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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].
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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 

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