Hostname: page-component-cd9895bd7-jn8rn Total loading time: 0 Render date: 2024-12-26T06:24:43.861Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  12 June 2017

David L. Lee ,
Michael P. Prisbylla ,
Thomas H. Cromartie ,
Derek P. Dagarin ,
Stott W. Howard ,
W. McLean Provan ,
Martin K. Ellis ,
Torquil Fraser  and
Linda C. Mutter
David L. Lee*
Affiliation:
Zeneca Ag Products, Western Research Center, 1200 South 47th Street, Richmond, CA 94804
Michael P. Prisbylla
Affiliation:
Zeneca Ag Products, Western Research Center, Richmond, CA 94804
Thomas H. Cromartie
Affiliation:
Zeneca Ag Products, Western Research Center, Richmond, CA 94804
Derek P. Dagarin
Affiliation:
Zeneca Ag Products, Western Research Center, Richmond, CA 94804
Stott W. Howard
Affiliation:
Zeneca Ag Products, Western Research Center, Richmond, CA 94804
W. McLean Provan
Affiliation:
Zeneca Central Toxicology Laboratory, Alderly Park, Nr Macclesfield, Cheshire SK10 4TJ, Great Britain
Martin K. Ellis
Affiliation:
Zeneca Central Toxicology Laboratory, Alderly Park, Nr Macclesfield, Cheshire SK10 4TJ, Great Britain
Torquil Fraser
Affiliation:
Zeneca Agrochemicals, Jealott's Hill Research Station, Bracknell, Berkshire RG12 6EY, Great Britain
Linda C. Mutter
Affiliation:
Athena Neuroscience, South San Francisco, CA 94080
*
[email protected].
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

Ivyleaf morninggloryIpomoea hederacea (L.)BenzoylcyclohexanedioneIPOHEtriketoneplastoquinonetyrosine
Type
Symposium
Information
Weed Science , Volume 45 , Issue 5 , October 1997 , pp. 601 - 609
Copyright
Copyright © 1997 by the Weed Science Society of America 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Literature Cited

Adams, R., Weiler, E. W., Kerber, E., Pfister, K., and Schar, H.-P. 1991. Studies on the action of the new growth retardant CGA 163&935. Br. Crop Prot. Conf. Weeds 3: 1133–1138.Google Scholar
Babczinski, P., Sandmann, G., Schmidt, R. R., Shiokawa, K., and Yasui, K. 1995. Substituted tetrahydropyrimidinones: a new herbicidal class of compounds inducing chlorosis by inhibition of phytoene desaturation. Pestic. Biochem. Physiol. 52: 33–44.CrossRefGoogle Scholar
Barta, I. C. and Böger, P. 1995. Benzoylcyclohexanedione herbicides are strong inhibitors of purified p-hydroxyphenylpyruvic acid dioxygenase of maize. Pestic. Sci. 45: 286–287.CrossRefGoogle Scholar
Böger, P. 1989. New plant-specific targets for future herbicides: C. Uncouplers. in Böger, P. and Sandmann, G., eds. Target Sites of Herbicide Action. Boca Raton, FL: CRC Press, pp. 256–257.Google Scholar
Cain, P. A. and Cramp, S. M., inventors; Rhone-Poulenc Agriculture, assignee. 1992 Jul 29. 2-Cyano-1,3-dione herbicides. Eur. patent application 0496631.Google Scholar
Cain, P. A., Cramp, S. M., Little, G. M., and Luscombe, B. M., inventors; Rhone-Poulenc Agriculture, assignee. 1993 Feb 10. Benzoylisoxazoles and their use as herbicides. Eur. patent application 0527036.Google Scholar
Ellis, M. K., Lindstedt, S. T., Lock, E. A., Markstedt, M.E.H., Mutter, L. C., and Prisbylla, M. P., inventors; Imperial Chemical Industries, assignee. 1993 Jan 7. Use of 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione in the treatment of tyrosinaemia and pharmaceutical compositions. WO patent 93/00080.Google Scholar
Ellis, M. K., Whitfield, A. C., Gowans, L. A., Auton, T. R., Provan, W. M., Lock, E. A., Lee, D. L., and Smith, L. L. 1996. Characterization of the interaction of 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6-tetramethylcyclohexen-1,3,5-trione with rat hepatic 4-hydroxyphenylpyruvare dioxygenase. Chem. Res. Toxicol. 9: 24–27.CrossRefGoogle Scholar
Ellis, M. K., Whitfield, A. C., Gowans, L. A., Auton, T. R., Provan, W. M., Lock, E. A., and Smith, L. L. 1995. Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol. Appl. Pharmacol. 133: 12–19.CrossRefGoogle Scholar
Fiedler, E., Soll, J., and Schultz, G. 1982. The formation of homogentisate in the biosynthesis of tocopherol and plastoquinone in spinach chloroplasts. Planta 155: 511–515.CrossRefGoogle ScholarPubMed
Gray, R. A., Tseng, C. K., and Rusay, R. J., inventors; Stauffer Chemical Company, assignee. 1980 May 3. 1-hydroxy-2-(alkylketo)-4,4,6,6-tetramethylcyclohexen-3,5-diones. US patent 4,202,840.Google Scholar
Grünanger, P. and Vita-Finzi, P. 1991. Isoxazoles—Part One. in Taylor, E. C., ed. The Chemistry of Heterocyclic Compounds. Volume 49. New York: J Wiley, pp. 298–303.Google Scholar
Hellyer, R. O. 1968. The occurrence of β-triketones in the steam-volatile oils of some myrtaceous Australian plants. Aust. J. Chem. 21: 2825–2828.CrossRefGoogle Scholar
Holme, E., Lindstedt, S., and Lock, E. A. 1995. Treatment of tyrosinemia type I with an enzyme inhibitor (NTBC). Int. Pediatr. 10: 41–43.Google Scholar
Koizumi, S., Nagatsu, T., Iinuma, H., Ohno, M., Takeuchi, T., and Umezawa, H. 1982. Inhibition of phenylalanine hydroxylase, a pterin-requiring monooxygenase, by oudenone and its derivatives. J. Antibiotics 35: 458–462.CrossRefGoogle ScholarPubMed
Lee, D. L., inventor; Stauffer Chemical Company, assignee. 1984 May 21. Certain 2-[2-(Substitutedphenyl)acetyl]-1,3-cyclohexancdiones. Eur. patent application 0162336.Google Scholar
Lee, D. L., Mutter, L. C., Dagarin, D. P., Howard, S. W., and Fraser, T. 1995. Structure-activity relationships of HPPD herbicides: Benzoylphenols and β-diketones. 1995 International Chemical Congress of Pacific Basin Societies. Washington, DC: American Chemical Society. Book of Abstracts, Agro 1: 91.Google Scholar
Lindsted, S. and Odelhög, B. 1987. 4-Hydroxyphenylpyruvate dioxygenase from human liver. Methods Enzymol. 142: 139–142.CrossRefGoogle Scholar
Lindstedt, S., Holme, E., Lock, E. A., Hjalmarson, O., and Strandvik, B. 1992. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340: 813–817.CrossRefGoogle ScholarPubMed
Löffelhardt, W. and Kindl, H. 1979. Conversion of 4-hydroxyphenylpyruvic acid into homogentisic acid at the thylakoid membrane of Lemna gibba . FEBS Lett. 104: 332–334.CrossRefGoogle Scholar
Mayer, M. P., Bartlett, D. L., Beyer, P., and Kleinig, H. 1989. The in vitro mode of action of bleaching herbicides on the desaturation of 15-cis-phytoene and cis-z-carotene in isolated daffodil chromoplasts. Pestic. Biochem. Physiol. 34: 111–117.CrossRefGoogle Scholar
Mayer, M. P., Beyer, P., and Kleinig, H. 1990. Quinone compounds are able to replace molecular oxygen as terminal electron acceptor in phytoene desaturation in chromoplasts of Narcissus pseudonarcissus L. Eur. J. Biochem. 191: 359–363.CrossRefGoogle ScholarPubMed
Mayer, M. P., Nievelstein, V., and Beyer, P. 1992. Purification and characterization of a NADPH dependent oxidoreductase from chromoplasts of Narcissus pseudonarcissus: a redox-mediator possibly involved in carotene desaturation. Plant Physiol. Biochem. 30: 389–398.Google Scholar
Mayonado, D. J., Hatzios, K. K., Orcutt, D. M., and Wilson, H. P. 1989. Evaluation of the mechanism of action of the bleaching herbicide SC-0051 by HPLC analysis. Pestic. Biochem. Physiol. 35: 138–145.CrossRefGoogle Scholar
Michaely, W. J. and Kratz, G. W., inventors; Stauffer Chemical Company, assignee. 1986 Mar 27. Certain 2-(2-subsrituted benzoyl)-1,3-cyclohexanediones. Eur. patent application 0135191.Google Scholar
Michaely, W. J. and Kratz, G. W., inventors; Stauffer Chemical Company, assignee. 1988 Oct 25. Certain 2-(2-substituted benzoyl)-1,3-cyclohexanediones. US patent 4,780,127.Google Scholar
Natt, E., Kida, K., Odievre, M., Rocco, M. D., and Scherer, G. 1992. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc. Natl. Acad. Sci. 89: 9297–9301.CrossRefGoogle ScholarPubMed
Norris, S. R., Barrette, T. R., and DellaPenna, D. 1995. Genetic dissection of carotenoid synthesis in arabidopsis defines plastoquinone as an essential component of phytoene desaturation. Plant Cell 7: 2139–2149.Google ScholarPubMed
Oya, E., Watanabe, J., Kondo, Y., Kakuta, T., Suzuki, K., Nawamaki, T., and Watanabe, S., inventors; Nissan Chemical Industries, assignee. 1990 Jan 1. Pyrazole derivatives and herbicides containing them. Eur. patent application 0352543.Google Scholar
Prisbylla, M. P., Lee, D. L., Cromartie, T. H., Dagarin, D. P., and Howard, S. W. 1995. Mode of action studies on structurally related triketone HPPD inhibitors. 1995 International Chemical Congress of Pacific Basin Societies. Washington, DC: American Chemical Society. Book of Abstracts, Agro 1: 94.Google Scholar
Prisbylla, M. P., Onisko, B. C., Shribbs, J. M., Adams, D. O., Liu, Y., Ellis, M. K., Hawkes, T. R., and Mutter, L. C. 1993. The novel mechanism of action of the herbicidal trikerones. Proc. British Crop Prot. Conf.—Weeds 2: 731–738.Google Scholar
Rhone-Poulenc Ag Company. 1996. A New Class of Corn Weed Control. Research Triangle, NC: RPA 201772 Technical Bull. 4 p.Google Scholar
Sandmann, G. and Böger, P. 1992. Chemical structure and activity of herbicida] inhibitors of phyroene desaturase. in Draber, W. and Fujita, T., eds. Rational Approaches to Structure, Activity, and Ecotoxicology of Agrochemicals. Boca Raton, FL: CRC Press, pp. 357–371.Google Scholar
Sandmann, G., Böger, P., and Kumita, I. 1990. Atypical inhibition of phytoene desaturation by 2-(4-chloro-2-nitrobenzoyl)-5,5-dimethylcyclohexane-1,3-dione. Pestic. Sci. 30: 353–355.Google Scholar
Schultz, A., Ort, O., Beyer, P., and Kleinig, H. 1993. SC-0051, a 2-benzoyicyclohexane-1,3-dione bleaching herbicide, is a potent inhibitor of the enzyme p-hydroxyphenylpyruvate dioxygenase. FEBS Lett. 318: 162–166.CrossRefGoogle Scholar
Schultz, G., Soll, J., Fielder, E., and Schulze-Siebert, D. 1985. Synthesis of prenylquinones in chloroplasts. Physiol. Plant. 64: 123–129.CrossRefGoogle Scholar
Secor, J. 1994. Inhibition of barnyardgrass 4-hydroxyphenylpyruvate dioxygenase by sulcotrione. Plant Physiol. 106: 1429–1433.CrossRefGoogle ScholarPubMed
Soeda, T. and Uchida, T. 1987. Inhibition of pigment synthesis by 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, norflurazon, and new herbicidal compounds in radish and flatsedge plants. Pestic. Biochem. Physiol. 29: 35–42.CrossRefGoogle Scholar
Tietz, N. W. 1986a. Ferric chloride test for phenylpyruvic acid in urine. in Tietz, N. W., ed. Textbook of Clinical Chemistry. Philadelphia: W. B. Saunders, p. 550.Google Scholar
Tietz, N. W. 1986b. Methods for the determination of tyrosine in serum. in Tietz, N. W., ed. Textbook of Clinical Chemistry. Philadelphia: W. B. Saunders, pp. 553–554.Google Scholar
Yamaoka, K., Shigematsu, Y., Ando, M., Tohjigamori, M., Nakagawa, M., and Ishida, M. 1988. Degradation of the herbicide pyrazolate in rice paddy soils. Pestic. Sci. 13: 571–577.CrossRefGoogle Scholar