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1

Lin, Hong-Yan, Xi Chen, Jia-Nan Chen, Da-Wei Wang, Feng-Xu Wu, Song-Yun Lin, Chang-Guo Zhan, Jia-Wei Wu, Wen-Chao Yang, and Guang-Fu Yang. "Crystal Structure of 4-Hydroxyphenylpyruvate Dioxygenase in Complex with Substrate Reveals a New Starting Point for Herbicide Discovery." Research 2019 (July 8, 2019): 1–11. http://dx.doi.org/10.34133/2019/2602414.

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4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a promising target for drug and pesticide discovery. The unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design. Herein, we determined the first crystal structure of Arabidopsis thaliana HPPD (AtHPPD) in complex with its natural substrate (HPPA) at a resolution of 2.80 Å. Then, combination of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations confirmed that HPPA takes keto rather than enol form inside the HPPD active pocket. Subsequent site-directed mutagenesis and kinetic analysis further showed that residues (Phe424, Asn423, Glu394, Gln307, Asn282, and Ser267) played important roles in substrate binding and catalytic cycle. Structural comparison between HPPA-AtHPPD and holo-AtHPPD revealed that Gln293 underwent a remarkable rotation upon the HPPA binding and formed H-bond network of Ser267-Asn282-Gln307-Gln293, resulting in the transformation of HPPD from an inactive state to active state. Finally, taking the conformation change of Gln293 as a target, we proposed a new strategy of blocking the transformation of HPPD from inactive state to active state to design a novel inhibitor with Ki value of 24.10 nM towards AtHPPD. The inhibitor has entered into industry development as the first selective herbicide used for the weed control in sorghum field. The crystal structure of AtHPPD in complex with the inhibitor (2.40 Å) confirmed the rationality of the design strategy. We believe that the present work provides a new starting point for the understanding of enzymatic reaction mechanism and the design of next generation HPPD inhibitors.
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2

Huang, Chih-Wei, Chi-Ching Hwang, Yung-Lung Chang, Jen-Tzu Liu, Sheng-Peng Wu, Kai-Ling Huang, Wei-min Huang, and Hwei-Jen Lee. "Functional role of residues involved in substrate binding of human 4-hydroxyphenylpyruvate dioxygenase." Biochemical Journal 478, no. 12 (June 18, 2021): 2201–15. http://dx.doi.org/10.1042/bcj20210005.

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4-Hydroxylphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate, the important step for tyrosine catabolism. Comparison of the structure of human HPPD with the substrate-bound structure of A. thaliana HPPD revealed notably different orientations of the C-terminal helix. This helix performed as a closed conformation in human enzyme. Simulation revealed a different substrate-binding mode in which the carboxyl group of HPP interacted by a H-bond network formed by Gln334, Glu349 (the metal-binding ligand), and Asn363 (in the C-terminal helix). The 4-hydroxyl group of HPP interacted with Gln251 and Gln265. The relative activity and substrate-binding affinity were preserved for the Q334A mutant, implying the alternative role of Asn363 for HPP binding and catalysis. The reduction in kcat/Km of the Asn363 mutants confirmed the critical role in catalysis. Compared to the N363A mutant, the dramatic reduction in the Kd and thermal stability of the N363D mutant implies the side-chain effect in the hinge region rotation of the C-terminal helix. The activity and binding affinity were not recovered by double mutation; however, the 4-hydroxyphenylacetate intermediate formation by the uncoupled reaction of Q334N/N363Q and Q334A/N363D mutants indicated the importance of the H-bond network in the electrophilic reaction. These results highlight the functional role of the H-bond network in a closed conformation of the C-terminal helix to stabilize the bound substrate. The extremely low activity and reduction in Q251E's Kd suggest that interaction coupled with the H-bond network is crucial to locate the substrate for nucleophilic reaction.
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3

Liu, Yong-Xuan, Shuang Gao, Tong Ye, Jia-Zhong Li, Fei Ye, and Ying Fu. "Combined 3D-quantitative structure–activity relationships and topomer technology-based molecular design of human 4-hydroxyphenylpyruvate dioxygenase inhibitors." Future Medicinal Chemistry 12, no. 9 (May 2020): 795–811. http://dx.doi.org/10.4155/fmc-2019-0349.

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Aim: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as an important target against tyrosinemia type I. This paper aimed to explore the structure–activity relationship of HPPD inhibitors with pyrazole scaffolds and to design novel HPPD inhibitors. Methodology & results: The best 3D-quantitative structure–activity relationships model was established by two different strategies based on 40 pyrazole scaffold-based analogs. Screening of molecular fragments by topomer technology, combined with molecular docking, 14 structures were identified for potential human HPPD inhibitory activity. Molecular dynamics results demonstrated that all the compounds obtained bound to the enzyme and possessed a satisfactory binding free energy. Conclusion: The quantitative structure–activity relationship of HPPD inhibitors of pyrazole scaffolds was clarified and 14 original structures with potential human HPPD inhibitory activity were obtained.
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4

Oliveira, Maxwel C., Amit J. Jhala, Todd Gaines, Suat Irmak, Keenan Amundsen, Jon E. Scott, and Stevan Z. Knezevic. "Confirmation and Control of HPPD-Inhibiting Herbicide–Resistant Waterhemp (Amaranthus tuberculatus) in Nebraska." Weed Technology 31, no. 1 (January 2017): 67–79. http://dx.doi.org/10.1017/wet.2016.4.

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Field and greenhouse experiments were conducted in Nebraska to (1) confirm the 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting resistant-waterhemp biotype (HPPD-RW) by quantifying the resistance levels in dose-response studies, and (2) to evaluate efficacy of PRE-only, POST-only, and PRE followed by POST herbicide programs for control of HPPD-RW in corn. Greenhouse dose-response studies confirmed that the suspected waterhemp biotype in Nebraska has evolved resistance to HPPD-inhibiting herbicides with a 2- to 18-fold resistance depending upon the type of HPPD-inhibiting herbicide being sprayed. Under field conditions, at 56 d after treatment, ≥90% control of the HPPD-RW was achieved with PRE-applied mesotrione/atrazine/S-metolachlor+acetochlor, pyroxasulfone (180 and 270 g ai ha−1), pyroxasulfone/fluthiacet-methyl/atrazine, and pyroxasulfone+saflufenacil+atrazine. Among POST-only herbicide programs, glyphosate, a premix of mesotrione/atrazine tank-mixed with diflufenzopyr/dicamba, or metribuzin, or glufosinate provided ≥92% HPPD-RW control. Herbicide combinations of different effective sites of action in mixtures provided ≥86% HPPD-RW control in PRE followed by POST herbicide programs. It is concluded that the suspected waterhemp biotype is resistant to HPPD-inhibiting herbicides and alternative herbicide programs are available for effective control in corn. The occurrence of HPPD-RW in Nebraska is significant because it limits the effectiveness of HPPD-inhibiting herbicides.
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5

Kosař, Michal, Lumila Holková, Natálie Březinová Belcredi, and Jaroslava Ehrenbergerová. "HPPD gene expression in relation to vitamin E content in spring barley." Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis 57, no. 4 (2009): 13–18. http://dx.doi.org/10.11118/actaun200957040013.

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The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) has a very important role in the biosynthetic pathway of vitamin E. Its activity influences the final level of tocols in plant tissues. Seven barley cultivars with different vitamin E level were grown under control conditions and activity of HPPD gene was measured four, eight and twelve days after pollination of ear tissues. It was found that activity of HPPD gene corresponded with vitamin E content detected in grains (r = 0.77*). The relationship between the gene activity for HPPD eight and twelve days after pollination and vitamin E content was also confirmed for analyzed cultivars grown in the field conditions (r = 0.85*).
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6

Fu, Ying, Tong Ye, Yong-Xuan Liu, Jian Wang, and Fei Ye. "Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors." International Journal of Molecular Sciences 21, no. 15 (August 3, 2020): 5546. http://dx.doi.org/10.3390/ijms21155546.

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4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an iron-dependent non-heme oxygenase involved in the catabolic pathway of tyrosine, which is an important enzyme in the transformation of 4-hydroxyphenylpyruvic acid to homogentisic acid, and thus being considered as herbicide target. Within this study, a set of multiple structure-based pharmacophore models for HPPD inhibitors were developed. The ZINC and natural product database were virtually screened, and 29 compounds were obtained. The binding mode of HPPD and its inhibitors obtained through molecular docking study showed that the residues of Phe424, Phe381, His308, His226, Gln307 and Glu394 were crucial for activity. Molecular-mechanics-generalized born surface area (MM/GBSA) results showed that the coulomb force, lipophilic and van der Waals (vdW) interactions made major contributions to the binding affinity. These efforts will greatly contribute to design novel and effective HPPD inhibitory herbicides.
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7

Wang, Man-Man, Hao Huang, Lei Shu, Jian-Min Liu, Jian-Qiu Zhang, Yi-Le Yan, and Da-Yong Zhang. "Synthesis and herbicidal activities of aryloxyacetic acid derivatives as HPPD inhibitors." Beilstein Journal of Organic Chemistry 16 (February 19, 2020): 233–47. http://dx.doi.org/10.3762/bjoc.16.25.

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A series of aryloxyacetic acid derivatives were designed and synthesized as 4-hydoxyphenylpyruvate dioxygenase (HPPD) inhibitors. Preliminary bioassay results reveal that these derivatives are promising Arabidopsis thaliana HPPD (AtHPPD) inhibitors, in particular compounds I12 (K i = 0.011 µM) and I23 (K i = 0.012 µM), which exhibit similar activities to that of mesotrione, a commercial HPPD herbicide (K i = 0.013 µM). Furthermore, the newly synthesized compounds show significant greenhouse herbicidal activities against tested weeds at dosages of 150 g ai/ha. In particular, II4 exhibited high herbicidal activity for pre-emergence treatment that was slightly better than that of mesotrione. In addition, compound II4 was safe for weed control in maize fields at a rate of 150 g ai/ha, and was identified as the most potent candidate for a novel HPPD inhibitor herbicide. The compounds described herein may provide useful guidance for the design of new HPPD inhibiting herbicides and their modification.
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8

O’Brien, Sarah R., Adam S. Davis, and Dean E. Riechers. "Quantifying Resistance to Isoxaflutole and Mesotrione and Investigating Their Interactions with Metribuzin POST in Waterhemp (Amaranthus tuberculatus)." Weed Science 66, no. 5 (September 2018): 586–94. http://dx.doi.org/10.1017/wsc.2018.36.

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AbstractGreenhouse experiments were conducted to quantify resistance levels to the 4-hydroxyphenyl-pyruvate dioxygenase (HPPD)-inhibiting herbicides mesotrione (MES) and isoxaflutole (IFT) in NEB (Nebraska HPPD- and atrazine-resistant) and SIR (Stanford, IL, HPPD- and atrazine-resistant) waterhemp [Amaranthus tuberculatus(Moq.) J. D. Sauer] populations. These populations differ in their field-use histories and resistance levels to MES. Foliar growth responses were compared with ACR (HPPD sensitive; metabolic atrazine-resistant) and SEN (sensitive to HPPD and photosystem II [PSII] inhibitors). A greenhouse dose–response study was conducted with each herbicide at two POST timings: early (EPOST) (5 cm; 4 to 5 true leaves) and POST (10 cm; 8 to 9 true leaves). At the EPOST timing, SIR was 10-fold resistant to IFT and 32-fold resistant to MES, while NEB was 4-fold resistant to IFT and 7-fold resistant to MES when compared with ACR. At the POST timing, SIR was 17-fold resistant to IFT and 21-fold resistant to MES, while NEB was 3-fold resistant to IFT and 7-fold resistant to MES when compared with ACR. Results overall indicated greater fold-resistance levels to MES relative to IFT at each timing. However, POST treatments to SIR showed contrasting effects on resistance levels relative to EPOST. To investigate potential management strategies for resistantA. tuberculatuspopulations, a POST interaction study was conducted using combinations of metribuzin and either IFT or MES. A metribuzin rate (191 g ai ha−1) causing an approximately 20% biomass reduction was chosen for interaction studies and combined with varying rates of either IFT or MES. Results indicated 52.5 g ai ha−1of MES combined with metribuzin displayed a synergistic effect on biomass reduction in SIR. However, other combinations of either MES or IFT and metribuzin resulted in additive effects on biomass reduction in both HPPD-resistant populations. These results provide insights into the joint activity between HPPD and PSII inhibitors for controlling metabolism-based, multiple herbicide–resistantA. tuberculatus.
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9

Chen, Jinsong, Lin Zhang, and Junwu Zhang. "Chondrocyte proliferation is promoted by 7-H-pyrrolo[2,3- d]pyrimidine via up-regulation of type II collagen matrix." Tropical Journal of Pharmaceutical Research 19, no. 4 (May 14, 2020): 683–89. http://dx.doi.org/10.4314/tjpr.v19i4.2.

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Purpose: To investigate the effect of 7-H-pyrrolo[2,3-d]pyrimidine derivative (7-HPPD) on the viability of chondrocytes in vitro, and to elucidate the associated mechanisms.Methods: Chondrocyte proliferation was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay while cell cycle was assessed by flow cytometry. Western blot and immunohistochemical staining assays were used to determine protein levels.Results: The results show that 7-HPPD significantly increased the proliferation rate of chondrocytes in a concentration-dependent manner (p < 0.05). The proportion of chondrocytes in S phase increased significantly with subsequent reduction in G0/G1 phase of cell cycle on treatment with 7-HPPD (p <0.05). Thus, 7-HPPD increased the rate of chondrocyte proliferation by promoting transition through G1/S phase of cell cycle. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis revealed that treatment of chondrocytes with 7-HPPD caused a marked increase in the level of cyclin D1, cyclin dependent kinase (CDK)-4 and CDK6 proteins (p < 0.05). Western blot and immunohistochemical staining assays showed that 7-HPPD treatment caused a significant increase in the levels of type II collagen matrix in the chondrocytes.Conclusion: Proliferation of chondrocytes is increased by 7-HPPD and this occurs by facilitating G1/S phase transition and increasing expression of cyclin D1, CDK4 and CDK6 proteins. Therefore, 7-HPPD may be developed as a chemotherapeutic agent for the treatment of osteoarthritis. Keywords: Immunohistochemistry, Type II collagen, G1/S phase, Cyclin D1, Osteoarthritis
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10

Evans, Cody M., Seth A. Strom, Dean E. Riechers, Adam S. Davis, Patrick J. Tranel, and Aaron G. Hager. "Characterization of a waterhemp (Amaranthus tuberculatus) population from Illinois resistant to herbicides from five site-of-action groups." Weed Technology 33, no. 03 (May 23, 2019): 400–410. http://dx.doi.org/10.1017/wet.2019.19.

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AbstractExperiments were initiated to characterize a waterhemp population (CHR) discovered in a central Illinois corn field after it was not controlled by the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor topramezone. Field experiments conducted during 2014–2015 indicated that acetolactate synthase (ALS)-, protoporphyrinogen oxidase (PPO)-, photosystem II (PSII)-, and HPPD-inhibiting herbicides and the synthetic auxin 2,4-D did not control the CHR population. Laboratory experiments confirmed target site–based resistance mechanisms to ALS- and PPO-inhibiting herbicides. Herbicide doses required to reduce dry biomass 50% (GR50) were determined in greenhouse dose–response experiments, and indicated 16-fold resistance to the HPPD inhibitor mesotrione, 9.5-fold resistance to the synthetic auxin 2,4-D, and 252-fold resistance to the PSII inhibitor atrazine. Complementary results from field, laboratory, and greenhouse investigations indicate that the CHR population has evolved resistance to herbicides from five sites of action (SOAs): ALS-, PPO-, PSII-, and HPPD-inhibiting herbicides and 2,4-D. Herbicide use history for the field in which CHR was discovered indicates no previous use of 2,4-D.
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11

Rodrigues, L. F., J. C. M. Ierich, M. A. Andrade, M. A. Hausen, F. L. Leite, Alberto L. D. Moreau, and Clarice Steffens. "Nanomechanical Cantilever-Based Sensor: An Efficient Tool to Measure the Binding Between the Herbicide Mesotrione and 4-Hydroxyphenylpyruvate Dioxygenase." Nano 12, no. 07 (July 2017): 1750079. http://dx.doi.org/10.1142/s1793292017500795.

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Nanomechanical biosensors based on atomic force microscopy (AFM) cantilevers have garnered considerable attention. AFM cantilevers are devices that can detect a target either via a surface functionalization process based on immobilization through molecular adsorption, or through the selective chemical binding of a specific molecule, transforming the device into a specific biosensor. In this study, we demonstrate that functionalized AFM cantilevers could be used, in a process involving self-assembling layers, to create a homogeneous surface layer of the widely used herbicide mesotrione. Controlled experiments to evaluate its detection were performed, and binding between mesotrione and its target molecule, 4-hydroxyphenylpyruvate dioxygenase (HPPD), was evaluated using deflection curves of functionalized cantilevers interacting with mesotrione. The cantilevers worked as nanomechanical sensors inside a fluid cell device, under different concentrations of HPPD diluted in PBS. After evaluating increasing concentrations of HPPD, the deflection curves showed a clear, dose-dependent pattern. The homogeneous dispersion of mesotrione on the cantilevers was assessed by confocal microscopy, and this corroborated the functionalization method. Thus, the results obtained by this functionalized cantilever presented a high efficiency in detecting binding between HPPD and mesotrione molecules at concentrations as low as 17[Formula: see text]ng mL[Formula: see text]. In this way, as a preliminary step for a future environmental contaminants nanosensor development, the described detection method showed a suitable capability for molecular recognition at the nanoscale.
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12

Feng, An-Ning, Chih-Wei Huang, Chi-Huei Lin, Yung-Lung Chang, Meng-Yuan Ni, and Hwei-Jen Lee. "Role of the N-terminus in human 4-hydroxyphenylpyruvate dioxygenase activity." Journal of Biochemistry 167, no. 3 (November 13, 2019): 315–22. http://dx.doi.org/10.1093/jb/mvz092.

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Abstract 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme in tyrosine catabolism, catalysing the oxidation of 4-hydroxyphenylpyruvate to homogentisate. Genetic deficiency of this enzyme causes type III tyrosinaemia. The enzyme comprises two barrel-shaped domains formed by the N- and C-termini, with the active site located in the C-terminus. This study investigated the role of the N-terminus, located at the domain interface, in HPPD activity. We observed that the kcat/Km decreased ∼8-fold compared with wild type upon removal of the 12 N-terminal residues (ΔR13). Interestingly, the wild-type level of activity was retained in a mutant missing the 17 N-terminal residues, with a kcat/Km 11-fold higher than that of the ΔR13 mutant; however, the structural stability of this mutant was lower than that of wild type. A 2-fold decrease in catalytic efficiency was observed for the K10A and E12A mutants, indicating synergism between these residues in the enzyme catalytic function. A molecular dynamics simulation showed large RMS fluctuations in ΔR13 suggesting that conformational flexibility at the domain interface leads to lower activity in this mutant. These results demonstrate that the N-terminus maintains the stability of the domain interface to allow for catalysis at the active site of HPPD.
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13

Jhala, Amit J., Lowell D. Sandell, Neha Rana, Greg R. Kruger, and Stevan Z. Knezevic. "Confirmation and Control of Triazine and 4-Hydroxyphenylpyruvate Dioxygenase-Inhibiting Herbicide-Resistant Palmer Amaranth (Amaranthus palmeri) in Nebraska." Weed Technology 28, no. 1 (March 2014): 28–38. http://dx.doi.org/10.1614/wt-d-13-00090.1.

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Palmer amaranth is a difficult-to-control broadleaf weed that infests corn and soybean fields in south-central and southwestern Nebraska and several other states in the United States. The objectives of this research were to confirm triazine and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide-resistant Palmer amaranth in Nebraska and to determine sensitivity and efficacy of POST-applied corn herbicides for control of resistant and susceptible Palmer amaranth biotypes. Seeds from a putative HPPD-resistant Palmer amaranth biotype from Fillmore County, NE were collected from a seed corn production field in fall 2010. The response of Palmer amaranth biotypes to 12 rates (0 to 12×) of mesotrione, tembotrione, topramezone, and atrazine was evaluated in a dose–response bioassay in a greenhouse. On the basis of the values at the 90% effective dose (ED90) level, the analysis showed a 4- to 23-fold resistance depending upon the type of HPPD-inhibiting herbicide being investigated and susceptible biotype used for comparison. This biotype also had a 9- to 14-fold level of resistance to atrazine applied POST. Results of a POST-applied herbicide efficacy study suggested a synergistic interaction between atrazine and HPPD-inhibiting herbicides that resulted in > 90% control of all Palmer amaranth biotypes. The resistant biotype had a reduced sensitivity to acetolactate synthase inhibiting herbicides (halosulfuron and primisulfuron), a photosystem-II inhibitor (bromoxynil), and a protoporphyrinogen oxidase inhibitor (fluthiacet-methyl). Palmer amaranth biotypes were effectively controlled (≥ 90%) with glyphosate, glufosinate, and dicamba, whereas 2,4-D ester provided 81 to 83% control of the resistant biotype and > 90% control of both susceptible biotypes.
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Kohrt, Jonathon R., and Christy L. Sprague. "Response of a Multiple-Resistant Palmer Amaranth (Amaranthus palmeri) Population to Four HPPD-Inhibiting Herbicides Applied Alone and with Atrazine." Weed Science 65, no. 4 (June 22, 2017): 534–45. http://dx.doi.org/10.1017/wsc.2017.28.

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Control of multiple-resistant Palmer amaranth populations in corn will rely heavily on the use of POST 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides. Therefore, field and greenhouse experiments were conducted to: (1) evaluate Palmer amaranth control with four HPPD inhibitors alone and in combination with atrazine at two application timings and (2) investigate the joint activity of HPPD-inhibiting herbicides and atrazine in atrazine-resistant (AR) and atrazine-susceptible (AS) Palmer amaranth populations. Control of the AR Palmer amaranth population varied among the HPPD-inhibiting herbicides with tolpyralate>tembotrione=topramezone>mesotrione based on GR50values in the greenhouse. In the field, Palmer amaranth control was lower when the HPPD-inhibiting herbicides, with the exception of tolpyralate, were applied to 15- vs. 8-cm-tall Palmer amaranth. Tolpyralate controlled Palmer amaranth ≥95% at both application timings. The addition of atrazine (560 g ai ha−1) improved Palmer amaranth control with mesotrione and topramezone at the 8-cm application timing and with mesotrione and tembotrione at the 15-cm application timing. In the greenhouse, joint activity of mesotrione and atrazine and tembotrione and atrazine was synergistic with both the AR and AS Palmer amaranth populations. In the AR population, an additional 980 g ai ha−1of atrazine (8X) was needed to cause a synergistic response compared with the AS population. Synergistic responses with mesotrione were detected with all atrazine rates for the AS population and for atrazine rates ranging from 280 to 2,240 g ai ha−1for the AR population. Only additive responses were observed when atrazine was applied with tolpyralate and topramezone, indicating that joint activity in the form of synergism occurs more readily with the triketones compared with the benzopyrazoles. When faced with an AR Palmer amaranth population, the addition of atrazine to HPPD inhibitors may increase the overall success of weed management due to joint activity.
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Alam, Mahboob, Youngwon Kim, and Soonheum Park. "Synthesis, characterization (IR, 1H, 13C & 31P NMR), fungicidal, herbicidal and molecular docking evaluation of steroid phosphorus compounds." Open Chemistry 17, no. 1 (August 27, 2019): 621–28. http://dx.doi.org/10.1515/chem-2019-0069.

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AbstractPhosphorus containing steroidal derivatives such as 3β-oxo-[diazaphosphalidine-2’-one] stigmast-5-ene and 3β-oxo-[diazaphosphalidine-2’-one] stigmast-5,22-diene were designed, synthesized and characterized using spectroscopic techniques (IR, 1H, 13C & 31P NMR, HRMS) and elemental analysis. The fungicidal and herbicidal studies of the compounds were performed and the experimental outcomes showed that compound 4 showed a good fungicidal activity against mycelium growth of fungi, while in the case of herbicidal activity, both compounds show a moderate activity compared to the commercial drug; Atrazine. The binding free energy of active compound 4 to the receptor named 4-Hydroxyphenylpyruvate dioxygenase (HPPD) was calculated using the molecular docking study. The HPPD is one of the most effective targets of plants for the herbicide study.
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16

Chahal, Parminder S., Mithila Jugulam, and Amit J. Jhala. "Mechanism of atrazine resistance in atrazine- and HPPD inhibitor-resistant Palmer amaranth (Amaranthus palmeri S. Wats.) from Nebraska." Canadian Journal of Plant Science 99, no. 6 (December 1, 2019): 815–23. http://dx.doi.org/10.1139/cjps-2018-0268.

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Palmer amaranth (Amaranthus palmeri S. Wats.) is one of the most problematic weed species in agronomic crops in the United States. A Palmer amaranth biotype multiple-resistant to atrazine and 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors was reported in a seed corn production field in Nebraska. Rapid detoxification mediated by cytochrome P450 monooxygenases and increased HPPD gene expression were reported as the mechanisms of mesotrione resistance in atrazine- and HPPD inhibitor-resistant Palmer amaranth biotype from Nebraska; however, the mechanism of atrazine resistance is unknown. The objectives of this study were to investigate target site or non-target site based mechanisms conferring atrazine resistance in Palmer amaranth from Nebraska. 14C-atrazine absorption and translocation studies revealed that reduced atrazine absorption or translocation were not involved as one of the mechanisms of atrazine resistance. Instead, greater 14C-atrazine absorption and recovery in treated leaves were observed in resistant compared with susceptible Palmer amaranth. No known mutations including Ser264Gly substitution in the psbA gene causing target site based atrazine resistance were observed. However, the parent 14C-atrazine was metabolized rapidly <4 h after treatment in resistant plants, conferring enhanced atrazine metabolism as the mechanism of resistance.
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17

Willemse, Christian, Nader Soltani, Lauren Benoit, Amit J. Jhala, David C. Hooker, Darren E. Robinson, and Peter H. Sikkema. "Is There a Benefit of Adding Atrazine to HPPD-Inhibiting Herbicides for Control of Multiple-Herbicide-Resistant, Including Group 5-Resistant, Waterhemp in Corn?" Journal of Agricultural Science 13, no. 7 (June 15, 2021): 21. http://dx.doi.org/10.5539/jas.v13n7p21.

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The evolution of multiple-herbicide-resistant (MHR) waterhemp (resistant to Groups 2, 5, 9, and 14) in Ontario, Canada is challenging for growers. The complementary activity of the co-application of hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides with atrazine has been well documented. The objective of this research was to determine if the addition of atrazine to 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides applied postemergence improves their consistency of MHR waterhemp (including Group 5 resistance) in corn. Five field trials were conducted over a two-year period (2018, 2019) in Ontario, Canada. Five HPPD-inhibiting herbicides [isoxaflutole (105 g ha-1), mesotrione (100 g ha-1), topramezone (12.5 g ha-1), tembotrione (90 g ha-1), and tolpyralate (30 g ha-1)] were applied postemergence with and without atrazine to 10-cm-tall waterhemp. Corn injury (&le; 10%) was observed at specific sites where the application of tembotrione, isoxaflutole and isoxaflutole + atrazine resulted in characteristic white bleaching of corn foliage; however, yield was not affected. Averaged across field sites, the addition of atrazine to isoxaflutole, mesotrione, topramezone, or tembotrione improved MHR waterhemp control 15%, 11%, 7%, and 7%, respectively at 4 weeks after application (WAA). Averaged across herbicide treatments and sites, the addition of atrazine reduced the standard error of MHR waterhemp control by 13% to 100%. This study concludes that the co-application of atrazine with HPPD-inhibitors applied postemergence reduced the risk of herbicide failure and resulted in greater and more consistent control of MHR waterhemp.
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Huang, Chih-Wei, Hsiu-Chen Liu, Chia-Pei Shen, Yi-Tong Chen, Sung-Jai Lee, Matthew D. Lloyd, and Hwei-Jen Lee. "The different catalytic roles of the metal-binding ligands in human 4-hydroxyphenylpyruvate dioxygenase." Biochemical Journal 473, no. 9 (April 26, 2016): 1179–89. http://dx.doi.org/10.1042/bcj20160146.

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4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a member of the non-haem Fe(II)/2-oxoacid-dependent oxygenase family. Each ligand in the catalytic triad that play unique role in the catalytic and regulatory function is correlated with their respective coordination position.
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Crouch, Nicholas P., Robert M. Adlington, Jack E. Baldwin, Meng Huee Lee, and Colin H. MacKinnon. "A mechanistic rationalisation for the substrate specificity of recombinant mammalian 4-hydroxyphenylpyruvate dioxygenase (4-HPPD)." Tetrahedron 53, no. 20 (May 1997): 6993–7010. http://dx.doi.org/10.1016/s0040-4020(97)00398-0.

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20

Chahal, Parminder S., Suat Irmak, Todd Gaines, Keenan Amundsen, Mithila Jugulam, Prashant Jha, Ilias S. Travlos, and Amit J. Jhala. "Control of Photosystem II– and 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor–Resistant Palmer Amaranth (Amaranthus palmeri) in Conventional Corn." Weed Technology 32, no. 3 (February 19, 2018): 326–35. http://dx.doi.org/10.1017/wet.2017.111.

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AbstractPalmer amaranth, a dioecious summer annual weed species, is the most troublesome weed in agronomic crop production systems in the United States. Palmer amaranth resistant to photosystem (PS) II- and 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors is of particular concern in south central Nebraska. The objectives of this study were to determine the effect of PRE followed by POST herbicide programs on PS II- and HPPD-inhibitor-resistant Palmer amaranth control, crop yield, and net economic return in conventional corn. A field study was conducted in 2014, 2015, and 2016 in a grower’s field infested with PS II- and HPPD-inhibitor-resistant Palmer amaranth near Shickley in Fillmore County, Nebraska. A contrast analysis suggested that mesotrione+S-metolachlor+atrazine applied PRE provided 83% Palmer amaranth control at 21 d after application compared to 78 and 72% control with pyroxasulfone+fluthiacet-ethyl+atrazine and saflufenacil+dimethenamid-P, respectively. Most of the PRE followed by POST herbicide programs provided ≥85% Palmer amaranth control. Based on contrast analysis, POST application of dicamba+diflufenzopyr provided 93% Palmer amaranth control compared to 87, 79, and 42% control with dicamba, dicamba+halosulfuron, and acetochlor, respectively, at 28 d after POST. All PRE followed by POST herbicide programs, aside from mesotrione+S-metolachlor+atrazine followed by acetochlor (2,530 to 7,809 kg ha−1), provided 9,550 to 10,500 kg ha−1corn yield compared with 2,713 to 6,110 kg ha−1from nontreated control. Similarly, PRE followed by POST herbicide programs, except for mesotrione+S-metolachlor+atrazine followed by acetochlor ($191 and $897 ha−1), provided similar net return of $427 to $707 ha−1and $1,127 to $1,727 ha−1in 2014 and 2015-16, respectively. It is concluded that herbicide programs based on multiple sites of action are available for control of PS II- and HPPD-inhibitor-resistant Palmer amaranth in conventional corn.
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Keith, Karen E., Lauren Killip, Panqing He, Graham R. Moran, and Miguel A. Valvano. "Burkholderia cenocepacia C5424 Produces a Pigment with Antioxidant Properties Using a Homogentisate Intermediate." Journal of Bacteriology 189, no. 24 (October 12, 2007): 9057–65. http://dx.doi.org/10.1128/jb.00436-07.

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ABSTRACT 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 H2O2 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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22

McMullan, Patrick M., and Jerry M. Green. "Identification of a Tall Waterhemp (Amaranthus tuberculatus) Biotype Resistant to HPPD-Inhibiting Herbicides, Atrazine, and Thifensulfuron in Iowa." Weed Technology 25, no. 3 (September 2011): 514–18. http://dx.doi.org/10.1614/wt-d-10-00150.1.

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Seeds of a putative 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide–resistant tall waterhemp biotype from Henry County, IA, were collected from a seed corn field in fall 2009 after plants were not controlled following a POST application of mesotrione plus atrazine. The response of this biotype to various herbicide modes of action was evaluated in greenhouse and field tests. Under greenhouse conditions, the suspect biotype showed an eightfold decrease in sensitivity to mesotrione with a 50% control rate of 21 g ha−1compared with 2.7 g ha−1for the susceptible biotype. The biotype also had a 10-fold decrease in sensitivity to atrazine and a 28-fold decrease in sensitivity to thifensulfuron. Under field conditions, tall waterhemp was not controlled POST at the label rate of 1,100 g ha−1of atrazine. Tall waterhemp control was less than 60% at the label rates of three commonly used POST HPPD-inhibiting herbicides in seed corn: 105 g ha−1of mesotrione, 92 g ha−1of tembotrione, or 18 g ha−1of topramezone. Thus, this new tall waterhemp biotype is resistant to three herbicide modes of action: HPPD inhibitors, photosystem-II inhibitors, and acetolactate synthase (ALS) inhibitors.
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23

Maeda, Hideo, Kazumasa Murata, Nozomi Sakuma, Satomi Takei, Akihiko Yamazaki, Md Rezaul Karim, Motoshige Kawata, et al. "A rice gene that confers broad-spectrum resistance to β-triketone herbicides." Science 365, no. 6451 (July 25, 2019): 393–96. http://dx.doi.org/10.1126/science.aax0379.

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The genetic variation of rice cultivars provides a resource for further varietal improvement through breeding. Some rice varieties are sensitive to benzobicyclon (BBC), a β-triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD). Here we identify a rice gene, HIS1 (HPPD INHIBITOR SENSITIVE 1), that confers resistance to BBC and other β-triketone herbicides. We show that HIS1 encodes an Fe(II)/2-oxoglutarate–dependent oxygenase that detoxifies β-triketone herbicides by catalyzing their hydroxylation. Genealogy analysis revealed that BBC-sensitive rice variants inherited a dysfunctional his1 allele from an indica rice variety. Forced expression of HIS1 in Arabidopsis conferred resistance not only to BBC but also to four additional β-triketone herbicides. HIS1 may prove useful for breeding herbicide-resistant crops.
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He, Bo, Dawei Wang, Wenchao Yang, Qiong Chen, and Guangfu Yang. "Advances in Research on 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) Structure and Pyrazole-Containing Herbicides." Chinese Journal of Organic Chemistry 37, no. 11 (2017): 2895. http://dx.doi.org/10.6023/cjoc201705031.

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25

Norsworthy, Jason K., Vijay K. Varanasi, Muthukumar Bagavathiannan, and Chad Brabham. "Recurrent Selection with Sub-Lethal Doses of Mesotrione Reduces Sensitivity in Amaranthus palmeri." Plants 10, no. 7 (June 25, 2021): 1293. http://dx.doi.org/10.3390/plants10071293.

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Amaranthus palmeri, ranked as the most prolific and troublesome weed in North America, has evolved resistance to several herbicide sites of action. Repeated use of any one herbicide, especially at lower than recommended doses, can lead to evolution of weed resistance, and, therefore, a better understanding of the process of resistance evolution is essential for the management of A. palmeri and other difficult-to-control weed species. Amaranthus palmeri rapidly developed resistance to 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors such as mesotrione. The objective of this study was to test the potential for low-dose applications of mesotrione to select for reduced susceptibility over multiple generations in an A. palmeri population collected from an agricultural field in 2001. F0 plants from the population were initially treated with sub-lethal mesotrione rates and evaluated for survival three weeks after treatment. All F0 plants were controlled at the 1× rate (x = 105 g ai ha−1). However, 2.5% of the F0 plants survived the 0.5× treatment. The recurrent selection process using plants surviving various mesotrione rates was continued until the F4 generation was reached. Based on the GR50 values, the sensitivity index was determined to be 1.7 for the F4 generation. Compared to F0, HPPD gene expression level in the F3 population increased. Results indicate that after several rounds of recurrent selection, the successive generations of A. palmeri became less responsive to mesotrione, which may explain the reduced sensitivity of this weed to HPPD-inhibiting herbicides. The results have significance in light of the recently released soybean and soon to be released cotton varieties with resistance to HPPD inhibitors.
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26

Bollman, Joseph D., Chris M. Boerboom, Roger L. Becker, and Vince A. Fritz. "Efficacy and Tolerance to HPPD-Inhibiting Herbicides in Sweet Corn." Weed Technology 22, no. 4 (December 2008): 666–74. http://dx.doi.org/10.1614/wt-08-036.1.

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The use of POST herbicides has been limited in sweet corn because of the narrow spectrum of weed control or potential crop injury. Field experiments were conducted to evaluate the 4-hydroxyphenyl pyruvate dioxygenase (HPPD)-inhibiting herbicides mesotrione, tembotrione, and topramezone applied POST in sweet corn at three locations. Efficacy of mesotrione, tembotrione, and topramezone applied alone or mixed with atrazine was compared to other labeled POST herbicides following PRE S-metolachlor. Giant foxtail control was greater with tembotrione or topramezone than mesotrione alone or mixed with atrazine. Common lambsquarters, velvetleaf, and common ragweed were controlled 98% or greater with the HPPD-inhibiting herbicides when mixed with atrazine. Tolerance of six sweet corn hybrids was determined in the field when treated with 1× and 2× rates of these herbicides mixed with atrazine. Tolerance of six sweet corn hybrids to these herbicides was determined in the greenhouse when treated with 0.5, 1, 2, 4, 8, and 16 times the labeled rate. Differential hybrid tolerance to each herbicide was observed in both the field and greenhouse evaluations. Tembotrione killed ‘Merit’ in both evaluations. Excluding Merit, hybrids generally had good tolerance to tembotrione and topramezone in the field, but had differential tolerance to mesotrione. With the exception of Merit, hybrids generally had greater tolerance to tembotrione than topramezone and less tolerance to mesotrione in the greenhouse. These HPPD-inhibiting herbicides provide POST weed control, but the potential for sweet corn injury varies among the herbicides and hybrids and warrants further characterization.
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Schmaler-Ripcke, Jeannette, Venelina Sugareva, Peter Gebhardt, Robert Winkler, Olaf Kniemeyer, Thorsten Heinekamp, and Axel A. Brakhage. "Production of Pyomelanin, a Second Type of Melanin, via the Tyrosine Degradation Pathway in Aspergillus fumigatus." Applied and Environmental Microbiology 75, no. 2 (November 21, 2008): 493–503. http://dx.doi.org/10.1128/aem.02077-08.

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ABSTRACT Aspergillus fumigatus is the most important airborne fungal pathogen of immunosuppressed humans. A. fumigatus is able to produce dihydroxynaphthalene melanin, which is predominantly present in the conidia. Its biosynthesis is an important virulence determinant. Here, we show that A. fumigatus is able to produce an alternative melanin, i.e., pyomelanin, by a different pathway, starting from l-tyrosine. Proteome analysis indicated that the l-tyrosine degradation enzymes are synthesized when the fungus is grown with l-tyrosine in the medium. To investigate the pathway in detail, we deleted the genes encoding essential enzymes for pigment production, homogentisate dioxygenase (hmgA) and 4-hydroxyphenylpyruvate dioxygenase (hppD). Comparative Fourier transform infrared spectroscopy of synthetic pyomelanin and pigment extracted from A. fumigatus cultures confirmed the identity of the observed pigment as pyomelanin. In the hmgA deletion strain, HmgA activity was abolished and the accumulation of homogentisic acid provoked an increased pigment formation. In contrast, homogentisic acid and pyomelanin were not observed with an hppD deletion mutant. Germlings of the hppD deletion mutant showed an increased sensitivity to reactive oxygen intermediates. The transcription of both studied genes was induced by l-tyrosine. These results confirmed the function of the deleted genes and the predicted pathway in A. fumigatus. Homogentisic acid is the major intermediate, and the l-tyrosine degradation pathway leading to pyomelanin is similar to that in humans leading to alkaptomelanin.
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Küpper, Anita, Falco Peter, Peter Zöllner, Lothar Lorentz, Patrick J. Tranel, Roland Beffa, and Todd A. Gaines. "Tembotrione detoxification in 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor-resistant Palmer amaranth (Amaranthus palmeriS. Wats.)." Pest Management Science 74, no. 10 (January 5, 2018): 2325–34. http://dx.doi.org/10.1002/ps.4786.

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29

Li, Hua‐Bin, Lei Li, Jun‐Xian Li, Ting‐Feng Han, Jing‐Li He, and You‐Quan Zhu. "Novel HPPD inhibitors: triketone 2 H ‐benzo[ b ][1,4]oxazin‐3(4 H )‐one analogs." Pest Management Science 74, no. 3 (November 2017): 579–89. http://dx.doi.org/10.1002/ps.4739.

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30

Brosnan, James T., Dean A. Kopsell, Matthew T. Elmore, Gregory K. Breeden, and Gregory R. Armel. "Changes in ‘Riviera’ Bermudagrass [Cynodon dactylon (L.) Pers.] Carotenoid Pigments after Treatment with Three p-Hydroxyphenylpyruvate Dioxygenase-inhibiting Herbicides." HortScience 46, no. 3 (March 2011): 493–98. http://dx.doi.org/10.21273/hortsci.46.3.493.

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Mesotrione, topramezone, and tembotrione are inhibitors of the enzyme p-hydroxyphenylpyruvate dioxygenase (HPPD), which impacts the carotenoid biosynthetic pathway. An experiment was conducted to determine the effects of mesotrione, topramezone, and tembotrione on carotenoid pigment concentrations in common bermudagrass [Cynodon dactylon (L.) Pers.; cv. Riviera] leaf tissues. Bermudagrass plants were treated with three rates of mesotrione (0.28, 0.35, and 0.42 kg·ha−1), topramezone (0.018, 0.025, and 0.038 kg·ha−1), and tembotrione (0.092, 0.184, and 0.276 kg·ha−1). The lowest rate of each herbicide represented the maximum labeled use rate for a single application. Percent visual bleaching was measured at 3, 7, 14, 21, 28, and 35 days after application (DAA). Leaf tissues were sampled on the same dates and assayed for carotenoids. Topramezone and tembotrione bleached bermudagrass leaf tissues to a greater degree than mesotrione. Concomitantly, topramezone and tembotrione also reduced total chlorophyll (chlorophyll a + b), β-carotene, lutein, and total xanthophyll cycle pigment concentrations (zeaxanthin + antheraxanthin + violaxanthin) more than mesotrione. Increases in visual bleaching resulting from application rate were accompanied by linear reductions in lutein, β-carotene, and violaxanthin for all herbicides. Topramezone and tembotrione increased the percentage of zeaxanthin + antheraxanthin in the total xanthophyll pigment pool (ZA/ZAV) 7 days after peak visual bleaching was observed at 14 DAA. Reductions in ZA/ZAV were reported after 21 DAA. This response indicates that sequential applications of topramezone and tembotrione should be applied on 14- to 21-day intervals, because stress induced by these herbicides is greatest at these timings. Increases in photoprotective xanthophyll cycle pigments (ZA/ZAV) at 14 to 21 DAA may be a mechanism allowing bermudagrass to recover from HPPD-inhibiting herbicide injury, because bermudagrass recovered from all treatments by 35 DAA. Data in the current study will allow turf managers to design physiologically validated bermudagrass control programs with HPPD-inhibiting herbicides. Chemical names: mesotrione [2-(4-methysulfonyl-2-nitrobenzoyl)-1,3-cyclohexanedione], tembotrione {2-[2-chloro-4-(methylsulfonyl)-3-[(2,2,2-(trifluoroethoxy)methyl]benzoyl]-1,3-cyclohexanedione}, topramezone {[3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)phenyl](5-hydroxy-1-nethyl-1H-pyrazol-4-yl)methanone}.
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31

Wiessner, Manuela, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S. Müller, Rolf Stucka, Christian Beetz, et al. "Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia." Brain 144, no. 5 (May 1, 2021): 1422–34. http://dx.doi.org/10.1093/brain/awab041.

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Abstract Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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32

Adlington, Robert M., Jack E. Baldwin, Nicholas P. Crouch, Meng-Huee Lee, and Colin H. MacKinnon. "Identification and stereochemistry of the product of 4-HPPD catalyzed oxidation of the ketoacid of methionine." Bioorganic & Medicinal Chemistry Letters 6, no. 16 (August 1996): 2003–6. http://dx.doi.org/10.1016/0960-894x(96)00362-9.

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33

Schryver, Mike G., Nader Soltani, David C. Hooker, Darren E. Robinson, Patrick J. Tranel, and Peter H. Sikkema. "Control of Glyphosate-Resistant Common waterhemp (Amaranthus rudis) in Three New Herbicide-Resistant Soybean Varieties in Ontario." Weed Technology 31, no. 6 (November 21, 2017): 828–37. http://dx.doi.org/10.1017/wet.2017.81.

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Glyphosate-resistant (GR) common waterhemp (CW) is a localized weed in Ontario and one of the most problematic weeds in the US Corn Belt. First confirmed in Ontario in 2014, GR CW has now been confirmed in forty fields in three counties in Ontario as of 2015. Historically, the primary POST herbicides used for the control of CW in soybean were glyphosate, acifluorfen and fomesafen, but resistance to all three has been confirmed in many US states. Research was conducted in 2015 and 2016 to determine the control of GR CW with some of the new herbicide-resistant soybean technologies including glufosinate (LibertyLink), 2,4-D and glyphosate (Enlist), and isoxaflutole, mesotrione, and glufosinate (HPPD-resistant). Glyphosate-resistant CW was controlled (≥90%) all season with a two-pass weed control system across all herbicide-resistant soybean technologies evaluated. The two-pass weed control system in this research is defined as a PRE herbicide followed by a POST herbicide. At 12 WAA, the two-pass programs in LibertyLink, Enlist, and HPPD-resistant systems controlled GR CW up to 98, 98, and 92%, respectively, and reduced GR CW densities to 0 to 2% of the weedy control at 4 WAA. The two-pass programs provided greater GR CW control than PRE or POST herbicides alone. This study found that the use of two-pass weed control programs in glufosinate-resistant, glyphosate DMA/2,4-D choline-resistant and HPPD-resistant soybean can provide excellent control of GR CW, and can be valuable tools to reduce the selection intensity for herbicide-resistant weeds. Through the rotational use of different technologies, growers may be able to better manage their weed populations in reducing the risk of resistance when compared to the use of one herbicide repeatedly.
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Schultz, John L., Michael Weber, Jayla Allen, and Kevin W. Bradley. "Evaluation of Weed Management Programs and Response of FG72 Soybean to HPPD-Inhibiting Herbicides." Weed Technology 29, no. 4 (December 2015): 653–64. http://dx.doi.org/10.1614/wt-d-14-00067.1.

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Field experiments were conducted at two locations in Missouri in 2012 and 2013 to evaluate herbicide programs in 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibitor-resistant soybean, referred to as FG72 soybean, and their tolerance to four HPPD-inhibiting herbicides. At the Columbia location, PRE followed by (fb) POST and two-pass POST treatments provided 97% or greater control of all weeds except ivyleaf morningglory. At Moberly in 2012, PRE fb POST treatments provided 95% or greater control and 100% biomass reduction (BR) of glyphosate-resistant (GR) waterhemp, with the exception of isoxaflutole at 0.04 kg ha−1plusS-metolachlor at 0.6 kg ha−1plus metribuzin at 0.2 kg ha−1. In 2013, PRE fb POST treatments provided greater than 89% control and 93% BR. Two-pass POST treatments of isoxaflutole plus glyphosate always provided greater control and BR of GR waterhemp compared with glyphosate fb glyphosate. However, at Columbia, where glyphosate-susceptible weeds were present, there were no differences in control or BR between two-pass POST treatments. In the soybean tolerance experiment, isoxaflutole provided the lowest levels of injury. Applications of tembotrione at the 1× rate resulted in the greatest injury in both years. Topramezone at the 1× rate always provided less injury than tembotrione, but was always similar in BR. The 2× rates increased soybean injury over the 1× rate for the third trifoliate (V3) application, but not for the PRE and first-flower (R1) applications. V3 and R1 applications of isoxaflutole and mesotrione resulted in similar injury, height reduction, and BR to soybean 28 d after application in 2012 and 2013. Overall these results indicate that FG72 soybean could allow the use of HPPD-inhibiting herbicides such as mesotrione PRE along with isoxaflutole PRE and POST to provide an additional herbicide mechanism of action that was not previously available in soybean.
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35

Nunes, Luiz R., Regina Costa de Oliveira, Daniela Batista Leite, Vivian Schmidt da Silva, Everaldo dos Reis Marques, Márcia Eliana da Silva Ferreira, Diógenes Custódio Duarte Ribeiro, et al. "Transcriptome Analysis of Paracoccidioides brasiliensis Cells Undergoing Mycelium-to-Yeast Transition." Eukaryotic Cell 4, no. 12 (December 2005): 2115–28. http://dx.doi.org/10.1128/ec.4.12.2115-2128.2005.

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ABSTRACT Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), a systemic mycosis prevalent in South America. In humans, infection starts by inhalation of fungal propagules, which reach the pulmonary epithelium and transform into the yeast parasitic form. Thus, the mycelium-to-yeast transition is of particular interest because conversion to yeast is essential for infection. We have used a P. brasiliensis biochip carrying sequences of 4,692 genes from this fungus to monitor gene expression at several time points of the mycelium-to-yeast morphological shift (from 5 to 120 h). The results revealed a total of 2,583 genes that displayed statistically significant modulation in at least one experimental time point. Among the identified gene homologues, some encoded enzymes involved in amino acid catabolism, signal transduction, protein synthesis, cell wall metabolism, genome structure, oxidative stress response, growth control, and development. The expression pattern of 20 genes was independently verified by real-time reverse transcription-PCR, revealing a high degree of correlation between the data obtained with the two methodologies. One gene, encoding 4-hydroxyl-phenyl pyruvate dioxygenase (4-HPPD), was highly overexpressed during the mycelium-to-yeast differentiation, and the use of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione], a specific inhibitor of 4-HPPD activity, as well as that of NTBC derivatives, was able to inhibit growth and differentiation of the pathogenic yeast phase of the fungus in vitro. These data set the stage for further studies involving NTBC and its derivatives as new chemotherapeutic agents against PCM and confirm the potential of array-based approaches to identify new targets for the development of alternative treatments against pathogenic microorganisms.
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36

Akasaka, Maiko, Hiroaki Watanabe, and Yoshiaki Kawana. "Inheritance for sensitivity of high-yielding rice cultivars, ‘Momiroman' and ‘Takanari', to benzobicyclon, a 4-HPPD inhibitor." Journal of Weed Science and Technology 56, no. 2 (2011): 89–94. http://dx.doi.org/10.3719/weed.56.89.

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37

Kim, Sang-Su, Jae-Eup Park, Ye-Jin Kim, Yong-Hwan Lee, In-Yong Lee, Jeongran Lee, Byeng-Chul Moon, and Yang-Bin Ihm. "Characteristics of Sensitive HIS1 Genes to the 4-HPPD Inhibiting Rice Herbicides Isolated from Several Rice Cultivars." Weed & Turfgrass Science 5, no. 4 (December 31, 2016): 187–90. http://dx.doi.org/10.5660/wts.2016.5.4.187.

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38

Woodyard, Andrew J., Germán A. Bollero, and Dean E. Riechers. "Broadleaf Weed Management in Corn Utilizing Synergistic Postemergence Herbicide Combinations." Weed Technology 23, no. 4 (December 2009): 513–18. http://dx.doi.org/10.1614/wt-08-188.1.

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POST combinations of photosystem II (PSII) and the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are effective for control of broadleaf weeds in corn. Field studies were conducted during 2007 and 2008 in Urbana and Dekalb, IL, to determine the nature of interactions between two PSII inhibitors, atrazine and bromoxynil, and the HPPD inhibitor mesotrione, based on control of common waterhemp, common lambsquarters, and giant ragweed. Two rates of each herbicide were evaluated, with the highest representing a typical recommended rate, and the lowest a fraction of that rate. Synergistic interactions occurred for common waterhemp control from 10 to 30 d after treatment (DAT) regardless of herbicide rates, rainfall accumulation, or plant height. Synergism between mesotrione and bromoxynil was not observed for common lambsquarters control at Urbana in 2008 at the lower herbicide rates, possibly due to taller weed heights at the time of herbicide application relative to 2007. Giant ragweed control indicated that a synergistic interaction occurred for all herbicides and rates in 2008. However, synergism between bromoxynil and mesotrione did not occur in 2007, likely due to limited rainfall before herbicide application. Reduced herbicide rates and adverse environmental conditions have the potential to regulate the expression of synergism between mesotrione and PSII inhibitors, and therefore may limit their effectiveness for weed management in corn.
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39

Strom, Seth A., Lisa C. Gonzini, Charlie Mitsdarfer, Adam S. Davis, Dean E. Riechers, and Aaron G. Hager. "Characterization of multiple herbicide–resistant waterhemp (Amaranthus tuberculatus) populations from Illinois to VLCFA-inhibiting herbicides." Weed Science 67, no. 4 (May 27, 2019): 369–79. http://dx.doi.org/10.1017/wsc.2019.13.

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AbstractField experiments were conducted in 2016 and 2017 in Champaign County, IL, to study a waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] population (CHR) resistant to 2,4-D and 4-hydroxyphenylpyruvate dioxygenase (HPPD)-, photosystem II–, acetolactate synthase (ALS)-, and protoporphyrinogen oxidase–inhibiting herbicides. Two field experiments were designed to investigate the efficacy of very-long-chain fatty-acid (VLCFA)-inhibiting herbicides, including a comparison of active ingredients at labeled use rates and a rate titration experiment. Amaranthus tuberculatus density and control were evaluated at 28 and 42 d after treatment (DAT). Nonencapsulated acetochlor, alachlor, and pyroxasulfone provided the greatest PRE control of CHR (56% to 75%) at 28 DAT, while metolachlor, S-metolachlor, dimethenamid-P, and encapsulated acetochlor provided less than 27% control. In the rate titration study, nonencapsulated acetochlor controlled CHR more than equivalent field use rates of S-metolachlor. Subsequent dose–response experiments with acetochlor, S-metolachlor, dimethenamid-P, and pyroxasulfone in the greenhouse included three multiple herbicide–resistant (MHR) A. tuberculatus populations: CHR-M6 (progeny generated from CHR), MCR-NH40 (progeny generated from Mclean County, IL), and ACR (Adams County, IL), in comparison with a sensitive population (WUS). Both CHR-M6 and MCR-NH40 are MHR to atrazine and HPPD, and ALS inhibitors and demonstrated higher survival rates (LD50) to S-metolachlor, acetochlor, dimethenamid-P, or pyroxasulfone than ACR (atrazine resistant but HPPD-inhibitor sensitive) and WUS. Based on biomass reduction (GR50), resistant to sensitive (R:S) ratios between CHR-M6 and WUS were 7.5, 6.1, 5.5, and 2.9 for S-metolachlor, acetochlor, dimethenamid-P, and pyroxasulfone, respectively. Values were greater for MCR-NH40 than CHR-M6, and ACR was the most sensitive to all VLCFA inhibitors tested. Complete control of all populations was achieved at or below a field use rate of acetochlor. In summary, field studies demonstrated CHR is not controlled by several VLCFA-inhibiting herbicides. Greenhouse dose–response experiments corroborated field results and generated R:S ratios (LD50) ranging from 4.5 to 64 for CHR-M6 and MCR-NH40 among the four VLCFA-inhibiting herbicides evaluated.
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40

Spaunhorst, Douglas J. "Spring-applied triclopyr mixtures for bermudagrass (Cynodon dactylon) suppression in Louisiana sugarcane." Weed Technology 35, no. 4 (April 6, 2021): 589–97. http://dx.doi.org/10.1017/wet.2021.20.

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AbstractSugarcane infested with bermudagrass and harvested as seed cane introduces the potential for weedy propagules to reinfest fields. Research was conducted in 2018 and 2019 following sugarcane harvest for seed cane to evaluate bermudagrass management with photosystem II (PSII)- and 4-hydroxyphenylpyruvate dioxygenase (HPPD)–inhibiting herbicides applied alone or mixed with triclopyr. Combinations of diuron at 2.8 kg ha–1 with clomazone at 1.5 kg ha–1 or triclopyr at 1.1 kg ha–1 and hexazinone at 0.74 kg ha–1 with triclopyr applied early POST (EPOST) in mid-February injured bermudagrass 85% to 86%, and injury was greater than diuron or hexazinone alone (16% and 10%) in mid-March. Bermudagrass injury decreased to 45% to 56% for these combination treatments by April; however, injury differences were similar to the earlier rating. Late POST (LPOST) mid-March application of these treatments indicated similar bermudagrass injury trends when evaluated in early April. By mid-May, however, no treatment resulted in greater than 18% bermudagrass injury. Clomazone plus diuron applied LPOST resulted in 19% sugarcane injury by early April; however, all other treatments resulted in 7% sugarcane injury or less. In mid-May, a mid-April EPOST application of topramezone at 0.025 kg ha–1 plus triclopyr at 1.1 kg ha–1 resulted in 62% bermudagrass injury, which was equivalent to that observed with other topramezone rates in this combination (0.012 and 0.037 kg ha–1) (54% to 60%). Bermudagrass injury from triclopyr mixed with mesotrione (32%) or triclopyr mixed with atrazine, mesotrione, and S-metolachlor (47% to 55%) resulted in bermudagrass injury similar to that with topramezone plus triclopyr (54% to 62%). Data showed the flexibility of triclopyr when mixed with several HPPD- or PSII-inhibitor herbicides for bermudagrass management in a Louisiana sugarcane cropping system. Greater flexibility in application timing for HPPD-inhibitor herbicides than for PSII-inhibitor herbicides (diuron or hexazinone), and mixed with triclopyr, may suppress bermudagrass POST in April and May with minimal sugarcane injury.
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ADLINGTON, R. M., J. E. BALDWIN, N. P. CROUCH, M. H. LEE, and C. H. MACKINNON. "ChemInform Abstract: Identification and Stereochemistry of the Product of 4-HPPD Catalyzed Oxidation of the Ketoacid of Methionine." ChemInform 27, no. 52 (August 4, 2010): no. http://dx.doi.org/10.1002/chin.199652045.

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42

Hausman, Nicholas E., Patrick J. Tranel, Dean E. Riechers, and Aaron G. Hager. "Responses of a Waterhemp (Amaranthus tuberculatus) Population Resistant to HPPD-Inhibiting Herbicides to Foliar-Applied Herbicides." Weed Technology 30, no. 1 (March 2016): 106–15. http://dx.doi.org/10.1614/wt-d-15-00098.1.

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Field and greenhouse experiments were conducted to characterize the response of a waterhemp population from McLean County, IL to foliar-applied 4-hydroxyphenylpyruvate dioxygenase (HPPD) –inhibiting herbicides and determine the population's sensitivity to herbicides from other site-of-action groups. In the field, 10 to 15–cm-tall waterhemp treated with mesotrione at 105 g ai ha−1, tembotrione at 92 g ai ha−1, or topromezone at 18 g ai ha−1had significantly greater biomass (≥ 10%) 14 d after treatment (DAT) than waterhemp harvested the day of herbicide application, indicating growth had occurred following herbicide application. Waterhemp growth stage at the time of herbicide application influenced control. Mesotrione applied at 105 g ha−1alone or combined with atrazine at 560 g ai ha−1provided significantly greater waterhemp control (≥ 66%) when applied to small waterhemp plants (2 to 5 cm tall) compared with applications made to plants 5 to 10 or 10 to 15 cm tall. Glyphosate, glufosinate, fomesafen, lactofen, or acifluorfen provided greater waterhemp control (≥ 68%) 7 and 14 DAT than mesotrione, dicamba, or 2,4-D. Control of this population with atrazine, chlorimuron, and imazethapyr did not exceed 12%. Results of a greenhouse experiment with waterhemp plants grown from field-collected seed were similar to field data, and confirm the McLean County population was poorly controlled with HPPD, photosystem II, and acetolactate synthase inhibitors.
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43

Elmore, Matthew T., James T. Brosnan, Dean A. Kopsell, Gregory K. Breeden, and Thomas C. Mueller. "Response of Hybrid Bermudagrass (Cynodon dactylon× C.transvaalensis) to Three HPPD-Inhibitors." Weed Science 59, no. 4 (December 2011): 458–63. http://dx.doi.org/10.1614/ws-d-11-00045.1.

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Mesotrione, topramezone, and tembotrione inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme integral to carotenoid biosynthesis. Research was conducted to evaluate the response of hybrid bermudagrass following mesotrione (280, 350, and 420 g ai ha−1), topramezone (18, 25, and 38 g ai ha−1), and tembotrione (92, 184, and 276 g ai ha−1) applications. Measurements of visual bleaching (VB) and chlorophyll fluorescence yield (Fv/Fm) were evaluated 3, 5, 7, 14, 21, 28, and 35 d after application (DAA). Leaf tissues were sampled on the same dates and assayed for chlorophyll and carotenoid pigments using high-performance liquid chromatography (HPLC). Responses of plants treated with topramezone and tembotrione were similar; these herbicides caused more VB and greater reductions in Fv/Fm, total chlorophyll, lutein, and xanthophyll cycle pigment concentrations than mesotrione 5 to 21 DAA. Increasing mesotrione application rate did not increase VB or lead to greater reductions in total chlorophyll, lutein, or xanthophyll pigment concentrations. Alternatively, increasing topramezone and tembotrione application rates above 18 and 92 g ha−1, respectively, extended VB and pigment reductions. Of the three HPPD-inhibitors tested, topramezone was the most active, because the low (18 g ha−1) rate of topramezone reduced lutein and total xanthophyll pigment concentrations more than the low rate of tembotrione (92 g ha−1) during periods of maximum activity (14 to 21 DAA). No necrosis was observed with any of the treatments, suggesting tank mixtures of topramezone with other herbicides might be required to provide long-term control of hybrid bermudagrass.
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44

Singh, Divya, Jay Kumar, and Ashok Kumar. "Isolation of pyomelanin from bacteria and evidences showing its synthesis by 4-hydroxyphenylpyruvate dioxygenase enzyme encoded by hppD gene." International Journal of Biological Macromolecules 119 (November 2018): 864–73. http://dx.doi.org/10.1016/j.ijbiomac.2018.08.003.

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45

Tukur, Saidu, Gideon Adamu Shallangwa, and Abdulkadir Ibrahim. "Theoretical QSAR modelling and molecular docking studies of some 4-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme inhibitors potentially used as herbicides." Heliyon 5, no. 11 (November 2019): e02859. http://dx.doi.org/10.1016/j.heliyon.2019.e02859.

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Dreesen, Rozemarijn, Annabelle Capt, Regina Oberdoerfer, Isabelle Coats, and Kenneth Edward Pallett. "Supplementary data on the characterization and safety evaluation of HPPD W336, a modified 4-hydroxyphenylpyruvate dioxygenase protein, which confers herbicide tolerance, and on the compositional assessment of field grown MST-FGØ72-2 soybean expressing HPPD W336." Data in Brief 21 (December 2018): 111–21. http://dx.doi.org/10.1016/j.dib.2018.08.035.

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47

Williams, Martin M., and Jerald K. Pataky. "Factors Affecting Differential Sensitivity of Sweet Corn to HPPD-Inhibiting Herbicides." Weed Science 58, no. 3 (September 2010): 289–94. http://dx.doi.org/10.1614/ws-d-09-00058.1.

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Mutation of a cytochrome P450 (CYP) allele on the short arm of chromosome 5 affects sensitivity in sweet corn to mesotrione and to tembotrione plus isoxadifen applied POST. Hybrids that are homozygous for the functional allele (i.e.,CYPCYP) are rarely injured at registered use rates, hybrids that are homozygous for mutant alleles (i.e.,cypcyp) are frequently injured, and hybrids that are heterozygous for a functional and mutant allele (i.e.,CYPcyp) have more variable responses over trials. The objectives of this work were (1) to conduct side-by-side comparisons of sweet corn hybrid responses to mesotrione, tembotrione plus isoxadifen, and topramezone under field conditions; and (2) to compare dose–response relationships amongCYPCYP,CYPcyp, andcypcyphybrids. Among 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors used POST in sweet corn, topramezone was safe on the 746 hybrids tested. When environmental conditions favored crop growth, mesotrione injured the largest number of hybrids, and these hybrids were almost exclusivelycypcyporCYPcyp. The safener isoxadifen added to the tembotrione product greatly reduced occurrence of injury to theCYPcypgenotypic class but not to thecypcyphybrids. Despite a common genetic basis for herbicide metabolism, genotypic classes of sweet corn hybrids did not have identical field responses to mesotrione, tembotrione plus isoxadifen, and topramezone.
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48

Williams, Martin M., and Jerald K. Pataky. "Genetic Basis of Sensitivity in Sweet Corn to Tembotrione." Weed Science 56, no. 3 (June 2008): 364–70. http://dx.doi.org/10.1614/ws-07-149.1.

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Tembotrione inhibits 4-hydroxyphenyl-pyruvate-dioxygenase (HPPD) and was recently registered for use in all types of corn. Some sweet corn hybrids are killed by tembotrione, yet a mechanistic understanding of sensitivity has not been reported. Sensitivity of mesotrione, another HPPD-inhibitor, is conditioned by a single allele. Two hypotheses were tested: (1) response to tembotrione and mesotrione are conditioned by alleles at the same or closely linked loci and (2) the extent of early-season injury from tembotrione and mesotrione is similar on hybrids. The first hypothesis was tested by comparing responses to tembotrione and mesotrione in 136 F3:5families derived from a cross of mesotrione-sensitive and mesotrione-tolerant sweet corn inbreds. F3families cosegregated for responses to tembotrione and mesotrione: 94% of the families had the same response to both herbicides. Thus, the same gene or very closely linked genes condition response to both herbicides. On the basis of chi-square goodness of fit tests, responses of families to tembotrione fit a 3 : 2 : 3 sensitive : segregating : tolerant ratio (P = 0.24), which would be expected if sensitivity to tembotrione was conditioned by a single recessive allele. The second hypothesis was tested in six field experiments by quantifying the extent of early-season injury to 249 sweet corn hybrids 1 wk after treatment (WAT) of tembotrione (184 g ha−1) or mesotrione (210 g ha−1). One hundred ninety-three hybrids were tolerant to both herbicides. Seven sensitive hybrids that were severely injured by both herbicides 1 WAT differed in their response 3 to 4 WAT; sensitive hybrids treated with mesotrione had apparently resumed normal growth, whereas those treated with tembotrione died. Conversely, hybrids with intermediate levels of injury (> 10 to 50%) 1 WAT with mesotrione had no visual symptoms of injury from applications of tembotrione. Despite the common genetic basis for response to mesotrione and tembotrione, hybrids with sensitive or intermediate responses to mesotrione did not have identical responses to tembotrione.
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Lei, Kang, Xue-Wen Hua, Yuan-Yuan Tao, Yang Liu, Na Liu, Yi Ma, Yong-Hong Li, Xiao-Hua Xu, and Chui-Hua Kong. "Discovery of (2-benzoylethen-1-ol)-containing 1,2-benzothiazine derivatives as novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibiting-based herbicide lead compounds." Bioorganic & Medicinal Chemistry 24, no. 2 (January 2016): 92–103. http://dx.doi.org/10.1016/j.bmc.2015.11.032.

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50

Yang, Haihua, Yang An, Linqi Wang, Shuli Zhang, Yue Zhang, Yuqing Tian, Gang Liu, and Huarong Tan. "Autoregulation of hpdR and its effect on CDA biosynthesis in Streptomyces coelicolor." Microbiology 156, no. 9 (September 1, 2010): 2641–48. http://dx.doi.org/10.1099/mic.0.038604-0.

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HpdR, an IclR-family regulator in Streptomyces coelicolor, is a substrate-dependent repressor for the tyrosine catabolic gene hppD. In this study, S1 nuclease protection assays revealed that hpdR is subject to a negative autoregulation. Purified HpdR showed specific DNA-binding activity for the promoter region of hpdR, indicating that the autoregulation of hpdR is performed directly. The disruption of hpdR led to reduced production of CDA by S. coelicolor J1501, suggesting a positive effect of hpdR on CDA biosynthesis. Electrophoretic mobility shift assays showed that HpdR specifically bound to the promoter region of hmaS (SCO3229 in the CDA gene cluster), encoding 4-hydroxymandelic acid synthase. Disruption of hmaS in J1501 abolished CDA production. It is possible that hpdR regulates CDA biosynthesis by controlling the transcription of hmaS.
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