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Design of high energy intermediate analogues to study sterol biosynthesis in higher plants
Author(s) -
Rahier Alain,
Taton Maryse,
BouvierNavé Pierrette,
Schmitt Paulette,
Benveniste Pierre,
Schuber Francis,
Narula Acharan S.,
Cattel Luigi,
Anding Claude,
Place Pierre
Publication year - 1986
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02534303
Subject(s) - cycloartenol , sterol , enzyme , biosynthesis , biochemistry , chemistry , isomerase , methyltransferase , stereochemistry , cholesterol , methylation , gene
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 Δ 8 ‐Δ 7 ‐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.