The discovery and structural requirements of inhibitors of p-hydroxyphenylpyruvate dioxygenase

Abstract

The benzoylcyclohexane-1,3-diones, the triketones, are potent bleaching herbicides whose structure-activity relationships and physical properties are substantially different from classical bleaching herbicides, which affect phytoene desaturase. The first clue to their unique mechanism of action was the discovery that rats treated with a triketone were found to be tyrosinemic. Additionally, examination of the rat urine revealed the accumulation of p-hydroxyphenylpyruvate (HPP) and p-hydroxyphenyllactate. These results suggested that this chemically induced tyrosinemia was the result of the inhibition of p-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27), and this suggestion was confirmed when a triketone was shown to be a potent inhibitor of rat liver HPPD. In plants, HPPD is a component of the biosynthetic pathway to plastoquinone (PQ), which in turn is a key cofactor of phytoene desaturase. The expectation that triketone-treated plants should accumulate tyrosine while having reduced PQ levels was dramatically demonstrated in the meristematic tissue of ivyleaf morningglory. Plant HPPD, like the mammalian enzyme, was inhibited in vitro by triketones. These biochemical effects provide evidence that the triketone herbicidal mechanism of action is HPPD inhibition leading to a deficiency of PQ, a key cofactor for carotenoid biosynthesis. Other chemical classes of bleaching herbicides 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 the structural and physical chemical requirements for an HPPD herbicide. Evidence is provided to support the claim that a 2-benzoylethen-1-ol substructure is the minimum substructure required for a potent HPPD inhibitor.

Using Herbicides and Perennial Ryegrass to Renovate Turf Dominated by Annual Bluegrass

“…All mesotrione treatments caused injury (bleaching) to PYRE 48 days after seeding (DAS) in 2015 and 2016; the severity of injury specific to PRYE versus ABG was indistinguishable due to the intensity of bleaching symptoms. Observed bleaching symptoms were consistent with previous reports of p-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides (Mitchell et al, 2001) on susceptible species (Lee et al, 1997) including ABG (Skelton et al, 2012) and PRYE (McCurdy et al, 2008).…”

Is There a Benefit of Adding Atrazine to HPPD-Inhibiting Herbicides for Control of Multiple-Herbicide-Resistant, Including Group 5-Resistant, Waterhemp in Corn?

“…Reactive oxygen species cause lipid peroxidation and cell membrane destruction, resulting in plant death (Bartosz, 1997;Hankamer et al, 1997). HPPD-inhibiting herbicides prevent the conversion of hydroxyphenyl pyruvate to homogentisate (Lee et al, 1997). Homogentisate is the precursor to antioxidant compounds plastoquinone, α-tocopherols and carotenoids.…”

“…Homogentisate is the precursor to antioxidant compounds plastoquinone, α-tocopherols and carotenoids. Antioxidant compounds quench ROS, reducing or eliminating the impact of oxidative stress on the plant (Lee et al, 1997). In the absence of plastoquinone, α tocopherols, and carotenoids the plant is unable to quench ROS and succumbs to oxidative stress resulting in plant death (Trebst et al, 2002).…”

Discovery and structure optimization of a novel corn herbicide, tolpyralate

“…7) The herbicidal mechanism is the inhibition of 4-HPPD that catalyzes the transformation of 4-hydroxyphenylpyruvate (4-HPPA) to homogentisate (HGA) in the biosynthesis pathway of plastoquinone (PQ), which gives rise to bleaching symptoms on target weeds. 8,9) These symptoms result from an indirect inhibition of carotenoid biosynthesis due to the involvement of PQ as a cofactor of phytoene desaturase (PDS).…”