Design of high energy intermediate analogues to study sterol biosynthesis in higher plants |
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Authors: | Alain Rahier Maryse Taton Pierrette Bouvier-Navé Paulette Schmitt Pierre Benveniste Francis Schuber Acharan S Narula Luigi Cattel Claude Anding Pierre Place |
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Affiliation: | (1) Department of Chemistry, Paul M. Gross Chemical Laboratory, Duke University, 27707 Durham, NC;(2) Istituto di Chimica Farmaceutica Applicata, Torino, Italy;(3) Rhone-Poulenc Agrochimie, Lyon, France;(4) Laboratoire de Biochimie Végétale et de Chimie Enzymatique, UA 570 du CNRS, Institut de Botanique, 28, rue Goethe, 67083 Strasbourg, France |
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Abstract: | Several enzymes of plant sterol biosynthesis involve during their catalysis postulated or demonstrated carbocationic high
energy intermediates (HEI). The aim of this study was to interfere with plant sterol biosynthesis by means of rationally designed
species able to mimic these carbocationic HEI. It has been demonstrated previously that the design of transition state (TS)
or HEI analogues could lead to powerful and specific inhibitors of enzymes. We applied this approach to the following target
enzymes: 2,3-epoxy-2,3-dihydroqualene cyclase, AdoMet-cycloartenol-C-24-methyltransferase (AdoMet CMT), cycloeucalenol-obtusifoliol
isomerase (COI) and Δ8-Δ7-sterol isomerase. Very potent inhibitors have been obtained in the four cases. As an example, analogues of cycloartenol substituted
at C-25 by a charged heteroatom (N, As, S) have been synthesized and shown to be able to mimic the C-25 carbocationic HEI
involved in the reaction catalyzed by the AdoMet CMT. These compounds were shown to be very potent and specific inhibitors
of this enzyme both in vitro (Ki=2.10−8 M, Ki/Km=10−3) and in vivo. The potent inhibitors described are powerful tools to control in vivo the sterol profile of plant cells and
therefore to study the structural and functional roles of sterols in cell membranes. Moreover, these compounds constitute
leader molecules of a new class of rationally designed inhibitors which could be of value in plant protection. |
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