4-Hydroxyphenylpyruvate dioxygenase HPPD , inhibition

The molecular target site of triketone herbicides is the enzyme -hydroxyphenylpyruvate dioxygenase (HPPD). Inhibition of this enzyme disrupts the biosynthesis of carotenoids and causes a bleaching (loss of chlorophyll) effect on the foliage similar to that observed with inhibitors ofphytoene desaturase (e.g. norflurazon). However, the mechanism of action of HPPD inhibitors is different. Inhibtion of HPPD stops the synthesis of homogen tisate (HGA), which is a key precursor of the 8 different tocochromanols (tocopherols and tocotrienols) and prenyl quinones. In the absence of prenylquinone plastoquinone, phytoene desaturase activity is interrupted. The bleaching of the green tissues ensues as if these compounds inhibited phytoene desaturase. 

HydroxYphenYlpyruvate Dioxygenase (HPPD) - the Herbicide Target 219 Table 4.2.1 Estimated inhibition constants of HPPD inhibitors. 

As discussed in detail in Chapter 4.2, triketones exert their herbicidal mode of action by inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) [6]. Triketones are not the only herbicide class that have this mode of action, and it has retrospectively been shown that apparently structurally non-related heterocyclic commercial herbicides such as isoxaflutole (7, BALANCE and MERLIN ), and the rice herbicides pyrazolate (8, SANBIRD ) and benzobicyclon (9, SHOW-ACE ) also cause these bleaching symptoms by the same mode of action. However, a common feature of these herbicides, after metabolic activation to the active metabolites (7 ) [7], (8 ) [8] and (9 ) [9] is the presence of an acidic 1,3-dicarbonyl moiety, which is also present in triketones (Fig. 4.3.2). Triketones and related her-... 

It has been shown that NTBC inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD) (Lock et al., 1994, Ellis et al, 1993 1994). This is the second enzyme in the normal catabolic cascade of tyrosine in mammals. Furthermore Lock et al., 1994 have demonstrated an increase in plasma tyrosine when rats are given a single oral dose of NTBC by gavage. The plasma tyrosine levels returned to normal 3 days later. 

We end this section on enzyme inhibition with a case study about 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) and disorders in tyrosine catabolism. After transamination of tyrosine, 4-hydroxyphenylpyruvate (148) is formed which is then decarboxylated, isomerized and oxygenated by HPPD to yield homogentisate (149) or by hydroxyman-delate synthase (HMS) to yield p-hydroxymandelate (150). 149 serves as the precursor for plastoquinones and tocopherols in plants . Thus, inhibitors of HPPD have been designed... 

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