4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical

Review pubs.acs.org/JAFC

4‑Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals Ferdinand Ndikuryayo,† Behrooz Moosavi,† Wen-Chao Yang,*,† and Guang-Fu Yang*,†,‡ †

Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30071, P. R. China ABSTRACT: The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions. KEYWORDS: 4-hydroxyphenylpyruvate dioxygenase, chemical biology, inhibitor, agrochemical, herbicide

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INTRODUCTION The world confronts widespread food scarcity due to several factors, including the increase in global population, the reduction of arable land, and the proliferation of weeds. To combat these weeds, farmers have resorted to various strategies, such as crop rotation, tilling, and usage of herbicides. However, new challenges, such as weed resistance,1 herbicide toxicity,2,3 low crop selectivity,4 and high cost of discovery, production, and registration of herbicides,5 have been raised over the years. Therefore, there is still a serious need to design potent, selective, environmentally friendly and cost-effective herbicides, which can limit a broad range of weeds as well as their resistant biotypes. For this purpose, 4-hydroxyphenylpyruvate dioxygenase is one of the most important target enzymes.6 Naturally occurring in all aerobic organisms apart from some Gram-positive bacteria,7,8 HPPD catalyzes the conversion of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA) (Figure 1A) in the tyrosine degradation pathway.9 The study of this pathway, which resulted in the development of several commercial HPPD-inhibiting herbicides (Table 1), engendered substantial research for pharmaceutical and agrochemical profits. The conclusions showed that HPPD-inhibiting herbicides have many benefits, such as broad-spectrum activity against broadleaf weeds including those resistant to other herbicides, excellent crop selectivity, low application rate, low toxicity, and a pre- and postemergence treatment.10−14 Although the toxicological effects of these herbicides on the ecosystem have not been investigated thoroughly, developers and farmers seem to agree on their weed control efficacy.15 However, the current knowledge on various aspects of HPPD inhibitors is still scattered and hence more clarification is required for the end users, i.e., researchers and farmers. Therefore, we prepared this review with the intention of © 2017 American Chemical Society

Figure 1. Coupled enzyme reaction used for the evaluation of the activity of HPPD and its inhibitors. (A) The conversion of 4hydroxyphenylpyruvate dioxygenase (HPPD) into homogentisic acid (HGA) and (B) the transformation of HGA into maleylacetoacetate (MAA).

assembling relevant knowledge. Our purpose is not to summarize all the current literature, but to propose more comprehensive knowledge based on recent reports that provided valuable information for the exploration of novel HPPD inhibitors. We emphasized HPPD structure and functions, chemistry (catalytic and inhibitory mechanisms), discovery and development of HPPD-inhibiting herbicides, and strategies to genetically engineer resistant crops. In addition, we raised some relevant gaps for future research directions in this area.

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THE BIOLOGICAL ROLE OF HPPD In humans, HPPD dysregulation is associated with the type I tyrosinemia,16 type III tyrosinemia, and hawkinsinuria.17 In Received: Revised: Accepted: Published: 8523

August 18, 2017 September 7, 2017 September 14, 2017 September 14, 2017 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537

Review

Journal of Agricultural and Food Chemistry Table 1. Most Representative Commercial HPPD-Based Herbicidesa market size class

%

USD (millions)

triketones

4.4

1,283

ingredient

year

company

crop

tefuryltrione tembotrione mesotrione

2010 2007 2001

Bayer CropScience Bayer Crop Science Syngenta

rice corn corn

annual and perennial broadleaf broadleaf

bicyclopyrone

2015b

Syngenta

corn

annual and broadleaf

sulcotrione benzobycyclon

1991 2001

ICI SDS Biotech

corn rice

broadleaf broadleaf

Bayer Crop Science

corn, sugar cane soybean rice

broadleaf

postemergent postemergent pre/ postemergent pre/ postemergent postemergent pre/ postemergent pre-emergent

annual and perennial broadleaf broadleaf

pre/ postemergent postemergent

annual and perennial broadleaf annual and perennial

pre/ postemergent pre/ postemergent postemergent

isoxazoles

0.9

255

isoxaflutole

pyrazoles

1.3

374

benzofenap

1998b 2013c 1987

pyrasulfotole

2008

Mitsubishi Chemical Bayer Crop Science

pyrazoxyfen

1985

Ishihara

wheat, barley, triticale rice

pyrazolynate

1980

Sankyo

rice

topramezone

2006

BASF

corn

a

This table was constructed on the basis of previous publications. (APHIS).

5,77,85 b

controlled weed

annual and broadleaf

application

c

EPA registration. Approved by Animal and Plant Health Inspection Service

microorganisms, the enzyme confers virulence to many pathogens due to the production of melanins.18 Dahnhardt et al.19 demonstrated that the disturbance of Synechocystis HPPD encoding gene, which has a high homology to plant gene, results in the shortage of tocopherol biosynthesis. In plants, HPPD is a physiological imperative for typical growth.20 Indeed, its product, HGA, is converted into plastoquinone-9, the essential component of carotenoid biosynthesis,20 and tocopherols (Figure 2). These compounds prevent plants from high-light, cold, drought, and salt stresses.21,22 Therefore, the inhibition of the HPPD-catalyzed reaction, which occurs in chloroplasts,23 leads to photosynthetic impairment11−14,24 followed by leaf bleaching.25

Figure 2. Biosynthesis of tocopherols and plastoquinone-9 in plants. Dashed arrows represent multiple steps. Homogentisate phytyltransferase (HPT) catalyzes the combination of homogentisic acid (HGA) and phytyldiphosphate (PDP), a chlorophyll byproduct, leading to 2methyl-6-phytyl-BQ (MPBQ), which, in turn, is methylated to 2,3dimethyl-6-phytyl-1,4-benzoquinol (DMPBQ) by MPBQ methyltransferase (MPBQ MT). HGA interacts with geranylgeranyl diphosphate (GGDP) to yield 2-methyl-6-geranylgeranyl-1,4-benzoquinol (MGGBQ), which is consecutively methylated into 2,3-dimethyl-5geranylgeranyl benzoquinol (DMGGBQ) by MPBQ MT. All HGA products undergo a tocopherol cyclase (TC)-catalyzed reaction resulting in γ- and δ-tocopherols that are then converted into α- and β-tocopherols by γ-tocopherol methyltransferase (γ-TMT). Abbreviations: TAT, tyrosine aminotransferase; PD, prephenate dehydrogenase; HPPA, 4-hydroxyphenylpyruvate acid; HPPD, 4-hydroxyphenylpyruvate dioxygenase; HST, homogentisate solanesyltransferase; PK, phytol kinase; CHLase, chlorophyllase; MSBQ, 2-methyl-6-solanesyl1,4-benzoquinol; PDP, phytyl diphosphate; SDP, solanesyl diphosphate; DXP, 1-deoxy-D-xylulose-5-phosphate; GGDP, geranylgeranyl diphosphate; HGGT, homogentisate geranylgeranyltransferase; MGGBQ, 2-methyl-6-geranylgeranyl-1,4-benzoquinol; DMGGBQ, 2,3-dimethyl-5-geranylgeranyl benzoquinol. This figure was constructed on the basis of previous publications.67,102−112

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THE STRUCTURE OF HPPD During more than 30 years of investigation, knowledge about HPPD has advanced with technology, including X-ray crystallography and bioinformatics. Consequently, HPPD structures have been determined, uploaded, and stored in protein data banks, where they are accessible either as primary structures (Table 2) or as three-dimensional (3D) structures (Table 3). With a subunit mass between 36 and 50 kDa,26−28 HPPD has a primary structure that comprises two major domains: the flexible N-terminus and the conserved C-terminus that contains the active site.29−31 In plants, the extension of at least 30 residues contributes to a substantial irregularity at the Nterminus with respect to mammalian and bacterial enzymes.32 A remarkable distinction in plant HPPDs is the inclusion in the last half of the primary structure of a supplementary disordered 15-residue segment close to comparatively unvarying Cterminus.16,32,33 This segment, whose removal is associated with the reduction of the reaction speed without affecting the substrate binding,16 has been observed to adopt multiple conformations in the presence or absence of ligands.34 Whether or not the specific activities of HPPD inhibitors are associated

with these additional residues is still vague, and more investigation may reveal their catalytic role. 8524

DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537

Review

Journal of Agricultural and Food Chemistry

structural similarity among HPPDs. The comparison of secondary structures shows that residues are generally made of α-helices and β-sheets at the rate of around 27% and 31%, respectively. Also, the analysis of the 3D structures of HPPDs stored in the Protein Data Bank (RCSB PDB37) shows that all HPPDs share the same 2-His-1-Glu facial triad (Figure 3), which is always connected to β-strands and binds to Fe(II). However, the location of the residues engaged in the facial triad is dependent on the source of HPPD. Another fundamental difference among HPPD structures is that bacterial HPPDs function as tetramers, whereas plant and mammalian HPPDs function as dimers, respectively.27,28,32 To understand the HPPD chemistry, 3D structures have considerably served the computational studies in the process of herbicide design. Interestingly, the corresponding predictions mostly correlate with experimental data and hence provide valuable insights into how substrate and inhibitor compete for the active site.11−14 It is noteworthy to mention that, like many enzymes, the point mutations of conserved residues significantly affect the activity of HPPD (Table 4).7,38,39

Table 2. Reviewed Primary Sequences of HPPD Stored in UniProtKB

a

entrya

entry name

organism

length

P32754 P32755 P93836 P49429 O52791 Q02110 P80064 Q53586 Q5EA20 Q5ZT84 Q76NV5 Q6TGZ5 P69053 Q22633 Q5BKL0 Q60Y65 O23920 Q27203 O48604 E9CWP5 Q4WHU1 Q1E803 Q9ARF9 P0CW94 Q9S2F4 Q9I576 O42764 Q6CDR5 Q557J8 Q8K248 Q96IR7 Q96X22 Q5XIH9 Q872T7 Q4WPV8 P23996 O06695 Q55810 Q18347

HPPD_HUMAN HPPD_RAT HPPD_ARATH HPPD_MOUSE HMAS_AMYOR HPPD_PIG HPPD_PSEUJ HPPD_STRAW HPPD_BOVIN LLY_LEGPH HPPD_DICDI HPPD_DANRE LLY_LEGPC HPPD_CAEEL HPPD_XENTR HPPD_CAEBR HPPD_DAUCA HPPD_TETTH HPPD_HORVU HPPD_COCPS HPPD1_ASPFU HPPD_COCIM HPPD_PLESU HPPD_COCP7 HPPD_STRCO HPPD_PSEAE HPPD_ZYMTR HPPD_YARLI HPDL_DICDI HPDL_MOUSE HPDL_HUMAN HPPD_MAGO7 HPDL_RAT HPPD_NEUCR HPPD2_ASPFU MELA_SHECO VLLY_VIBVU Y090_SYNY3 YBWL_CAEEL

Homo sapiens Rattus norvegicus Arabidopsis thaliana Mus musculus Amycolatopsis orientalis Sus scrofa Pseudomonas sp. Streptomyces avermitilis Bos taurus Legionella pneumophila Dictyostelium discoideum Danio rerio Legionella pneumophila Caenorhabditis elegans Xenopus tropicalis Caenorhabditis briggsae Daucus carota Tetrahymena thermophila Hordeum vulgare Coccidioides posadasii Neosartorya f umigata Coccidioides immitis Plectranthus scutellarioides Coccidioides posadasii Streptomyces coelicolor Pseudomonas aeruginosa Zymoseptoria tritici Yarrowia lipolytica Dictyostelium discoideum Mus musculus Homo sapiens Magnaporthe oryzae Rattus norvegicus Neurospora crassa Neosartorya f umigata Shewanella colwelliana Vibrio vulnificus Synechocystis sp. Caenorhabditis elegans

393 393 445 393 357 393 357 381 393 348 367 397 348 393 394 393 442 404 434 399 403 399 436 399 381 357 419 394 494 371 371 419 371 412 406 346 357 339 364

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ENZYME ACTIVITY AND ASSAY It is required to carefully determine the enzyme activity with a reliable assay prior to subsequent analyses, i.e., mechanistic and inhibitory studies. For this purpose, the most common early stage consists in determination of optimal reaction conditions according to the method of choice. Therefore, a basic reaction mixture mainly comprises HPPD, HPPA, Fe2+, and reductant for which reduced 2,6-dichlorophenolindophenol or ascorbate are almost equally effective.27 Moreover, glutathione can be added to block a nonenzymatic decarboxylation during incubation.27 More interestingly, in the absence of HPPA, the natural substrate of HPPD, the addition of L-tyrosine, the precursor of HPPA, to the bacterial culture permits the determination of the enzyme activity. This is possible because Escherichia coli contains endogenous transaminases transforming L-tyrosine into HPPA, which, in turn, is catalyzed by the recombinant HPPD.31 To evaluate the enzyme activity, various methods relying on the measurement of the changes in reagents or products have been developed. For example, Lindblad40 determined the activity of HPPD by following the release of 14CO2 from 14Clabeled HPPA or the formation of HGA. On the basis of the reaction depicted in Figure 1, conventional methods were developed such as the measurement of the volume of consumed O2 and produced CO2,38,41 liquid chromatography,42 mass spectrometry, 43 fluorescence,44 and tandem mass spectrometry.45 An easy and rapid method might be either the spectrophotometric measurement of the production of HGA or the consumption of HPPA, but these potential methods are unsuitable because these compounds have a close UV absorption. Fortunately, resorting to a supplementary enzyme, homogentisate 1,2-dioxidase (HGD), enabled the measurement of HPPD activity based on a coupled enzyme reaction46 (Figure 1) in which the final product, maleylacetoacetate (MAA), has an intense absorption in the range of 300− 350 nm.47 This indirect measurement has many advantages as follows: (i) both HPPD- and HGD-catalyzed reactions can take place in the same reaction system, which is widely used for the evaluation of the activity of both HPPD and its inhibitors;11−14,48 (ii) it is user-friendly; and (iii) it enables a highthroughput screening that greatly saves time and minimizes experimental errors. Recently, Rocaboy-Faquet et al.49 have

These structures were downloaded from the UniProt Web site.36

While many authors agree that the C-terminus fulfills the catalytic capability of HPPD, Norris et al.20 showed that the removal of 17-bp in the N-terminal domain of HPPD gene in Arabidopsis thaliana gives rise to the complete loss of its activity. Subsequently, Tomoeda et al.17 demonstrated that patients suffering from hawkinsinurea had an A33T mutation in the HPPD-coding gene although the actual cause was later established to be associated with N241S variant.35 Moreover, the addition of Ala18−Asn33 peptide to Phe34−Glu435, which initially yielded insoluble protein, enabled the recovery of both solubility and activity of maize HPPD variant.32 Although the corresponding catalytic mechanism has remained unclear so far, the previous findings have suggested that the N-terminal sequence may considerably influence the enzyme functionality, despite its poor homology. Using the Clustal Omega program,36 multiple sequence alignment of 39 reviewed HPPD sequences (Table 2) revealed 32 conserved and 60 similar residues, suggesting a high 8525


Review

Journal of Agricultural and Food Chemistry Table 3. Current HPPD Three Dimensional Structures Stored in Protein Data Bank PDB entrya

resolution (Å)

released date

source

5CTO 1T47 1CJX 1TFZ 1TG5 1SP9 1SQD 1SQI 3ISQ 5HMQ 5DHW 5EC3 1SP8 5XGK

2.62 2.5 2.4 1.8 1.9 3.0 1.8 2.15 1.75 2.37 2.62 2.1 2.0 2.6

7/24/2015 6/15/2004 4/26/2000 8/17/2004 8/17/2004 9/21/2004 8/17/2004 8/17/2004 9/15/2009 10/19/2016 09/07/2016 11/18/2015 09/21/2004 not yet

Arabidopsis thaliana Streptomyces avermitilis Pseudomonas f luorescens Arabidopsis thaliana Arabidopsis thaliana Arabidopsis thaliana Arabidopsis thaliana Rattus noregicus H. Sapiens Pseudomonas putida Arabidopsis thaliana Homo sapiens Zea mays Arabidopsis thaliana

chain(s) A, B, A, B, A, B, A A A, B A A A A, B, A,B A A, B, A, B,

C, D C, D C, D

ligand NTBC NTBC DAS869 DAS645

DAS869 C sulcotrione C, D C, D

HPPA

ref 68 29 30 47 47 32 47 47 113 114 115 116 32 b

a

These 3D structures, which were obtained by X-ray diffraction, are downloaded from the Protein Data Bank (RCSB PDB37). bVery recently deposited by Yang, G. F., Yang, W. C., and Lin, H. Y. Crystal structure of Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD) complexed with its substrate 4-hydroxyphenylpyruvate acid (HPPA) (Deposition ID: 1300003469). Except 5XGK, only inhibitors are presented as ligands (Figure 9) in complex with HPPD.

the inhibition parameters, IC50 and Ki, represent the activity of its inhibitors. It has been shown that the previous HPPD characteristics are species dependent (Table 4).

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THE EXPRESSION OF RECOMBINANT HPPD In the course of the development of HPPD inhibitors, recombinant HPPDs are essentially required to be expressed sufficiently. To this end, laborious techniques ranging from gene identification to protein purification are carefully performed to produce sufficient quantities of recombinant HPPD. In general, the coding gene from the organism of interest is inserted onto a plasmid that, in turn, is transformed into different bacterial strains (usually E. coli BL21 strain). The HPPD gene is under the control of an inducible promoter which allows HPPD overexpression. The HPPD gene from various species should be specifically chosen and assessed since the behavior of each enzyme is species dependent (Table 4). Arabidopsis thaliana is commonly used as a biological model for weeds.12,50 Although the utilization of strains whose growing medium has been adjusted for high level protein expression precludes the requirement for further optimization of specific strains,51 studies have pointed out that the same strain may grow distinctly under different conditions, e.g., temperature and incubation time.12,52,53 Consequently, the most suitable conditions should be determined for new enzyme and plasmid to optimize the amount and activity of the recombinant HPPD.

Figure 3. Crystal structure of Arabodopsis thaliana HPPD (AtHPPD) complexed with sulcotrione (yellow). The facial triad (green) binds to Fe(II). The picture was drawn by PyMol software (Version 1.8 Schrödinger, LLC) based on 5DHW deposited in Protein Data Bank by Yang, W. C., and Yang, G. F. Crystal structure of AtHPPD complexed with sulcotrione. Unpublished results.

Table 4. Kinetic Parameters of Some Wild Type (WT) and Mutants of Recombinant Carrot and Human HPPD HPPD

enzyme

Km (μM)

kcat (S1−)

ref

carrot

WT Q372E Q300E Q286E N275D S260A WT H183A H266A E349G E349Q

1.8 7.5 2.1 0.1 0.2 0.3 200 90 180 100 200

7.5 ± 25 286 ± 22 551 ± 76 452 ± 63 153 ± 32 9±3 3.3 ± 0.4 0.16 ± 0.004 0.13 ± 0.01 0.05 ± 0.002 0.4 ± 0.1

38

human

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THE CATALYTIC MECHANISM The catalytic mechanism of HPPD has been extensively investigated. Various studies have been carried out using a combination of structural, spectroscopic, pre-steady state kinetic, and theoretical computations. The conclusions of these studies led to agreements on some common steps. For example, HPPD chemistry is similar to that of other α-keto acid-dependent oxygenases (α-KAOs) in which the addition of substrate is ordered. Also, in the HPPA to HGA conversion reaction, HPPD receives electrons from the α-keto acid of the pyruvate substituent of HPPA, yielding decarboxylated and hydroxylated products.16 The data obtained from the combination of site-directed mutagenesis and computational calculations have revealed the interactions between the

39

developed an easy and cost-effective colorimetric method based on the release of a melanin-like pigment that is repressed by the presence of HPPD inhibitor in bacterial culture media. However, the activity of HPPD is commonly assessed by measuring the kinetic parameters, Vmax, Km, and kcat, whereas 8526


Review


Figure 4. Simplified catalytic mechanism of HPPD: (1) formation of HPPD−HPPA complex; (2) dioxygen addition; (3) decarboxylation; (4) O−O cleavage; (5) acetic acid chain migration; (6) C1 hydroxylation.

MM calculations based on the crystal structure of AtHPPD (PDB entry: 1SQD) and carrot HPPD, Raspail et al.38 recently confirmed this hypothesis. Indeed, the authors demonstrated that Gln358 binds to the carboxylate moiety of HPPA, whereas Gln272 and Gln286 attach the 4-hydroxy group. This conclusion was confirmed by Huang et al.39 in human HPPD. In addition, Raspail et al.38 have concluded that the hydrogen bond is weakened in the Q286E variant whereas Km and kcat remain unchanged in native HPPD. This finding highlights not only the implication of glutamine residue in the formation of the complex through hydrogen bonding via 4hydroxy group but also its role in the first nucleophilic attack by oxygen. Dioxygen Addition. While the resting enzyme has only a slight tendency to oxidize in the presence of dioxygen, the first nucleophilic attacker, the enzyme−substrate complex, has high molecular oxygen reactivity, which is associated with the complex planarity.38 This configuration augments the electron density at the metal and hence activates the reduction of dioxygen.16,38,56 This changing reactivity of Fe(II) toward O2 in the presence of HPPA, which is an effector for the enzyme to reduce dioxygen, is proposed as the starting point for the ordered addition of O2 and HPPA.9,16 The carboxylate group of HPPA may also be critically involved in the activation of the dioxygen, the early and key step for oxygenase activity.57 Although a 5-coordination iron center may be available for O2 binding,58 a recent report showed that this geometry is not a conditional requirement for increased dioxygen reactivity.55

substrate or intermediates and key residues in the active site. Although the HPPD chemistry governing the catalytic cycle remains unknown, we summarize the relevant and current knowledge as depicted in Figure 4. The Formation of HPPD−HPPA Complex. In the resting state of HPPD, Fe(II) has an octahedral ligand field arrangements with three water molecules in coordination site not filled by the facial triad16,29,30,38 (Figure 3) that fasten the Fe(II) into the active site for catalysis.39 HPPA can then bind to HPPD−Fe(II) under anaerobic conditions, and a charge transfer commences when the α-keto acid part contacts the Fe(II) with bidentate coordination.54 Consequently, two water molecules are relocated and thereby the HPPD−Fe(II)−HPPA complex retains six-coordinate geometry55 in which HPPA presumably binds to Fe(II) through its carboxylate group.39 Using the quantum mechanics/molecular mechanics (QM/ MM) and molecular modeling, the interaction between HPPA and the active site of Arabidopsis thaliana HPPD (AtHPPD) was investigated. This study led to the hypothesis that the facial triad might stabilize the substrate38 even though their substitution resulted in decreased enzyme activity.39 Therefore, much attention has been returned to the binding mode of 4hydroxy group of the substrate, and multiple hypotheses have been formulated. For example, Brownlee et al.29 suggested the involvement of 4-hydroxy group in π-stacking interactions with the rings of two conserved phenylalanine residues, whereas Serre et al.30 hypothesized its connection to conserved glutamine residues through hydrogen bonding. Using QM/ 8527


Review

Journal of Agricultural and Food Chemistry Decarboxylation and O−O Cleavage. The dioxygen addition to HPPD−Fe(II)−HPPA complex results in quintet iron−dioxygen species, Fe(III)−O2−•, in which CO2 molecule is very lightly bound to iron and readily detached from the active site.33,59,60 The decarboxylation produces Fe(III)− peracid species whose O−O bond is cleaved, leading to activated oxygen species.33 Fe(II) is then transformed into Fe(IV) due to the presence of two negatively charged ligands in the iron coordination shell.16,33 This assumption was confirmed in AtHPPD where conserved residues (Asn261 and Ser246) properly orient the HPPA intermediate for the Fe(IV)−oxene electrophilic attack at the aromatic C1.7,28,38 However, clear functions of individual residues and the means by which the enzymes orchestrate the catalytic cycles are largely unknown.16 Fe(IV)−Oxene Electrophilic Attack at the Aromatic Ring. Subsequently, the iron double-bonded oxygen binds to the ring C1,17,16 leading to an epoxide that is the first intermediate in the native HPPD-catalyzed reaction.16 To explain this predilection to C1 in HPPA, Borowsky et al.33 compared the activation energies at C1 and C2. The results showed high activation energy at C2 due to electronic effects, conferring the specificity to HPPD toward HPPA. However, Shah et al.61 stated that other pathways, such as a benzylic cation pathway, could take place in variant forms of HPPD. Acetic Acid Side-Chain Migration and C1 Hydroxylation. The transformation of Fe(IV)−oxene leads to the formation of a bond between oxygen and C1 atom, which implies the lowest energy barrier.33 The rupture of epoxide ring results in products that are not immediately involved in the catalytic reaction but possibly released into the solution by HPPD variants due to the lack of native product specificity.7 For instance, arene is not considered as a catalytic intermediate since it is suggested to be neither directly formed from oxene nor a necessary intermediate.33 During this critical step, Raspail et al.38 demonstrated that 4-hydroxy group of the intermediate maintains the interactions with Asn261 and Ser246 residues through hydrogen bonding network by acting as acceptor and donor, respectively. The rupture of epoxide ring then commences the displacement of acetic acid side chain to the neighboring carbon through NIH shift.62 However, although this shift was believed to be unique to HPPD activity, it has been shown that it can be catalyzed by an unrelated enzyme.38 At present, no definitive data support the mechanism by which this catalysis occurs. The ring recovers its aromatic character through a tautomerization reaction in which a proton transfer, self C1 hydroxylation, takes place from the C2 carbon to the ketone oxygen.33 Clearly, the residue Ser246 of AtHPPD is essential for this step.38 Finally, HPPD undergoes rate-limiting conformational changes and proton movement during HGA release that leave the active site unable to reconnect to the product.63 Interestingly, this reaction can take place in solution where it can enable the kinetic study of HPPD-catalyzed reaction in vitro.

Figure 5. Chemical structures of some compounds involved in the early discovery of HPPD inhibitors: 1, 2-(3-methylbutanoyl)cyclohexane-1,3,5-trione (leptospermone); 2, 3-hydroxy-2-(2phenoxyacetyl)cyclohex-2-enone; 3, 1,1′-(3,7,9-trihydroxy-8,9b-dimethyl-1-oxo-1,9b-dihydrodibenzo[b,d]furan-2,6-diyl)diethanone (usnic acid); 4, 2-(2-chlorobenzoyl)-5,5-dimethylcyclohexane-1,3dione; 5, 2-chloro-4-(trifluoromethyl)benzoic acid.

diversity of HPPD inhibitors has given rise to relative activities due to their various structures that may influence their chemistry. For example, DAS869 is a potent inhibitor of both plant and mammalian HPPDs, whereas DAS645 is highly selective for plant enzymes.47 Moreover, HPPD inhibitors tend to undergo a tautomerization reaction to form enols in aqueous solution.66 The investigation of the interaction between DAS645 and AtHPPD (PDB entry: 1TG5) led to the conclusion that the triketone moiety can form a bidentate interaction with Fe(II) in the active site.12,48,67 Another interaction, π−π interaction, was found between the quinoline motif and Phe360 and Phe403.11 A similar conclusion, which was supported by other reports,13,24 was also drawn from the study of the interactions between 2 and AtHPPD (PDB entry: 5CTO). 13,68 While Fe(II) coordination is accomplished by the usual facial triad, the remaining coordinating water molecules are substituted by the β-keto−enol system from the inhibitor. The loading and accommodation of the inhibitor, which requires a diketone moiety to mimic the α-keto acid group of the substrate,13,65,69 are fulfilled by phenylalanine residues.47 In the HPPD−Fe(II)−inhibitor complex, the inhibitor interacts uniquely with Fe(II) prior to oxidization into Fe(III).70 It is noteworthy that no hydrogen bonds or ionic interactions participate in the complex but van der Waals contacts.16 The conclusions from kinetic studies stated that inhibitors, triketones in particular, bind progressively to the catalytic site and compete with HPPA over time,11,65,71,72 leading to irreversibility.73 However, Ellis et al.74 have observed a 90% recovery of the HPPD inhibitor activity from crude rat cytosol over 10 h after inhibition, initiating a slow dissociation of the inhibitor from HPPD−Fe(II)−inhibitor complex. The investigation of inhibitory reactions becomes more complicated when the inhibitor binds only to one site. For instance, Garcia et al.73 have concluded that the binding of diketonitile, the degradation product of isoxaflutole, to one catalytic site of dimeric carrot HPPD results in a nonlinear consumption of O2. Despite their importance to medicine and agriculture, how such inhibitors interact with HPPD is still largely unclear, and further investigation is necessary.

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INHIBITORY MECHANISM The research on HPPD inhibitors for clinical and agricultural purposes increased with the observation that leptospermone 1 (Figure 5), the natural HPPD inhibitor secreted by Callistemon citrinus L., had the capability of inhibiting the growth of the surrounding grasses.64,65 Consequently, several HPPD inhibitors were designed and synthesized on the basis of this observation. However, a solid understanding of their inhibitory mechanism of the inhibitors was lacking. Unlike HPPA, the

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THE DISCOVERY AND DEVELOPMENT OF HPPD INHIBITORS HPPD can be inhibited either by natural products such as leptospermone 1,15,64 usnic acid 3,65 and benzoquinones75 or synthetic compounds (Figure 5).12,15,50 Since leptospermone 8528


Review


Figure 6. Iterative process of the discovery and development of HPPD-based herbicides.

Table 5. Postemergent Crop Selectivity of Selected Compounds at Dose Rate of 150 g ai/ha AtHPPD inhibn a

compd

15 16 mesotrione 14 mesotrione 9 10 mesotrione 11 12 13 mesotrione

b

inhibn (%)

Ki (μM)

maize

soybean

rice

wheat

cotton

canola

ref

± ± ± ± ± ± ± ± ± ± ± ±

5 0 0 2.5 0 0 10 10 5 0 0 10

10 2.5 60 50 55 60 75 55 30 25 30 55

0 0 0 40 50 50 20 50 40 0 30 50

0 0 0 80 40 0 85 40 30 0 20 40

5 17.5 65 100 80 50 60 70 40 20 40 70

0 0 95 10 100 nd nd nd 80 55 80 100

14

0.012 0.055 0.013 0.189 0.013 0.032 0.005 0.013 0.009 0.017 0.035 0.013

0.006 0.030 0.001 0.040 0.001 0.001 0.001 0.001 0.001 0.001 0.007 0.001

13 12

11

a

Chemical structures of the compounds are given in Figures 8 and 9. bKi, inhibition constant of the enzyme reaction. For mesotrione, it is a mean value calculated from different data.

then, intensive investigation was undertaken particularly in favor of triketones and led to the development and launch of the corn HPPD herbicides (sulcotrione and mesotrione).77 In the late 1980s, the optimization of 5 led to isofluxatole, establishing a new class of HPPD inhibitors containing an isoxazole heterocycle.77 HPPD inhibitors belonging to this class are also prodrugs, because they are rapidly degraded in soil and plants to the corresponding diketonitriles, which exhibit a good herbicidal activity.78,79 Intensive and laborious work has

was found to possess the basic requisite characteristics for in vivo herbicidal activity,76 these compounds were subjected to structural optimization for commercial use.52 Subsequently, the first two HPPD inhibitors, pyrazolinate and pyrazoxyphen, were developed in the early 1970s and 1985, respectively.77 Both turned out to be prodrugs because they released the free hydroxypyrazole that bound to and inhibited the HPPD enzyme. In 1982, 4 was discovered as the first active triketonetype HPPD inhibitor with unique bleaching symptoms.25 Since 8529


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Figure 7. Some typical structures of patented HPPD inhibitors by Sygenta (A), Nippon Soda (B), Nissan (C), and BASF (D).

data, due to the complexity of the HPPD-catalyzed reaction, the diversity of HPPD inhibitors, and the plant metabolic specificity.25,38,83 Therefore, the synthetic lead compounds are usually subjected to in vitro and in vivo screening to verify the activity of the HPPD inhibitor candidates and their harmful effects on the ecosystem.84 Following this process has enabled various companies to design and develop a large number of active compounds including those patented,85 of which some examples are given in Table 5. To date, three main classes of commercial HPPD inhibitors are known, namely, izoxazoles, pyrazoles, and triketones.77 Based on the structure−activity relationship (SAR), an increased number of emerging compounds with commercial potential have been discovered (Figure 7).85 Recently, valuable efforts have been focused on triketones, in particular those of Wang and collaborators.12,13,48 They have demonstrated that the introduction of 6 onto the benzoyl moiety of triketone motif could be utilized as an innovative lead structure for herbicide discovery.48 Interestingly, compound 7 was two times more potent than mesotrione, a commercial HPPD-based herbicide, whereas compound 8 showed more than 85% inhibition against four tested weeds, even at a low dose rate of 37.5 g ai/ha. More interestingly, the same compound was also safe for both rice and wheat by postemergent application at a high rate. Likewise, the substitution of 6 at the N-1 position

followed and resulted in commercial HPPD-based herbicides (Table 1). As depicted in Figure 6, with the computer-aided ligand design approach, both ligand- and target-based virtual screening are currently used to identify HPPD inhibitor candidates. To this end, the correlation between their biological activities and 3D forms at the molecular level are mostly calculated using a comparative molecular field analysis (CoMFA).80−82 A typical example is the discovery of novel HPPD inhibitors on the basis of receptor-based virtual screening that was more effective in detecting novel chemical scaffolds.81 For example, the docking of 151,047 small molecules into the active site of AtHPPD (PDB entry: 1TFZ) has shown the interactions between hydrophobic groups and certain amino acids. Using the HipHop model, only four lead compounds (ratio of 1:37762) were finally identified with potential inhibitory effects.81 This approach has significantly reduced the time and cost required for the discovery and development of HPPD inhibitors. Indeed, it provides a clear and solid insight into how HPPD and inhibitors interact, the basis on which potential inhibitors can be designed. Therefore, this approach provides guidelines that will greatly contribute to designing novel and more effective HPPD-inhibiting herbicides. However, the expected inhibitory activities of in silico validated compounds do not always match with the in vivo 8530


Review


Figure 8. Some lead compounds with the most potential for commercial HPPD-based herbicides. (A) The schematic approach of Wang et al.12,13,48 and chemical scaffolds. (B) Other lead compounds. Dashed arrows represent multiple steps.

Figure 9. Chemical structures of common commercial HPPD inhibitors. Some of them (fourth row) are used as ligands in current 3D structures.

al.14 obtained compounds 14 and 15 that displayed not only a good herbicidal activity but also an effective winter broadleaf weed control. This series of experiments resulted in two important compounds, Y13161 and Y13287 (Figure 9), that demonstrated an excellent herbicidal activity, very much comparable to that of mesotrione, in corn field. Interestingly, Y13161 demonstrated an excellent herbicidal activity and crop safety in sorghum field, whereas the mesotrione showed similar herbicidal activity but with high phytotoxicity. Due to its great commercial potential, Y13161 is undergoing new pesticide registration in China as a selective herbicide for sorghum production. This is particularly

resulted in compounds 9 and 10. It is noteworthy that these compounds show a strong broad-spectrum and postemergent herbicidal activity in maize and wheat, even at a low dose rate of 37.5 g ai/ha.12 To search for new HPPD inhibitors, Yang et al.12 designed and optimized the triketone−quinoline hybrids (Figure 8) and concluded that compound 11 might be a promising herbicide for maize fields whereas compound 12 was found to be selective to maize, rice, and wheat. For the first time, in addition to its safety to maize, compound 13 was discovered to be safe to canola.13 Hence it might have the potential to be exploited as a postemergence herbicide for weed control in maize and canola fields. At the same time, Yang et 8531


Review


For example, the substitution of the benzoyl moiety led to the conclusion that the electron-withdrawing substituents are an unquestionable requirement for the herbicidal activity due to an increased acidity of the molecule.11,13,25,77 This statement is also applicable to the quinoline ring of 11 and 9 analogues.11,12 Moreover, the introduction of methylthio and methoxy groups at the 1,3-cyclohexane ring considerably increased the herbicidal activity of 11 analogues by increasing their uptake in plants.11 However, positioning the aryl-containing substituents on the same ring reduced the activity presumably due to steric hindrance.12 The same effect was observed at the 1,3cyclohexane ring of 11 analogues on which successive methylation led to the loss of activity.11 While the substitution with para-nitro groups on the benzoyl moiety was not fruitful, ostensibly due to their susceptibility to reduction in plants and soil, their replacement by para-methylsulfonyl group showed a high herbicidal activity. Interestingly, ortho-nitro analogues were consistently active compared to their ortho-chloro analogue counterparts.25 However, Wang et al.13 found that more powerful electron-withdrawing groups on the benzene ring were detrimental to herbicidal activity due to increased metabolism once absorbed by plants. The dione moiety was investigated for its implication in crop selectivity. The conclusions of this study stated that the addition of substituents to the cyclohexanedione can block the sites of metabolism by plants,11,12,71 resulting in greater herbicidal activity as the plants have greater difficulty in detoxifying the molecule.87,88 Although the potential of herbicidal activity is more significant in grass than in broadleaf species, the cyclohexanedione ring substitution can effect a loss of maize selectivity and increase soil persistence.71 Therefore, unsubstituted cyclohexanediones are preferred. Of note, the reported in vitro and in vivo data sometimes lead to contradictory conclusions about SAR. This ambiguity may be due to the poor understanding of the HPPD-catalyzed reaction, the diversity of HPPD inhibitors, and the plant metabolic specificity.25,38

important, because currently there is no HPPD-inhibiting herbicide for weed control in sorghum field. Recently, the crystal structure of AtHPPD complexed with Y13161 (not shown) was obtained.

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THE STRUCTURE−ACTIVITY RELATIONSHIPS OF HPPD INHIBITORS The Structure−Activity Relationships of Natural Products. Recombinant AtHPPD is very sensitive to βtriketones, but less sensitive to benzoquinones, naphthoquinones, and anthraquinones. Moreover, triketone natural products were known to act as competitive tight-binding inhibitors, whereas the others did not appear to bind tightly to HPPD. In vitro investigations revealed that their inhibitory activity is largely associated with the chemical structure. Subsequently, it was demonstrated that the position of saturated side chain, high steric hindrance, asymmetry, molecular planarity, enantiomer, and higher lipophilicity of alkyl chain could influence the enzyme activity.52 These findings were later confirmed by Dayan et al.,80 who showed that the introduction of C9 alkyl side chain to β-triketone resulted in a 13-fold increase in inhibitory activity compared with sulcotrione. The Structure−Activity Relationships of Pyrazole and Its Hybrids. On the basis of in vivo SAR studies of pyrazoles, Witschel75 suggested that the combination of the chelating motif N−O with CO should be remarkably promising for the development of HPPD inhibitors belonging to the class of pyrazoles. In addition, a SAR study of pyrazole−benzimidazolone hybrids has been recently published86 and revealed that the generic chemical structure of these compounds can be broken down into pyrazole ring and benzimidazolone (Figure 10A). The introduction of methyl group at the 3-position of

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THE FATE AND EFFECTS OF HPPD INHIBITORS ON THE ECOSYSTEM Traditional pesticides have been blamed to have hazardous impact on the ecosystem. To minimize the impact, some new synthetic and marketed pesticides evolved from natural products. After a long application, agrochemicals can either remain in the soil under their native state or undergo the degradation process.88−90 In the case of HPPD inhibiting herbicides, a few available reports have pointed out that some commercial grade products and their metabolites, if they exist, can have toxic effects toward living organisms.91 Fortunately, some available studies have shown that technical grade products are not harmful,92 suggesting that the observed toxicity may be due to either additional compounds in the course of formulation or metabolites. For example, Chaima et al.93 demonstrated that sulcotrione could induce cell stress in Vicia faba. This stress, which was amplified by the addition of compounds, might be followed by cell death. Consequently, the interaction of herbicides may change the biological properties of herbicide. By exposing the microorganisms Tetrahymena pyriformis and Vibrio f ischeri to mesotrione, sulcotrione, and their metabolites (Figure 11), Bonnet et al.91 concluded that products 17, 18, 19, and 20 have a greater toxicity than their parent molecules. Given that herbicide active ingredients are rarely used alone in commercial formulations, it is more

Figure 10. Structure−activity relationship of HPPD inhibitors. (A) Pyrazole−benzimidazolone hybrid: inhibitory activity decreases when R1 = −CH3 and decreases when R3 = big substituent. (B) Synthetic triketones: electron-withdrawing substituents on benzoyl moiety and substitution of the cyclohexanedione on the dione moiety increase the biological activity.

pyrazole ring resulted in a decreased biological activity due to stronger hindrance between the compounds and the active site. On the other hand, the increased size of substituent on the R3 position of the benzimidazolone moiety led to reduced activity due to steric hindrance.86 The Structure−Activity Relationships of Synthetic Triketones. The SAR of triketones is the most investigated framework for developing HPPD inhibitors. They share the same template that can be broken into the benzoyl and dione parts (Figure 10B); each one appears to play distinct roles in the overall expression of herbicidal activity and crop selectivity. 8532


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of new herbicides and (ii) extend the utilization of HPPD-based herbicides to other crops.10 Although few weed species are resistant to HPPD herbicides yet, this resistance is expected to have a considerable impact in the next decade regarding the potential of HPPD herbicides.83,96,99 Therefore, with the purpose of taking advantages of these promising herbicides, experimental attempts have been focused on three main strategies (Figure 12). HPPD Overproduction. This strategy consists of three steps as follows: (i) identification of relevant residues engaged in the active site; (ii) modification of the target gene, i.e., HPPD; and (iii) transformation of the plant by the plasmid harboring the modified gene followed by its overexpression in the target plant which has already exhibited a low resistance to a given HPPD-based herbicide. The first successful transgenic crops were made in 1996 by Sailland et al.100 by cloning and expressing the modified Pseudomonas f luorescens HPPD (Pf HPPD) gene in tobacco, maize, and soybean. The resulting transgenic plants exhibited a high resistance to isoxaflutole compared with their wild counterparts. More recently, Siehl et al.4 achieved field tolerance in transgenic soybean plants to the HPPD-inhibiting herbicides mesotrione, isoxaflutole, and tembotrione. HPPD Bypass. As depicted in Figure 12A, this strategy relies on the synthesis of HGA independent of HPPD. For this purpose, three exogenous genes are introduced into the usual HPPD-catalyzed pathway: first, HPPO from Arthrobacter globiformis, which encodes the hydroxyphenylpyruvate oxidase (HPPO, EC 1.2.3.13) and transforms HPPA into 2-(4hydroxyphenyl)acetic acid (4-HPA); second and third, HPAH and HPAC from Pseudomonas acidovorans, which encode 4HPA hydroxylase (HPAH) and 4-HPA catalase (HPAC), respectively. These enzymes catalyze the two-step conversion of 4-HPA into HGA. Because the product of each of the previous three genes is insensitive to HPPD inhibitors,10 their overexpression in a target crop should significantly increase its resistance toward these herbicides. The Increase of HPPA Expression in Plants. This strategy relies on the hypothesis that the inhibitor and HPPA may compete for the active site.10 Therefore, more substrate molecules may prevent the inhibitor from binding and hence enable the production of higher amounts of HGA, leading to the production of more indispensable substances for plant growth.20 The technique refers to the metabolism of shikimate

Figure 11. Molecular structures of the degradation products of sulcotrione: 17, 1,3-cyclohexanedione; 18, 2-chloro-4-methylsulfonylbenzoic acid; 19, 2-amino-4-methylsulfonylbenzoic acid; and 20, 4methylsulfonyl-2-nitrobenzoic acid.

appropriate to test the single compounds as well as the mixture, and that is because the toxicity of a molecule usually depends on the metabolites91 and the biological model.94

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TRANSGENIC CROPS RESISTANT TO HPPD INHIBITORS Selective herbicides control specific weed species, while leaving the desired crop unharmed. Unfortunately, most marketed herbicides control only certain types of weeds while the number of resistant species is increasing.1 This situation signals a need for new effective herbicides and traits. In 1996, the commercial glyphosate-resistant crops, namely, soybean, corn, cotton, and canola, have been proved to be easy to use, effective, economical, and more environmentally friendly than the nonengineered crops which were replaced by them.91,95 Based on their advantages,8,12,15 HPPD-inhibiting herbicides have potential to be successfully used against weeds in the fields of tolerant crops in which they are rapidly degraded.71,73 However, two cases of resistance to mesotrione, tembotrione, and topramezone mainly used in maize and soybean fields were reported in Amaranthus tuberculatus in Illinois96 and Iowa97 in 2009. Recently, two additional HPPD-inhibiting herbicides (pyrasulfotole and isoxaflutole) have been reported in corn, sorghum, and soybean,98 suggesting a need for development of new weed management strategies. As for glyphosate, the recourse to engineered HPPDinhibitor resistant crops is preferred because they can (i) minimize the cost allocated to the discovery and development

Figure 12. Strategies for development of transgenic crops tolerant to HPPD inhibitors: (A) HPPD bypass; (B) increase of HPPA for the competition with the inhibitor to the active site of HPPD. 8533


Review


*E-mail: [email protected]. Tel: 86-27-67867706. Fax: 86-27-67867141.

(Figure 12B) in which the phenylalanine and tyrosine pathways separate only at arogenate in most plants. Theoretically, it seemed plausible to increase the HPPA amount by bypassing its synthesis at the prephenate level. However, the major challenge turned out to be the natural and irreversible transmission of the plant prephenate into arogenate, which is converted into tyrosine by arogenate dehydrogenase. Fortunately, these reactions are reversed in yeasts and E. coli in which prephenate dehydrogenase transforms prephenate into HPPA, which is in turn transaminated into tyrosine.10 Consequently, the overexpression of the yeast prephenate dehydrogenase (PDH) (EC 1.3.1.43) in tobacco resulted in a nearly 40- to 60-fold increase in resistance with respect to wild-type plants.101

ORCID

Wen-Chao Yang: 0000-0002-6722-0441 Guang-Fu Yang: 0000-0003-4384-2593 Funding

This work was funded by the National Key R&D Program (2017YFD0200507) and National Natural Science Foundation of China (No. 21332004, 21672079 and 21372093). Notes

The authors declare no competing financial interest.

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IMPLICATIONS This review scrutinizes the most recent and relevant literature that has advanced the understanding of HPPD and the development of its inhibitors as agrochemicals. The comprehension of the HPPD biology, catalytic mechanism, and structural relevance of its inhibition is a starting point for the development of new, broad-spectrum and safe herbicides. The discovery of natural and synthetic small molecules which can block the physiological function of HPPD activity has resulted in a number of marketed herbicides. To date, most of them are used in monoculture due to their limited crop selectivity and weed resistance. Of note, the ongoing discovery process has led to the production of very promising lead compounds. This valuable and laborious work can be significantly simplified by the mastery of the chemical interactions between HPPD and its inhibitors. Indeed, efficient HPPD inhibitors have been designed by chemical modifications of natural products or lead compounds, through rational design followed by synthesis and biological evaluation. The core step relies on the understanding of the catalytic role of HPPD. This challenging chemistry is under intensive investigation regarding the increasing number of recent reports. Interestingly, strategies to engineer crops that can tolerate HPPD-based herbicides have been developed, which not only enable the use of HPPDbased herbicides for various crops but also abate the need to fight weed resistance. However, despite the significant achievements in this area, the data still seem incoherent presumably due to the lack of understanding of the biological role of some conserved residues, particularly those located in N-terminus. Furthermore, unambiguous identification of intermediates is necessary. The analysis of structure−activity relationship offers a solid basis for a better rational design, and its implementation is believed to considerably reduce the time and cost allocated to each stage of the discovery of HPPD inhibitors. Nevertheless, this analysis does not consider the biological difference between weeds and crops; hence the correlation between in vitro and in vivo data has remained ambiguous. Therefore, a more comprehensive investigation in this direction may provide a basis for improving the crop selectivity. Also, the investigation of the structure−activity relationships of other main classes of HPPD inhibitors, such as pyrazoles and izoxazoles, would be a valuable contribution.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: 86-27-67867800. Fax: 86-27-67867141. 8534


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