IUPAC Use of rationally designed inhibitors to study sterol and triterpenoid biosynthesis

Several enzymes of plant sterol or triterpenoid biosynthesis involve during their catalysis postulated or demonstrated carbocationic high energy intermediates. It has been demonstrated previously that the design of transition state or high energy intermediate analogues could lead to powerful and specific inhibitors of enzymes. The aim of the present study was to interfere with plant sterol or triterpenoid biosynthesis by means of rationally designed species able to mimic the carbocationic high energy intermediates. We applied this approach to the following target enzymes : 2,3-oxidosqualene cyclase, 5—adenosyl methio— nine , cycloeucalenol—obtusifoliol isomerase and t8 ' t7-sterol isomerase. Very potent inhibitors have been obtained in each case. As an example N—substituted—8—azadecalins were shown to inhibit strongly Lri vLt'w the cycloeucalenol-obtusifoliol isomerase and the A8 -L17—sterol isomerase (Ki/Km = 103). N—I (1,5,9)— trimethyl-decyl I-4cx, 1O-dimethyl-8-aza-trans-decal-3-ol was shown to inhibit also the 2(3)-oxido-squalene-cycloartenol cyclase in cell-free extracts from maize (Zecz mcty4) seedlings ; in the same plant material, the 2(3)-oxido-squalene--amyrin cyclase was not inhibited. Hence for the first time, these two cyclases have been discriminated by use of a specific inhibitor.