Skip to main content
Springer Nature Link
Log in

Homology modeling of 5-lipoxygenase and hints for better inhibitor design

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Lipoxygenases (LOXs) are a group of enzymes involved in the oxygenation of polyunsaturated fatty acids. Among these 5-lipoxygenase (5-LOX) is the key enzyme leading to the formation of pharmacologically important leukotrienes and lipoxins, the mediators of inflammatory and allergic disorders. In view of close functional similarity to mammalian lipoxygenase, potato 5-LOX is used extensively. In this study, the homology modeling technique has been used to construct the structure of potato 5-LOX. The amino acid sequence identity between the target protein and sequence of template protein 1NO3 (soybean LOX-3) searched from NCBI protein BLAST was 63%. Based on the template structure, the protein model was constructed by using the Homology program in InsightII. The protein model was briefly refined by energy minimization steps and validated using Profile-3D, ERRAT and PROCHECK. The results showed that 99.3% of the amino acids were in allowed regions of Ramachandran plot, suggesting that the model is accurate and its stereochemical quality good. Like all LOXs, 5-LOX also has a two-domain structure, the small N-terminal β-barrel domain and a larger catalytic domain containing a single atom of non-heme iron coordinating with His525, His530, His716 and Ile864. Asn720 is present in the fifth coordination position of iron. The sixth coordination position faces the open cavity occupied here by the ligands which are docked. Our model of the enzyme is further validated by examining the interactions of earlier reported inhibitors and by energy minimization studies which were carried out using molecular mechanics calculations. Four ligands, nordihydroguaiaretic acid (NDGA) having IC50 of 1.5 μM and analogs of benzyl propargyl ethers having IC50 values of 760 μM, 45 μM, and no inhibition respectively were selected for our docking and energy minimization studies. Our results correlated well with the experimental data reported earlier, which proved the quality of the model. This model generated can be further used for the design and development of more potent 5-LOX inhibitors.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gerwick WH (1994) Biochim Biophys Acta 1211:243

    CAS  Google Scholar 

  2. De Petrocellis L, Di Marzo V (1994) Prostaglandins Leukot Essent Fatty Acids 51:215

    Article  Google Scholar 

  3. Funk CD (1996) Biochim Biophys Acta 1304:65

    Google Scholar 

  4. Yamamoto S, Suzuki H, Ueda N (1997) Prog Lipid Res 36:23

    Article  CAS  Google Scholar 

  5. Zimmerman DC, Vick BA (1973) Lipids 8:264

    Article  CAS  Google Scholar 

  6. Krieg P, Kinzig A, Heidt M, Marks F, Fürstenberger G (1998) Biochim Biophys Acta 1391:7

    CAS  Google Scholar 

  7. Boeglin WE, Kim RB, Brash AR (1998) Proc Natl Acad Sci USA 95:6744

    Article  CAS  Google Scholar 

  8. Sun D, Elsea SH, Patel PI, Funk CD (1998) Cytogenet Cell Genet 81:79

    Article  CAS  Google Scholar 

  9. Reddanna P, Whelan J, Maddipati KR, Reddy CC (1990) Methods Enzymol 187:268

    Article  CAS  Google Scholar 

  10. Chen X, Reddanna P, Reddy GR, Kidd R, Hildebrandt G, Reddy CC (1998) Biochem Biophys Res Commun 243:438

    Article  CAS  Google Scholar 

  11. Whelan J, Reddanna P, Nikolaev V, Hildebrandt G, Reddy CC (1988) In: Reddy CC, Hamilton GA, Madyastha KM (eds) Biological oxidation systems, vol 2. Academic Press, San Diego, CA, p 765

    Google Scholar 

  12. Nikolaev V, Reddanna P, Whelan J, Hildebrandt G, Reddy CC (1990) Biochem Biophys Res Commun 170:491

    Article  CAS  Google Scholar 

  13. Rapoport SM, Schewe T, Wiesner R, Halangk W, Ludwig P, Janicke-Höhne M, Tannert C, Hiebsch C, Klatt D (1979) Eur J Biochem 96:545

    Article  CAS  Google Scholar 

  14. Brash AR (1999) J Biol Chem 274:23679

    Article  CAS  Google Scholar 

  15. Shibata D, Axelrod B (1995) J Lipid Mediat Cell Signal 12:213

    Article  CAS  Google Scholar 

  16. Minor W, Steczko J, Stec B, Otwinowski Z, Bolin JT, Walter R, Axelrod B (1996) Biochemistry 35:10687

    Article  CAS  Google Scholar 

  17. Prigge ST, Boyington JC, Faig M, Doctor KS, Gaffney BJ, Amzel LM (1997) Biochimie 79:629

    Article  CAS  Google Scholar 

  18. Sunitha M, Matthias W, Igor I, Sven H, Gerhard F, Peter K, Reddanna P, Hartmut K (2005) J Biol Chem 280:36633

    Article  CAS  Google Scholar 

  19. Bigby TD, Levy BD, Serhan CN (1998) In: Drazen JM, Dahlén S-E, Lee TH (eds) Five-lipoxygenase products in asthma. Marcel Dekker, New York, p 125

    Google Scholar 

  20. Funk CD (2001) Science 294:1871

    Article  CAS  Google Scholar 

  21. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK (1990) Nature 343:282

    Article  CAS  Google Scholar 

  22. Chang M, Rao MK, Reddanna P, Li CH, Tu CP, Corey EJ, Reddy CC (1987) Arch Biochem Biophys 259:536

    Article  CAS  Google Scholar 

  23. Reddanna P, Sandeep Prabhu K, Whelan J, Reddy CC (2003) Arch Biochem Biophys 413:158

    Article  CAS  Google Scholar 

  24. Fitzaimmons BJ, Rokach J (1989) In: Rokach J (ed) Leukotrienes and lipoxygenases. Elsevier, New York, NY, p 427

    Google Scholar 

  25. Reddanna P, Rao MK, Reddy CC (1985) FEBS Lett 193:39

    Article  CAS  Google Scholar 

  26. Barhate NB, Reddy CM, Reddy PS, Wakharkar RD, Reddanna P (2002) Indian J Biochem Biophys 39:264

    CAS  Google Scholar 

  27. Du L, Zhang Z, Luo X, Chen K, Shen X, Jiang H (2006) J Biol Chem 139:715

    CAS  Google Scholar 

  28. Hammarberg T, Provost P, Persson B, Rådmark O (2000) J Biol Chem 295:38787

    Article  Google Scholar 

  29. Hemak J, Gale D, Brock TG (2002) J Mol Model 8:102

    Article  CAS  Google Scholar 

  30. Bindu PH, Sastry GM, Sastry GN (2004) Biochem Biophys Res Commun 320:461

    Article  CAS  Google Scholar 

  31. Werz O, Tretiakova I, Michel A, Ulke-Lemee A, Hörnig M, Franke L, Schneider G, Samuelsson B, Rådmark O, Steinhilber D (2005) Proc Natl Acad Sci USA 102:13164

    Article  CAS  Google Scholar 

  32. Skrzypczak-Jankun E, Borbulevych OY, Jankun J (2004 Acta Crystallogr D Biol Crystallogr 60:613

    Article  CAS  Google Scholar 

  33. INSIGHT II. (2000) Molecular Modeling Software. Accelrys, Inc., San Diego, USA

    Google Scholar 

  34. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235

    Article  CAS  Google Scholar 

  35. Homology user guide, Accelrys, Inc., San Diego, USA (1999)

  36. CHARMM user guide, Accelrys, Inc., San Diego, USA (1999)

  37. Profile-3D user guide, Accelrys, Inc., San Diego, USA (1999)

  38. Laskowski RA, Moss DS, Thornton JM (1993) J Mol Biol 231:1049

    Article  CAS  Google Scholar 

  39. Colovos C, Yeates TO (1993) Protein Sci 2:1511

    CAS  Google Scholar 

  40. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727

    Article  CAS  Google Scholar 

  41. Sansom CE, Wu J, Weber IT (1992) Protein Eng 5:659

    Article  CAS  Google Scholar 

  42. Montgomery JA, Niwas S, Rose JD, Secrist JA 3rd, Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE (1993) J Med Chem 36:55

    Article  CAS  Google Scholar 

  43. Erion MD, Stoeckler JD, Guida WC, Walter RL, Ealick SE (1997) Biochemistry 36:11735

    Article  CAS  Google Scholar 

  44. Reddy MR, Viswanadhan VN, Erion MD (1998) In: Kubinyi H, Folkers G, Martin YC (eds) 3D QSAR in drug design, vol 2. Kluwer Academic Publishers, New York, NY, p 85

    Chapter  Google Scholar 

  45. Reddy RN, Mutyala R, Aparoy P, Reddanna P, Reddy MR (2007) Curr Pharm Des 13:3505

    Article  CAS  Google Scholar 

  46. Reddy MR, Erion MD (2005) Curr Pharm Des 11:283

    Article  CAS  Google Scholar 

  47. Reddy MR, Erion MD (2001) J Am Chem Soc 123:6246

    Article  CAS  Google Scholar 

  48. Singh UC, Weiner PK, Caldwell JK, Kollman PA (1986) AMBER version 3.0. University of California, San Francisco, CA

    Google Scholar 

  49. Needleman SB, Wunch CD (1970) J Mol Biol 48:443

    Article  CAS  Google Scholar 

  50. Prigge ST, Boyington JC, Faig M, Doctor KS, Gaffney BJ (1997) Biochimie 79:629

    Article  CAS  Google Scholar 

  51. Zhang YY, Lind B, Radmark O, Samuelsson B (1993) J Biol Chem 268:2535

    CAS  Google Scholar 

  52. Hammerberg T, Zhang YY, Lind B, Radmark O, Samuelsson B (1995) Eur J Biochem 230:401

    Article  Google Scholar 

  53. QUANTA, Accelrys Inc., San Diego, CA, USA (2000)

  54. Brash AR (1999) J Biol Chem 274:23679

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants from Department of Biotechnology (DBT), Govt. of India (Grant # 37(1221)/05/EMR-II). We thank Centre for Modelling, Simulation and Design (CMSD), University of Hyderabad for permitting us to use the SGI workstation and InsightII facilities. We duly acknowledge Council of Scientific and Industrial Research (CSIR), Govt. of India for providing junior research fellowship to P. Aparoy.

Author information

Authors and Affiliations

  1. School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, India

    P. Aparoy & P. Reddanna

  2. Rational Labs (P) Limited, Plot # 177, IDA Mallapur, Hyderabad, 500 076, India

    R. N. Reddy & M. R. Reddy

  3. School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India

    Lalitha Guruprasad

Authors
  1. P. Aparoy
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. R. N. Reddy
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Lalitha Guruprasad
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. M. R. Reddy
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. P. Reddanna
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to P. Reddanna.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aparoy, P., Reddy, R.N., Guruprasad, L. et al. Homology modeling of 5-lipoxygenase and hints for better inhibitor design. J Comput Aided Mol Des 22, 611–619 (2008). https://doi.org/10.1007/s10822-008-9180-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-008-9180-0

Keywords