Inhibition of 2,3-oxidosqualene cyclases

• Published in: Biochemistry (Easton) Vol. 31; no. 34; pp. 7892 - 7898
• Main Authors: Taton, Maryse, Benveniste, Pierre, Rahier, Alain, Johnson, William S, Liu, Hshiou Ting, Sudhakar, Anantha R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1992
• Subjects: 2,3,-oxidosqualene cyclase; activity; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cyclization; Enzymes and enzyme inhibitors; Fabaceae - enzymology; Fundamental and applied biological sciences. Psychology; inhibition; Intramolecular Transferases; Isomerases; Isomerases - antagonists & inhibitors; Liver - enzymology; Molecular Structure; N-alkyl-hydroxypiperidine; Plants, Medicinal; Rats; Squalene - analogs & derivatives; Squalene - chemical synthesis; Squalene - chemistry; Squalene - pharmacology; Structure-Activity Relationship; Zea mays - enzymology; Monocotyledones; Zea mays; Enzyme; 2,3-Oxidosqualene lanosterol-cyclase; Rosaceae; Enzyme inhibitor; Rubus fruticosus; Leguminosae; Enzymatic activity; Gramineae; Dicotyledones; Pisum sativum; Angiospermae; Spermatophyta; 2,3-Oxidosqualene cycloartenol-cyclase; Inhibition; Comparative study
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00149a021

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.