Skip to main content
SpringerLink
Log in

Synthesis of 3-oxalinolenic acid and β-oxidation-resistant 3-oxa-oxylipins

  • Method
  • Published:
Lipids

Abstract

3-Oxalinolenic acid (3-oxa-9(Z), 12(Z), 15(Z)-octadecatrienoic acid or (6(Z), 9(Z), 12(Z)-pentadecatrienyloxy)acetic acid) was synthesized from 5(Z), 8(Z), 11(Z), 14(Z), 17(Z)-eicosapentaenoic acid by a sequence involving the C15 aldehyde 3(Z), 6(Z), 9(Z), 12(Z)-pentadecatetraenal as a key intermediate. Conversion of the aldehyde by isomerization and two steps of reduction afforded 6(Z), 9(Z), 12(Z)-pentadecatrienol, which was coupled to bromoacetate to afford after purification by HPLC >99%-pure 3-oxalinolenic acid in 10–15% overall yield. 3-Oxalinolenic acid was efficiently oxygenated by soybean lipoxygenase-1 into 3-oxa-13(S)-hydroperoxy-9(Z), 11(E), 15(Z)-octadecatrienoic acid, and this hydroperoxide could be further converted chemically into 3-oxa-13(S)-hydroxy-9(Z), 11(E), 15(Z)-octadecatrienoic acid and 3-oxa-13-oxo-9(Z), 11(E), 15(Z)-octadecatrienoic acid. The 3-oxa-hydroperoxide also served as the substrate for the plant enzymes allene oxide synthase, divinyl ether synthase, and hydroperoxide lyase to produce 3-oxa-12-oxo-10, 15(Z)-phytodienoic acid and other 3-oxa-oxylipins that were characterized by MS, 3-Oxalinolenic acid was not oxygenated by 9-lipoxygenase from tomato but was converted at a slow rate into 3-oxa-9(S)-hydroperoxy-10(E), 12(Z), 15(Z)-octadecatrienoic acid by recombinant maize 9-lipoxygenase. Recombinant α-dioxygenase-1 from Arabidopsis thaliana catalyzed the conversion of 3-oxalinolenic acid into a 2-hydroperoxide, which underwent spontaneous degradation into a mixture of 6,9,12-pentadecatrienol and 6,9,12-pentadecatrienyl formate. A novel α-dioxygenase from the moss Physcomitrella patens was cloned and expressed and was found to display the same activity with 3-oxalinolenic acid as Arabidopsis thaliana α-dioxygenase-1. Lipoxygenase-generated 3-oxa-oxylipins are resistant toward β-oxidation and have the potential for displaying enhanced biological activity in situations where activity is limited by metabolic degradation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

At-DOX1:

recombinant α-dioxygenase-1 from Arabidopsis thaliana

12-oxo-PDA:

12-oxo-10,15(Z)-phytodienoic acid

Pp-DOX:

recombinant α-dioxygenase from Physcomitrella patens

References

  1. Feussner, I., and Wasternack, C. (2002) The Lipoxygenase Pathway, Annu. Rev. Plant Biol. 53, 275–297.

    Article  PubMed  CAS  Google Scholar 

  2. Hamberg, M., Ponce de Leon, I., Rodriguez, M.J., and Castresana, C. (2005) α-Dioxygenases, Biochem. Biophys. Res. Commun. 338, 169–174.

    Article  PubMed  CAS  Google Scholar 

  3. Farmer, E.E., Alméras, E., and Krishnamurthy, V. (2003) Jasmonates and Related Oxylipins in Plant Responses to Pathogenesis and Herbivory, Curr. Opin. Plant Biol. 6, 372–378.

    Article  PubMed  CAS  Google Scholar 

  4. Howe, G.A. and Schilmiller, A.L. (2002) Oxylipin Metabolism in Response to Stress, Curr. Opin. Plant Biol. 5, 230–236.

    Article  PubMed  CAS  Google Scholar 

  5. Weber, H., Chételat, A., Caldelari, D., and Farmer, E.E. (1999) Divinyl Ether Fatty Acid Synthesis in Late Blight-Diseased Patato Leaves, Plant Cell 11, 485–493.

    Article  PubMed  CAS  Google Scholar 

  6. Granér, G., Hamberg, M., and Meijer, J. (2003) Screening of Oxylipins for Control of Oilseed Rape (Brassica napus) Fungal Pathogens, Phytochemistry 63, 89–95.

    Article  PubMed  CAS  Google Scholar 

  7. Prost, I., Dhondt, S., Rothe, G., Vicente, J., Rodriguez, M.J., Kift, N., Carbonne, F., Griffiths, G., Esquarré-Tugayé, M.T., Rosahl, S., Castresana, C., Hamberg, M., and Fournier, J. (2006) Evaluation of the Antimicrobial Activities of Plant Oxylipins Supports Their Involvement in Defense Against Pathogens, Plant Physiol. 139, 1902–1913.

    Article  CAS  Google Scholar 

  8. Lau, S.M., Brantley, R.K., and Thorpe, C. (1988) The Reductive Half-Reaction in Acyl-CoA Dehydrogenase from Pig Kidney: Studies with Thiaoctanoyl-CoA and Oxaoctanoyl-CoA Analogues. Biochemistry 27, 5089–5095.

    Article  PubMed  CAS  Google Scholar 

  9. Pitt, M.J., Easton, C.J., Ferrante, A., Poulos, A., and Rathjen, D. A. (1998) Synthesis of Polyunsaturated β-Thia and γ-Thia Fatty Acids from Naturally Derived Polyunsaturated Fatty Alcohols and in vitro Evaluation of Their Susceptibility to β-Oxidation, Chem. Phys. Lipids 92, 63–69.

    Article  CAS  Google Scholar 

  10. Flock, S., Lundquist, M., and Skattebol, L. (1999) Syntheses of Some Polyunsaturated Sulfur- and Oxygen-Containing Fatty Acids Related to Eicosapentaenoic and Docosahexaenoic Acids, Acta Chem. Scand. 53, 436–445.

    Article  PubMed  CAS  Google Scholar 

  11. Holmeide, A.K., and Skattebol, L. (2000) Syntheses of Some Polyunsaturated Trifluoromethyl Ketones as Potential Phospholipase A2 Inhibitors. J. Chem. Soc. Perkin. Trans. 1, 2271–2276.

    Article  Google Scholar 

  12. Baertschi, S.W., Ingram, C.D., Harris, T.M., and Brash, A.R. (1988) Absolute Configuration of cis-12-Oxophytodienoic Acid of Flax seed: Implications for the Mechanism of Biosynthesis from the 13(S)-Hydroperoxide of Linolenic Acid, Biochemistry 27, 18–24.

    Article  PubMed  CAS  Google Scholar 

  13. Hamberg, M., and Fahlstadius, P. (1990) Allene Oxide Cyclase: A New Enzyme in Plant Lipid Metabolism, Arch. Biochem. Biophys. 276, 518–526.

    Article  PubMed  CAS  Google Scholar 

  14. Wilson, R.A., Gardner, H.W., and Keller, N.P. (2001) Cultivar-Dependent Expression of a Maize Lipoxygenase Responsive to Seed Infesting Fungi, Mol. Plant Microbe Interact. 14, 980–987.

    PubMed  CAS  Google Scholar 

  15. Matthew, J.A., Chan, H.W.-S., and Galliard, T. (1977) A Simple Method for the Preparation of Pure 9-D-Hydroperoxide of Linoleic Acid and Methyl Linoleate Based on the Positional Specificity of Lipoxygenase in Tomato Fruit, Lipids 12, 324–326.

    Article  PubMed  CAS  Google Scholar 

  16. Sanz, A., Moreno, J.I., and Castresana, C. (1998) PIOX, a New Pathogen-Induced Oxygenase with Homology to Animal Cyclooxygenase, Plant Cell 10, 1523–1527.

    Article  PubMed  CAS  Google Scholar 

  17. Nishiyama, T., Fujita, T., Shin-I, T., Seki, M., Nishide, H., Uchiyama, I., Kamiya, A., Carninci, P., Hayashizaki, Y., Shinozaki, K., Kohara, Y., and Hasebe, M. (2003) Comparative Genomics of Physcomittrella patens Gametophytic Transcriptome and Arabidopsis thaliana: Implication for Land Plant Evolution, Proc. Natl. Acad. Sci. USA 100, 8007–8012.

    Article  PubMed  CAS  Google Scholar 

  18. Grechkin, A.N., and Hamberg, M. (2004) The “Heterolytic Hydroperoxide Lyase” Is an Isomerase Producing a Short-Lived Fatty Acid Hemiacetal, Biochim. Biophys. Acta 1636, 47–58.

    PubMed  CAS  Google Scholar 

  19. Grechkin, A.N., Fazliev, F.N., and Mukhtarova, L.S. (1995) The Lipoxygenase Pathway in Garlic (Allium sativum L.) Bulbs: Detection of the Novel Divinyl Ether Oxylipins, FEBS Lett. 371, 159–162.

    Article  PubMed  CAS  Google Scholar 

  20. Hamberg M. (1998) A Pathway for Biosynthesis of Divinyl Ether Fatty Acids in Green Leaves. Lipids 33, 1061–1071.

    Article  PubMed  CAS  Google Scholar 

  21. Corey, E.J., Niwa, H., and Falck, J.R. (1979) Selective Epoxidation of Eicosa-cis-5,8,11, 14-Tetraenoic (Arachidonic) Acid and Eicosa-cis-8,11, 14-Trienoic Acid, J. Am. Chem. Soc. 101, 1586–1587.

    Article  CAS  Google Scholar 

  22. Holmeide, A.K., and Skattebol, L. (2003) Oxidative Degradation of Eicosapentaenoic Acid into Polyunsaturated Aldehydes, Tetrahedron 59, 7157–7162.

    Article  CAS  Google Scholar 

  23. Easton, C.J., Robertson T.A., Pitt, M.J., Rathjen, D.A., Ferrante, A., and Poulos, A. (2001) Oxidation of Oxa and Thia Fatty Acids and Related Compounds Catalysed by 5- and 15-Lipoxygenase, Bioorg. Med. Chem. 9, 317–322.

    Article  PubMed  CAS  Google Scholar 

  24. Costabile, M., Hii, C.S.T., Melino, M., Easton, C., and Ferrante, A. (2005) The Immunomodulatury Effects of Novel β-Oxa, β-Thia, and γ-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs, J. Immunol. 174, 233–243.

    PubMed  CAS  Google Scholar 

  25. Blechert, S., Bockelmann, C., Brümmer, O., Füsslein, M., Gundlach, H., Haider, G., Hölder, S., Kutchan, T.M., Weiler, E.W., and Zenk, M.H. (1997) Structural Separation of Biological Activaties of Jasmonates and Related Compounds, J. Chem. Soc. Perkin Trans, 1, 3549–3559.

    Article  Google Scholar 

  26. Lauchli, R., and Boland, W. (2003) Efficient Synthesis of [2H2]-Tetrahy drodicranenone B and a 3-Oxa-Analogue Resistant Against β-Oxidation Tetrahedron 59, 149–153.

    Article  CAS  Google Scholar 

  27. Guilford, W.J., and Parkinson, J.F. (2005) Second-Generation beta-Oxidation Resistant 3-Oxa-Lipoxin A4 Analogs. Prostaglandins, Leukotrienes and Essential Fatty Acids 73, 245–250.

    Article  CAS  Google Scholar 

  28. Hamberg, M., Sanz, A., Rodriguez, M.J., Calvo, A.P., and Castresana, C. (2003) Activation of the Fatty Acid α-Dioxygenase Pathway During Bacterial Infection of Tobacco Leaves. Formation of Oxylipins Protecting against Cell Death. J. Biol. Chem. 278, 51796–51805.

    Article  PubMed  CAS  Google Scholar 

  29. Butovich, I.A., Lukyanova, S.M., and Reddy, C.C. (1998) Oxidation of Linoleyl Alcohol by Potato Tuber Lipoxygenase: Possible Mechanism and the Role of Carboxylic Group in Substrate Binding. Biochem. Biophys. Res. Commun. 249, 344–349.

    Article  PubMed  CAS  Google Scholar 

  30. van Zadelhoff, G., Veldink, G.A., and Vliegenthart, J.F.G. (1998) With Anandamide as Substrate Plant 5-Lipoxygenases Behave Like 11-Lipoxygenases, Biochem. Biophys. Res. Commun. 248, 33–38.

    Article  PubMed  Google Scholar 

  31. Adam, W., Boland, W., Hartmann-Schreier, J., Humpf, H.-U., Lazarus, M., Saffert, A., Saha-Möller, C.R., and Schreier, P. (1998) α-Hydroxylation of Carboxylic Acids with Molecular Oxygen Catalyzed by the α-Oxidase of Peas (Pisum sativum): A Novel Biocatalytic Synthesis of Enantiomerically Pure (R)-2-Hydroxy Acids, J. Am. Chem. Soc. 120, 11044–11048.

    Article  CAS  Google Scholar 

  32. Hamberg, M., Sanz, A., and Castresana, C. (1999) α-Oxidation of Fatty Acids in Higher Plants: Identification of a Pathogen-Inducible Oxygenase (PIOX) as an α-Dioxygenase and Biosynthesis of 2-Hydroperoxylinolenic acid, J. Biol. Chem. 274, 24503–24513.

    Article  PubMed  CAS  Google Scholar 

  33. Grechkin, A.N., Mukhtarova, L.S., and Hamberg, M. (2005) Thermal Conversions of Trimethylsilyl Peroxides of Linoleic and Linolenic Acids, Chem. Phys. Lipids 138, 93–101.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Kazan Institute of Biochemistry and Biophysics, Russian Academy of Sciences, 420111, Kazan, Russia

    Ivan R. Chechetkin & Alexander N. Grechkin

  2. Departamento Biología Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay

    Inés Ponce de León

  3. Centro Nacional de Biotecnología, Consejo Superior de Investigaciónes Cientificas, Campus Universidad Autónoma, 28049, Cantoblanco, Madrid, Spain

    Carmen Castresana & Gerard Bannenberg

  4. Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-17177, Stockholm, Sweden

    Mats Hamberg

Authors
  1. Mats Hamberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivan R. Chechetkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander N. Grechkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inés Ponce de León
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carmen Castresana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerard Bannenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mats Hamberg.

About this article

Cite this article

Hamberg, M., Chechetkin, I.R., Grechkin, A.N. et al. Synthesis of 3-oxalinolenic acid and β-oxidation-resistant 3-oxa-oxylipins. Lipids 41, 499–506 (2006). https://doi.org/10.1007/s11745-006-5123-5

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-006-5123-5

Keywords

Search

Navigation