A conformationally restricted uniconazole analogue as a specific inhibitor of rice ent-kaurene oxidase, CYP701A6.

Yasushi Todoroki, Kumi Naiki, Taku Muramatsu, Toshiyuki Ohnishi, Kotomi Ueno, Masaharu Mizutani, Nobuhiro Hirai

Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan. aytodor@ipc.shizuoka.ac.jp

Bioorganic & medicinal chemistry letters 2012 May 1

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The plant growth retardant uniconazole (UNI), which has been used as an effective inhibitor of ent-kaurene oxidase (CYP701A) involved in gibberellin biosynthesis, also strongly inhibits ABA 8'-hydroxylase (CYP707A), a key enzyme in abscisic acid catabolism. Azole P450 inhibitors bind to the P450 active site by both coordinating to the heme-iron atom via an sp(2) nitrogen and interacting with surrounding protein residues through a lipophilic region. We hypothesized that poor selectivity of UNI may result from its small molecular size and flexible conformation that allows it to fit into active sites differing in size and shape. To find a selective inhibitor of CYP701A based on this hypothesis, we examined inhibitory activities of three types of UNI analogues, which were conformationally constrained, enlarged in width, and enlarged in length, against recombinant rice CYP701A6 and Arabidopsis CYP707A3. Conformationally restricted analogues, UFAP2 and UFAP2N, inhibited CYP701A6 as strongly as UNI, whereas it inhibited CYP707A3 less than UNI. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Yasushi Todoroki, Kumi Naiki, Taku Muramatsu, Toshiyuki Ohnishi, Kotomi Ueno, Masaharu Mizutani, Nobuhiro Hirai. A conformationally restricted uniconazole analogue as a specific inhibitor of rice ent-kaurene oxidase, CYP701A6. Bioorganic & medicinal chemistry letters. 2012 May 1;22(9):3240-3