Submitted to: Phytochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2007
Publication Date: 3/26/2007
Citation: Dayan, F.E., Duke, S.O., Sauldubois, A., Singh, N., Mccurdy, C., Cantrell, C.L. 2007. p-Hydroxyphenylpyruvate Dioxygenase is a Herbicidal Target Site for B-triketones from Leptospermum Scoparium. Phytochemistry. 68:2004-2014. Interpretive Summary: The enzyme p-hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes important reaction in plants. It is responsible for the biosynthesis of prenyl quinones and tocopherol, and is the target site a class of herbicides. The essential oil of manuka (Leptospermum scoparium), and its components leptospermone, grandiflorone and flavesone were tested for their activity in whole-plant bioassays and for their potency against HPPD. Plants exposed to manuka oil or its purified components had symptoms similar to that of plants treated with a conventional synthetic inhibitor of this enzyme. The relative inhibitory activities on the enzyme were grandiflorone > leptospermone > flavesone. The herbicidal activity of the semi-purified oil may be sufficient to be used as a natural herbicide.
Technical Abstract: p-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme in tyrosine catabolism and is the molecular target site of B-triketone pharmacophores used to treat hypertyrosinemia in humans. In plants, HPPD is involved in the biosynthesis of prenyl quinones and tocopherol, and is the target site of B-triketone herbicides. The B-triketone-rich essential oil of manuka (Leptospermum scoparium), and its components leptospermone, grandiflorone and flavesone were tested for their activity in whole-plant bioassays and for their potency against HPPD. The phenotype of developing plants exposed to manuka oil or its purified B-triketone components was similar to that of plants exposed to a synthetic HPPD inhibitor. Chlorophyll and carotenoid levels decreased in a dose-dependent manner upon inhibition of HPPD. Unlike their synthetic counterpart, steady-state O2 consumption experiments revealed that the natural triketones behaved as competitive reversible inhibitors of HPPD, with the relative inhibitory activities of grandiflorone > leptospermone > flavesone. Structure-activity relationships indicate that the size and lipophilicity of the side chain affected the potency of the compounds. Computational analysis of the catalytic domain of HPPD indicates that a lipophilic domain proximate from the Fe2+ favors the binding of ligands with lipophilic moieties.