Inhibition of <i>p</i>-Hydroxyphenylpyruvate Dioxygenase by the Diketonitrile of Isoxaflutole:  A Case of Half-Site Reactivity

Garcia, Isabelle; Job, Dominique; Matringe, Michel

doi:10.1021/bi000135h

Cited by 47 publications

(44 citation statements)

References 31 publications

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“…Both mass spectra give the same pseudomolecular ion peak at mass-tocharge ratio 423.28 atomic mass unit [MϪH] Ϫ , which is characteristic of ␣-tocotrienol. (Ellis et al, 1996;Viviani Garcia et al, 1998;Garcia et al, 2000). Therefore, an increase of the concentration of HPP will prevent the binding of DKN at the active site of both native and recombinant HPPD.…”

Section: Discussionmentioning

confidence: 99%

Engineering Plant Shikimate Pathway for Production of Tocotrienol and Improving Herbicide Resistance

et al. 2004

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Tocochromanols (tocopherols and tocotrienols), collectively known as vitamin E, are essential antioxidant components of both human and animal diets. Because of their potential health benefits, there is a considerable interest in plants with increased or customized vitamin E content. Here, we have explored a new strategy to reach this goal. In plants, phenylalanine is the precursor of a myriad of secondary compounds termed phenylpropanoids. In contrast, much less carbon is incorporated into tyrosine that provides p-hydroxyphenylpyruvate and homogentisate, the aromatic precursors of vitamin E. Therefore, we intended to increase the flux of these two compounds by deriving their synthesis directly at the level of prephenate. This was achieved by the expression of the yeast (Saccharomyces cerevisiae) prephenate dehydrogenase gene in tobacco (Nicotiana tabacum) plants that already overexpress the Arabidopsis p-hydroxyphenylpyruvate dioxygenase coding sequence. A massive accumulation of tocotrienols was observed in leaves. These molecules, which were undetectable in wild-type leaves, became the major forms of vitamin E in the leaves of the transgenic lines. An increased resistance of the transgenic plants toward the herbicidal p-hydroxyphenylpyruvate dioxygenase inhibitor diketonitril was also observed. This work demonstrates that the synthesis of p-hydroxyphenylpyruvate is a limiting step for the accumulation of vitamin E in plants.

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Section: Discussionmentioning

confidence: 99%

Engineering Plant Shikimate Pathway for Production of Tocotrienol and Improving Herbicide Resistance

et al. 2004

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“…Vector pTrc99A-The pTrc99A-HPPD Car 13 plasmid coding for the carrot HPPD protein was described previously (24,25).…”

Section: Cloning Of the Carrot Hppd Sequence Into The Expressionmentioning

confidence: 99%

“…Assay for HPPD Activity O 2 Consumption Method-The activity of the purified recombinant proteins was monitored by measuring the consumption of O 2 during the formation of homogentisate from HPP (25). The reaction was initiated by the addition of purified carrot HPPD, and O 2 consumption was recorded versus time at 30°C.…”

Section: Cloning Of the Pseudomonas Acidovorans 14-dihydroxyphenylacmentioning

confidence: 99%

“…Kinetic Properties of Mutant HPPD-HPPD enzymatic activity was assessed by two different methods as follows: (i) measuring O 2 consumption during HGA formation from HPP and (ii) monitoring HGA formation by HPLC (24,25). For the five carrot HPPD mutants a plot of v (steady-state O 2 consumption rate) versus HPP concentration fits the Michaelis-Menten hyperbolic equation (supplemental Fig.…”

Section: Identification Of Key Residues Involved In Substrate Bindingmentioning

confidence: 99%

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4-Hydroxyphenylpyruvate Dioxygenase Catalysis

Raspail

Graindorge

Moreau

et al. 2011

Journal of Biological Chemistry

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4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) intohomogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease. The reaction mechanism of this key enzyme in both plants and animals has not yet been fully elucidated. In this study, using site-directed mutagenesis supported by quantum mechanical/molecular mechanical theoretical calculations, we investigated the role of catalytic residues potentially interacting with the substrate/intermediates. These results highlight the following: (i) the central role of Gln-272, Gln-286, and Gln-358 in HPP binding and the first nucleophilic attack; (ii) the important movement of the aromatic ring of HPP during the reaction, and (iii) the key role played by Asn-261 and Ser-246 in C1 hydroxylation and the final ortho-rearrangement steps (numbering according to the Arabidopsis HPPD crystal structure 1SQD). Furthermore, this study reveals that the last step of the catalytic reaction, the 1,2 shift of the acetate side chain, which was believed to be unique to the HPPD activity, is also catalyzed by a structurally unrelated enzyme. 4-Hydroxyphenylpyruvate dioxygenase (HPPD)3 is an Fe II -dependent non-heme oxygenase catalyzing the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate (HGA). In most aerobic life forms, HPPD catalyzes the second step in tyrosine catabolism. In all photosynthetic organisms, HPPD also plays an anabolic role, as HGA is essential for the formation of isoprenoid redox molecules such as plastoquinone and tocochromanols (1, 2). Plant HPPD is the molecular target of several natural compounds (3, 4) and of a range of very effective synthetic herbicides that are currently used commercially (5-9). In mammals, inborn defects in this pathway give rise to metabolic disorders of different degrees of severity (5, 10). Among these, two involve HPPD. Type III tyrosinemia arises from low HPPD activity (11) caused by an alanine to valine mutation at position 268 in the human enzyme (12). Hawkinsinuria, linked with an active enzyme with almost uncoupled turnover, is a result of an alanine to threonine mutation at position 33 in the human enzyme (12). This mutant enzyme releases an arene oxide-derived intermediate excreted in large quantities in the urine (13).Interestingly, HPPD inhibitor/herbicide molecules also act as therapeutic agents for the debilitating and lethal inborn defects associated with type I tyrosinemia. Inhibition of HPPD prevents the accumulation of toxic metabolites in this disease (5). HPPD inhibitors are also currently being used in trials for treatment of Parkinson disease, based on the premise that inhibition of tyrosine catabolism will increase tyrosine availability for conversion to 3,4-dihydroxyphenylalanine in the brain.The reaction mechanism of HPPD is complex; it first involves the nucleophilic attack of the ␣-keto ...

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“…HppD has been described in humans (4,44), mouse (9), and rat (10), as well as plants (14,16), fungi (63), and prokaryotes (8,45). There is considerable interest in the HGA catabolic pathway, because HppD in plants is an important herbicide target (5,15,23) and many severe human diseases, like phenylketonuria (18); alkaptonuria (52); tyrosinemias I, II, and III; and hawkinsinuria (48), are associated with enzyme deficiencies in the catabolism of tyrosine.…”

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Burkholderia cenocepacia C5424 Produces a Pigment with Antioxidant Properties Using a Homogentisate Intermediate

Keith¹,

Killip²,

et al. 2007

J Bacteriol

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Burkholderia cenocepacia is a gram-negative opportunistic pathogen that belongs to the Burkholderia cepacia complex. B. cenocepacia can survive intracellularly within phagocytic cells, and some epidemic strains produce a brown melanin-like pigment that can scavenge free radicals, resulting in the attenuation of the host cell oxidative burst. In this work, we demonstrate that the brown pigment produced by B. cenocepacia C5424 is synthesized from a homogentisate (HGA) precursor. The disruption of BCAL0207 (hppD) by insertional inactivation resulted in loss of pigmentation. Steady-state kinetic analysis of the BCAL0207 gene product demonstrated that it has 4-hydroxyphenylpyruvic acid dioxygenase (HppD) activity. Pigmentation could be restored by complementation providing hppD in trans. The hppD mutant was resistant to paraquat challenge but sensitive to H 2 O 2 and to extracellularly generated superoxide anions. Infection experiments in RAW 264.7 murine macrophages showed that the nonpigmented bacteria colocalized in a dextran-positive vacuole, suggesting that they are being trafficked to the lysosome. In contrast, the wild-type strain did not localize with dextran. Colocalization of the nonpigmented strain with dextran was reduced in the presence of the NADPH oxidase inhibitor diphenyleneiodonium, and also the inducible nitric oxide inhibitor aminoguanidine. Together, these observations suggest that the brown pigment produced by B. cenocepacia C5424 is a pyomelanin synthesized from an HGA intermediate that is capable of protecting the organism from in vitro and in vivo sources of oxidative stress.

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Inhibition of p-Hydroxyphenylpyruvate Dioxygenase by the Diketonitrile of Isoxaflutole: A Case of Half-Site Reactivity

Cited by 47 publications

References 31 publications

Engineering Plant Shikimate Pathway for Production of Tocotrienol and Improving Herbicide Resistance

Engineering Plant Shikimate Pathway for Production of Tocotrienol and Improving Herbicide Resistance

4-Hydroxyphenylpyruvate Dioxygenase Catalysis

Burkholderia cenocepacia C5424 Produces a Pigment with Antioxidant Properties Using a Homogentisate Intermediate

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