta(alpha)-amyrin-cyclases in vitro and in vivo, and their affinity was compared to that of formerly synthesized 8-aza-bicyclic compounds [Taton et al. (1986) Biochem. Biophys. Res. Commun. 138, 764-770]. A monocyclic N-alkyl-hydroxypiperidine was shown to be the strongest inhibitor of the series upon cycloartenol-cyclase (I50 = 1 microM) from maize embryos but was much less effective on the beta(alpha)-amyrin-cyclases from Rubus fruticosus suspension cultures or pea cotyledons. In contrast, 13-aza-tricyclic derivatives displayed little inhibition on 2,3-oxidosqualene cycloartenol-, lanosterol-, and beta(alpha)-amyrin-cyclases. The obtained data exemplify the differences existing in the cyclization process between cycloartenol- (lanosterol-) cyclases on one hand and beta(alpha)-amyrin-cyclases on the other. The results are discussed with respect to current mechanisms postulated for 2,3-oxidosqualene cyclization. Because of its activity in vivo and in vitro the monocyclic N-alkyl-hydroxypiperidine appears to be a potent and promising tool to study sterol biosynthesis regulation.
Taton
M
M
Laboratoire d'Enzymologie Cellulaire et Moléculaire, Institut de Biologie Moléculaire des Plantes du CNRS, Strasbourg, France.
Benveniste
P
P
Rahier
A
A
Johnson
W S
WS
Liu
H T
HT
Sudhakar
A R
AR
D000818:Animals; D003500:Cyclization; D007887:Fabaceae / Q000201:enzymology; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D010946:Plants, Medicinal; D051381:Rats; D013185:Squalene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D003313:Zea mays / Q000201:enzymology
C002821:2,3-oxidosqualene; D013185:Squalene; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase