THE DISCOVERY AND STRUCTURAL REQUIREMENTS OF INHIBITORS OF P-HYDROXYPHENYLPYRUVATE DIOXYGENASE

The benzoylcyclohexane-1,3-diones, the triketones, are potent bleachin g herbicides whose structure-activity relationships and physical prope rties are substantially different from classical bleaching herbicides, which affect phytoene desaturase. The first clue to their unique mech anism of action was the discovery that rats treated with a triketone w ere found to be tyrosinemic. Additionally, examination of the rat urin e revealed the accumulation of p-hydroxyphenylpyruvate (HPP) and p-hyd roxyphenyllactate. These results suggested that this chemically induce d tyrosinemia was the result of the inhibition of p-hydroxyphenylpyruv ate dioxygenase (HPPD, EC 1.13.11.27), and this suggestion was confirm ed when a triketone was shown to be a potent inhibitor of rat liver HP PD. In plants, HPPD is a component of the biosynthetic pathway re plas toquinone (PQ), which in turn is a key cofactor of phytoene desaturase . The expectation that triketone-treated plants should accumulate tyro sine while having reduced PQ levels was dramatically demonstrated in t he meristematic tissue of ivyleaf morningglory. Plant HPPD, li!ce the mammalian enzyme, was inhibited in vitro by triketones. These biochemi cal effects provide evidence that the triketone herbicidal mechanism o f action is HPPD inhibition leading to a deficiency of PQ, a key cofac tor for carotenoid biosynthesis. Other chemical classes of bleaching h erbicides were also examined for their ability to elevate tyrosine and deplete PQ as a definitive means of establishing their mode of action and for delineating tile structural and physical chemical requirement s for an HPPD herbicide. Evidence is provided to support the claim tha t a 2-benzoylethen-1-ol substructure is the minimum substructure requi red for a potent HPPD inhibitor.