Exploring the structural requirements for jasmonates and related ...

MINI REVIEW

review

Plant Signaling & Behavior 4:11, 1007-1009; November 2009; © 2009 Landes Bioscience

Exploring the structural requirements for jasmonates and related compounds as novel plant growth regulators A current computational perspective Ke-Xian Chen and Zu-Guang Li* College of Chemical Engineering and Materials Science; Zhejiang University of Technology; Hangzhou, China

Key words: jasmonates, amino acid conjugates of jasmonic acid, plant growth regulators, quantitative structure-activity relationship, quantitative structure-property relationship, a mini-review

Jasmonates and related compounds have been highlighted recently in the field of plant physiology and plant molecular biology due to their significant regulatory roles in the signaling pathway for the diverse aspects of plant development and survival. Though a considerable amount of studies concerning their biological effects in different plants have been widely reported, the molecular details of the signaling mechanism are still poorly understood. This review sheds new light on the structural requirements for the bioactivity/property of jasmonic acid derivatives in current computational perspective, which differs from previous research that mainly focus on their biological evaluation, gene and metabolic regulation and the enzymes in their biosynthesis. The computational results may contribute to further understanding the mechanism of drug-receptor interactions in their signaling pathway and designing novel plant growth regulators as high effective ecological pesticides.

Introduction Over the past decades, a tremendous amount of studies has led to new insights into the growth, development and survival of various plants in different places. It has been found that plants have built up highly effective and complex octadecanoid signaling pathways known as “signal transduction”.1,2 If rapid and effective defense responses are triggered by biotic and abiotic stresses, the defensive signals will surely be transduced and amplified via a number of pre-existing complex signaling pathways, activating systemic acquired resistance (SAR).3,4 Jasmonates and related compounds, a family of signaling mediators, are locally and systemically involved in these actions as regulators controlling the expression of many genes that encode defensive proteins,5,6 thus have attracted much interest lately.7-11 Therefore, plants can equilibrate the exoteric stresses as well as coordinate the developmental processes by themselves in the life cycle. *Correspondence to: Zu-Guang Li; Email: [email protected] Submitted: 08/03/09; Accepted: 08/03/09 Previously published online: www.landesbioscience.com/journals/psb/article/9717

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Since the initial discovery of bioactivity jasmonic acid and its methyl ester respectively in 1962 and 1971,12 jasmonates are a growing class of signaling molecules and plant hormones which are derived from polyunsaturated fatty acids via the octadecanoid pathway and characterized by a pentacyclic ring structure. Jasmonates and related compounds, including amino acid conjugates of jasmonic acid, are ubiquitous in the plant kingdom.13 Considerable studies have shown that they have various physiological activity in response to environmental stresses and biotic challenges and many aspects of plant developmental processes.14-21 Based on their significance to plants, they have been highlighted in the field of plant physiology and plant molecular biology recently.19 Though their biological effects, gene and metabolic regulation and the enzymes in their biosynthesis have been studied for years, the molecular details of the signaling mechanism at biochemical level are still poorly understood.10,11,22 This review presents a new way to study the possible signaling mechanism and the substitutional requirements for the bioactivity/property of jasmonates and related compounds in plants. Quantitative structure-activity relationship (QSAR) analysis pioneered by Hansch et al.23 helps to quantitatively correlate the activity or properties of compounds in series with their measured or computed physiochemical properties and has proved to be an useful approach in modern drug discovery.24,25 They rationalize the drug synthesis and provide an insight into the mechanism of drug-receptor interactions. Until now, there are few systematical structure-activity studies about them available,26-31 indicating that C-1, C-2 and C-3 positions of jasmonic acid are important for their various activity. But these previous studies were just performed in the non-quantitative traditional ways that different substituents changed in these positions vary their activity. Thus the quantitative results obtained in the computational perspective can be of great help. Quantitative Structure-Activity Relationship (QSAR) Until now, there are fewer research papers reporting the accurate numeric activity of jasmonates and related compounds, such as references 28 and 29. Without the accurate activity data, it

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is difficult to perform computer-assisted drug design (CADD) methods, which may explain why many experts focus on the synthesis and biological evaluation of the analogs of jasmonic acid and finally discuss the various substituents in cyclopentanone of jasmonic acid influencing the activity in the traditional ways. Currently, quantitative structure-activity relationship (QSAR) method was first applied to 18 jasmonates and related compounds32 that were reported by Blechert et al.28 quantitatively studying the relationships between chemical structure and their biological activity in barley and tomato bioassay. Statistically significant 2D-QSAR models (r2 > 0.880 and cross-validated r2 > 0.820) were developed by genetic function approximation (GFA)33 in Cerius2 software (Version 4.10), indicating that the biological activity (pKi-1) was principally influenced by thermodynamic descriptors (Atype_C_60 and Atype_C_38), electronic descriptor (Dipole-mag) and spatial descriptor (Jurs-RPSA) and the biological activity (pKi-2) was principally governed by electronic descriptor (HOMO), structural descriptor (Hond Acceptor) and thermodynamic descriptor (Atype_C_16). Here, Ki-1 (%) and Ki-2 (%) represented relative chlorophyll loss ratio (%) in barley and tomato senescence bioassays, respectively, which had already been expressed as log (1/Ki). The detailed meaning of descriptors can be seen in the paper.32 Besides, molecular field analysis (MFA)34 coupled with genetic partial least squares (G/PLS) method35,36 were also employed to derive 3D-QSAR models, investigating the substitutional requirements for the favorable receptor-drug interaction, and quantitatively indicating the important regions of molecules for their activity.32 MFA attempts to postulate and represent the essential features of a receptor site from the aligned common features of the molecules that bind to it, which is especially effective for the analysis of the data sets with available activity data but unknown receptor site structure.36 At present, the receptors that jasmonates and related compounds bind to are still unclear yet. Thus, MFA-G/PLS study of these compounds will contribute to further understanding the structural requirements for the bioactivity of jasmonates and related compounds. The 3D-QSAR models showed that electrostatic interactions are crucial to pKi-1 and moderate steric interactions are favored to pKi-2, indicating tiny transformation in the meso-position and para-position of cyclopentanone may greatly change the biological activity. These results are also approximately in accordance with the previous studies.26-31 Therefore, combination of 2D-QSAR and 3D-QSAR models can be of great help for experts to better predict the possible activity of compounds in series and design novel analogs of jasmonic acid with high biological activity. Quantitative Structure-Property Relationship (QSPR) Lipophilicity, usually expressed as the logarithm of n-octanol/ water partition coefficient (logP), plays an important role in ligand-receptor interactions,37 and is one of the major properties that influence the transport, absorption and distribution of chemicals in biological systems.38 Recently, how plants manage events has been suggested to be related to jasmonates’ natural workings in the form of direct or indirect penetration of their

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cells.9 Thus, logP is essential for the signaling abilities of jasmonates and related compounds, whether they are exogenous or endogenous. Lately, quantitative structure-property relationship (QSPR) was first performed on the 59 reported amino acid conjugates of jasmonic acid with lipophilicity in form of log P calculated in Cerius2 software (Version 4.10).19 Statistically significant 2D-QSPR model (r2 = 0.990 and cross-validated r2 = 0.987) developed by GFA method showed that the calculated logP of amino acid conjugates of jasmonic acid was influenced by structural descriptors (Hond Donor and Density), electronic descriptor (Apol) and E-State-keys (S_ssO), which could be approved by the usage of descriptors during QSPR models generation. The detailed meaning of descriptors can be seen in the paper.19 In addition, the results of the 2D-QSPR model were further compared with 3D-QSPR model. 3D-QSAR model (r2 = 0.922 and cross-validated r2 = 0.841) with good stability and predictability was generated by MFA-GFA method to further study the structural requirements for the logP of these compounds in series, indicating bulky substituents at C7 position were unfavored to the logP and both steric and electrostatic substituents at C3 position were important to logP. The logP values of test set molecules were also well predicted, thus the derived QSPR models were significant and the important regions and the molecular structural parameters were found for these series. Another paper39 (words in Chinese) also presented the QSPR study on the physiochemical properties (AlogP, logP and AlogP98) of 30 jasmonates and related derivatives, and the results were interesting. Conclusion and Prospect Jasmonates and related compounds are essential for plants’ survival in nature.40 Along with the application of modern techniques and methods, more and more analogs of jasmonic acid will be discovered and exogenous applied in the plants to further study their roles in regulate plants’ developmental processes and defensive responses against exoteric attack. For these compounds are universal in plants, they have the effects of ecological pesticides.32 The biological activity evaluation of them will be surely further investigated in the coming years, not restricted in a few biological systems, which will affirmatively interpret the data to fully understand the perception of mechanism of them in various plants. Due to the successful application of CADD methods to modern drug discovery, it makes possible that quantitative microstructure required for activity of jasmonates and related compounds will be explored. At present, only three papers ( refs. 19, 32 and 39) reported the study of them using computational methods. Thus, there is an urgent need to further study these compounds in computational perspective, quickening the design of analogs of jasmonic acid in series with high biological activity. Besides the 2D/3D-QSAR/QSPR methods, the following methods may be also of great help. Quantum chemistry and molecular mechanics can be employed to study the optimum conformations of compounds with lowest energy that are supposed to be existing steadily in plants, and the relationships between the activity and


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charge distribution, bond length, angle and molecular occupied or virtual orbital can be studied for further molecular design. Furthermore, pharmacophore can also be used to explore specific, three dimensional maps of biological properties common to all active conformations of a set of analogs of jasmonic acid that exhibit particular activity, showing the specific molecular regions that interact with surrounding hydrophobic, aromatic, a hydrogen bond acceptor and so on in plants. This method can be widely used not only in drug identification and design studies, but also in lead optimization for potency and reduction of toxicity. Quantitative structure-retention relationship (QSRR) method41,42 can also be employed to predict the chromatographic retention indexes of unknown analogs of jasmonic acid, which can help References 1.

2. 3.

4.

5. 6. 7.

8.

9. 10.

11.

12. 13.

14.

15.

16.

Menke FLH, Champion A, Kijne JW, Memelink J. A novel jasmonate- and elicitor-responsive element in the periwinkle secondary metabolite biosynthetic gene Str interacts with a jasmonate- and elicitorinducible AP2-domain transcription factor, ORCA2. EMBO J 1999; 18:4455-63. Pauw B, Memelink J. Jasmonate-responsive gene expression. J Plant Growth Regul 2005; 23:200-10. Carrasco JL, Ancillo G, Mayda E, Vera P. A novel transcription factor involved in plant defense endowed with protein phosphatase activity. EMBO J 2003; 22:337684. Vlot AC, Klessig DF, Park SW. Systemic acquired resistance: the elusive signal(s). Curr Opin Plant Biol 2008; 11:436-42. Koda Y. Possible involvement of jasmonates in various moiphogenic events. Physiol Plant 1997; 100:639-46. Gfeller A, Farmer EE. Keeping the leaves green above us. Science 2004; 306:1515-6. Kessler A, Halitschke R, Baldwin IT. Silencing the jasmonate cascade: Induced plant defenses and insect populations. Science 2004; 305:665-8. Wasternack C. Jasmonates: An update on biosynthesis, signal transduction and action in plant stress response, growth and development. Ann Bot 2007; 100:681-97. Farmer EE. Plant biology: Jasmonate perception machines. Nature 2007; 448:659-60. Thines B, Katsir L, Melotto M, Niu Y, Mandaokar A, Liu G, et al. JAZ repressor proteins are targets of the SCFCOI1 complex during jasmonate signalling. Nature 2007; 448:661-5. Chini A, Fonseca S, Fernández G, Adie B, Chico JM, Lorenzo O, et al. The JAZ family of repressors is the missing link in jasmonate signaling. Nature 2007; 448:666-71. Beale MH, Ward JL. Jasmonates: Key Players in the Plant Defence. Nat Prod Sci 1998; 15:533-48. Schaller F, Schaller A, Stintzi A. Biosynthesis and metabolism of jasmonates. J Plant Growth Regul 2005; 23:179-99. Pluskota WE, Qu N, Maitrejean M, Boland W, Baldwin IT. Jasmonates and mimics differentially elicit systemic defense responses in Nicotiana attenuata. J Exp Bot 2007; 58:4071-82. Wang L, Halitschke R, Kang JH, Berg A, Harnisch F, Baldwin IT. Independently silencing two members of the JAR family impairs levels of trypsin proteinase inhibitors but not nicotine. Planta 2007; 226:159-67. Wang L, Allmann S, Wu J, Baldwin IT. Comparisons of LIPOXYGENASE3- and JASMONATERESISTANT4/6-silenced plants reveal that jasmonic acid and jasmonic acid-amino acid conjugates play different roles in herbivore resistance of Nicotiana attenuata. Plant Physiol 2008; 146:904-15.

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experts to estimate the compounds in series found accidentally. Through the various computational studies on the jasmonates and related compounds, the mechanism of drug-receptor interactions in their signaling pathway will be well understood and novel analogs of jasmonic acid with high biological activity will be designed fleetly. Acknowledgements

This work is supported by the National Natural Science Foundation of China (No. 30500339), the Natural Science Foundation Program of Zhejiang Province (No. Y407308) and the merit based research project for scholars returning from abroad.

17. Galis I, Gaquerel E, Pandey SP, Baldwin IT. Molecular mechanisms underlying plant memory in JA-mediated defense responses. Plant Cell Environ 2009; 32:617-27. 18. Wasternack C, Hause B. Emerging complexity: jasmonate-induced volatiles affect parasitoid choice. J Exp Bot 2009; 60:2451-3. 19. Li ZG, Chen KX, Xie HY, Gao JR. Quantitative structure-property relationship studies on amino acid conjugates of jasmonic acid as defense signalling molecules. J Integr Plant Biol 2009; 51:581-92. 20. Xu MJ, Dong JF. Synergistic action between jasmonic acid and nitric oxide in inducing matrine accumulation of sophora flavescens suspension cells. J Integr Plant Biol 2008; 50:92-101. 21. Chen QF, Dai LY, Xiao S, Wang YS, Liu XL, Wang GL. The COI1 and DFR genes are essential for regulation of jasmonate-induced anthocyanin accumulation in Arabidopsis. J Integr Plant Biol 2007; 49:1370-7. 22. Walter A, Mazars C, Maitrejean M, Hopke J, Ranjeva R, Boland W, et al. Structural requirements of jasmonates and synthetic analogues as inducers of Ca 2+ signals in the nucleus and the cytosol of plant cells. Angew Chem Int Ed 2007; 46:4783-5. 23. Hansch C, Maloney PP, Fujita T, Muir RM. Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature 1962; 194:178-80. 24. Yang GF, Huang XQ. Development of quantitative structure-activity relationships and its application in rational drug design. Curr Pharm Des 2006; 12:4601-11. 25. Lill MA. Multi-dimensional QSAR in drug discovery. Drug Discov Today 2007; 12:1013-7. 26. Ishikawa A, Yoshihara T, Nakamura K. Structureactivity relationships of jasmonates in the induction of expression of two proteinase inhibitor genes of potato. Biosci Biotech Biochem 1994; 58:544-7. 27. Bodnaryk R, Yoshihara T. Structure-activity relationships of cyclopentane analogs of jasmonic acid for induced responces of canola seedlings, Brassica napus L. J Chem Ecol 1995; 21:1735-43. 28. Blechert S, Bockelmann C, Brümmer O, Füßlein M, Gundlach H, Haider G, et al. Structural separation of biological activities of jasmonates and related compounds. J Chem Soc Perkin Trans I 1997; 1:3549-59. 29. Miersch O, Kramell R, Parthier B, Wasternack C. Structure-activity relations of substituted, deleted or stereospecically altered jasmonic acid in gene expression of barley leaves. Phytochemistry 1999; 50:353-61. 30. Blechert S, Bockelmann C, Füßlein M, Schrader Tv, Stelmach B, Niesel U, et al. Structure-activity analyses reveal the existence of two separate groups of active octadecanoids in elicitation of the tendrilcoiling response of Bryonia dioica Jacq. Planta 1999; 207:470-9.


31. Haider G, von Schrader T, Fusslein M, Blechert S, Kutchan TM. Structure-activity relationships of synthetic analogs of jasmonic acid and coronatine on induction of benzo[c]phenanthridine alkaloid accumulation in Eschscholzia californica cell cultures. Biol Chem 2000; 381:741-8. 32. Li ZG, Chen KX, Xie HY, Chen KY, Shen DL. QSAR analysis of jasmonates as novel plant growth regulators. Chin J Pestic Sci 2009; 11:166-75. 33. Rogers D, Hopfinger AJ. Application of genetic function approximation to quantitative structure-activity relationships and quantitative structure-property relationships. J Chem Inf Comput Sci 1994; 34:854-66. 34. Chen KX, Li ZG, Xie HY, Gao JR, Zou JW. Quantitative structure-activity relationship analysis of aryl alkanol piperazine derivatives with antidepressant activities. Eur J Med Chem 2009; 44:4367-75. 35. Chen KX, Xie HY, Li ZG, Gao JR. Quantitative structure-activity relationship studies on 1-aryl-tetrahydroisoquinoline analogs as active anti-HIV agents. Bioorg Med Chem Lett 2008; 18:5381-6. 36. Li ZG, Chen KX, Xie HY, Gao JR. Quantitative structure-activity relationship analysis of some thiourea derivatives with activities against HIV-1 (IIIB). QSAR & Comb Sci 2009; 28:89-97. 37. Marisa C, Eugene B, Elena R, Ivonne H, Sergio R, Hilda B, et al. Biological activity of novel progesterone derivatives having a bulky ester side chains at C-3. Steroids 2008; 73:838-43. 38. Bartalis J, Halaweish FT. Relationship between cucurbitacins reversed-phase high-performance liquid chromatography hydrophobicity index and basal cytotoxicity on HepG2 cells. J Chromatogr B 2005; 818:159-66. 39. Cao H, Li ZG, Chen KX, Gao JR, Shen DL. QSPR studies on the physicochemical properties of jasmonates and related derivatives. Comput Appl Chem 2008; 25:957-63. 40. Vandenbussche F, Van Der Straeten D. One for all and all for one: Cross-talk of multiple signals controlling the plant phenotype. J Plant Growth Regul 2007; 26:178-87. 41. Farkas O, Zenkevich IG, Stout F, Kalivas JH, Heberger K. Prediction of retention indices for identification of fatty acid methyl esters. J Chromatogr A 2008; 1198:188-95. 42. Li ZG, Cao H, Wang LL, Mo WM, Shen DL. Quantitative structure-retention relationship for terpenes and their application in structure characterization. Acta Chim Sinica 2009; 67:289-94.

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