4-Hydroxyphenylpyruvate inhibitors

SCHULZ A, CRT o, BEYER P and KLEINIG H (1993) SC-0051, a 2-benzoyl-cyclohexane-l,3-dione bleaching herbicide, is a potent inhibitor of the enzyme /<-hydroxyphenylpyruvate dioxygenase , Terr, 318, 162-6. 

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. 

Lee DL, PrisbyUaMP, CromartieTH, Dagarin DP, Howard SW, Provan WM, EUis MK, Fraser T, Mutter LC, The discovery and structural requirements of inhibitors of hydroxyphenylpyruvate dioxygenase. Weed Sci 45 601—609,... 

Romagni, J.G., Meazza, G, Nanayakkara, N.P.D., Dayan, F.E. The phytotoxic lichen metabolite, usnic acid, is a potent inhibitor of plant p-hydroxyphenylpyruvate dioxygenase. FEBS Letters 2000 480 301-305. 

Romagni, J. G., Meazza, G., Nanayakkara, and D., Dayan, F. E., 2000. The Phytotoxic Lichen Metabolite, Usnic Acid, is a Potent Inhibitor of Plant p-Hydroxyphenylpyruvate Dioxygenase. FEBS Letters 480 (2-3), 301-305. 

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... 

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

Further, owing to deamination, p-hydroxyphenylpyruvic acid (15), a well-known inhibitor of tyrosinase, was produced from tyrosine. This product underwent further transformation to yield biphenyl 16 while indolylpyruvic acid (22) and subsequently indole (19) were formed from tryptophan. Hence, in biological systems, the loss of the starting material, i.e. tyrosine, for melanin synthesis due to the formation of 15, 16 and 18 may be counteracted by tryptophan, as an alternative substrate in the pathway of melanogenesis through 22 and 19. However, such a replacement of substrate for melanin by tryptophan is not possible in... 

The effects of this inhibitor on the metabolism of A. fumigatus were very different from those of the other compounds used, since formation of all the characteristic acetate-derived phenols was strongly suppressed (Packter and Collins, 1974). Treatment of cultures gave a completely altered pattern and led unexpectedly to the secretion of atypical shikimic acid-derived phenols, including 2,3-dihydroxybenzoic acid, 4-hydroxyphenylpyruvic acid, and 4-hydroxybenzyl cyanide. In addition, the inhibitor was metabolized directly by transamination to fluorophenylpyruvic acid. 

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