Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Bioconversion of lovastatin to a novel statin by Amycolatopsis sp.

  • 209 Accesses

  • 13 Citations

Abstract

3-Hydroxy-3-methylglutaryl–coenzyme A (HMG–CoA) reductase catalyzes the conversion of HMG–CoA to mevalonic acid, which plays a significant role in cholesterol synthesis. Several statins, inhibitors of HMG–CoA reductase, can be synthesized and converted by microorganisms. Among 700 strains obtained from culture collections, one strain could convert lovastatin to a novel statin, wuxistatin. The strain was identified as a member of the genus Amycolatopsis based on 16S rRNA gene sequence, morphology analysis, and chemotaxonomic properties. Wuxistatin, a novel HMG–CoA reductase inhibitor, was purified by chromatography, and the structure was determined by electrospray ionization mass and nuclear magnetic resonance spectroscopy. The results show that wuxistatin was butanoic acid, 2-methyl-,1,2,3,5,8,8a-hexahydro-5-hydroxy-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethy]-1-naphthalenyl ester. An additional hydroxyl group was added to lovastatin at the 5-position to yield wuxistatin. This modification enhanced the intrinsic inhibitory activity (IC50) of wuxistatin (41 ± 5 nM) for fourfold compared with lovastatin (160 ± 10 nM). A stoichiometric conversion of lovastatin to wuxistatin occurred.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Alberts AW (1990) Lovastatin and simvastatin—inhibitors of HMG CoA reductase and cholesterol biosynthesis. Cardiology 77:14–21

  2. Anderson JF, Tatsuta K, Gunji H, Ishiyama T, Hutchinson CR (1993) Substrate specificity of 6-deoxyerythronolide B hydroxylase, a bacterial cytochrome P450 of erythromycin A biosynthesis. Biochemistry 32:1905–1913

  3. Batal HA, Krantz MJ, Dale RA, Mehler PS, Steiner JF (2007) Impact of prescription size on statin adherence and cholesterol levels. BMC Health Serv Res 7:175

  4. Berger S, Braun S (2004) 200 and more NMR experiments: a practical course. Wiley–VCH, Weinhei

  5. Bousquet P, Gayet JL (2003) Pharmacologic characteristics of rosuvastatin, a new HMG–CoA reductase inhibitor. Therapie 58:113–121

  6. Chapman MJ, McTaggart F (2002) Optimizing the pharmacology of statins: characteristics of rosuvastatin. Atheroscler Suppl 2:33–36

  7. Davidson MH (2002) Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drug 11:125–141

  8. Edwards PA, Lemongello D, Fogelman AM (1979) Improved methods for the solubilization and assay of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase. J Lipid Res 20:40–46

  9. Endo A, Kuroda M, Tsujita Y (1976) ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J Antibiot (Tokyo) 29:1346–1348

  10. Ferris MJ (1990) Process for the preparation of 6-alpha-hydroxymethyl lovastatin derivatives. European Patent Application A1 0381478

  11. Frost FJ, Petersen H, Tollestrup K, Skipper B (2007) Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest 131:950–951

  12. Gunde-Cimerman N, Plemenitas A, Cimerman A (1993) Pleurotus fungi produce mevinolin, an inhibitor of HGM CoA reductase. FEMS Microbiol Lett 133:333–338

  13. Hajjaj H, Niederberger P, Duboc P (2001) Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Environ Microbiol 67:2596–2602

  14. Horiguchi A, Sumitomo M, Asakuma J, Asano T, Asano T, Hayakawa M (2004) 3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, fluvastatin, as a novel agent for prophylaxis of renal cancer metastasis. Clin Cancer Res 10:8648–8655

  15. Ishida W, Kajiwara T, Ishii M, Fujiwara F, Taneichi H, Takebe N, Takahashi K, Kaneko Y, Segawa I, Inoue H, Satoh J (2007) Decrease in mortality rate of chronic obstructive pulmonary disease (COPD) with statin use: a population-based analysis in Japan. Tohoku J Exp Med 212:265–73

  16. Istvan E (2003) Statin inhibition of HMG–CoA reductase: a 3-dimensional view. Atheroscler Suppl l4:3–8

  17. Istvan ES, Deisenhofer J (2007) Structural mechanism for statin inhibition of HMG–CoA reductase. Science 292:1160–1164

  18. Jekkel A, Kónya A, Ilkóy E, Boros S, Horváth G, Sütó J (1997) Microbial conversion of mevinolin. J Antibiot 50:750–754

  19. Joshua H, Schwartz MS, Wilson KE (1991) L-669, 262, a potent HMG–CoA reductase inhibitor. J Antibiot 44:366–370

  20. Kim B, Sahin N, Tan GY, Zakrzewska-Czerwinska J, Goodfellow M (2002) Amycolatopsis eurytherma sp. nov., a thermophilic actinomycete isolated from soil. Int J Syst Evol Microbiol 52:889–894

  21. Kodach LL, Bleuming SA, Peppelenbosch MP, Hommes DW, van den Brink GR, Hardwick JC (2007) The effect of statins in colorectal cancer is mediated through the bone morphogenetic protein pathway. Gastroenterology 133:1272–1281

  22. Lorke DA (1983) New approach to practical acute toxicity testing. Arch Toxicol 54:275–287

  23. Manzoni M, Rollini M (2002) Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol 58(5):555–64

  24. Mason NA, Bailie GR, Satayathum S, Bragg-Gresham JL, Akiba T, Akizawa T, Combe C, Rayner HC, Saito A, Gillespie BW, Young EW (2005) HMG–coenzyme A reductase inhibitor use is associated with mortality reduction in hemodialysis patients. Am J Kidney Dis 45:119–26

  25. Mendes MV, Anton N, Martin JF, Aparicio JF (2005) Characterization of the polyene macrolide P450 epoxidase from Streptomyces natalensis that converts de-epoxypimaricin into pimaricin. Biochem J 386:57–62

  26. Miyadoh S, Hamada M, Hotta K, Kudo T, Seino A, Vobis G, Yokota A (1997) Atlas of Actinomycetes. Asakura, Tokyo

  27. Park EJ, Lee D, Shin YG, Lantvit DD, van Breemen RB, Kinghorn AD, Pezzuto JM (2001) Analysis of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors using liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl 754:327–332

  28. Park JW, Lee JK, Kwon TJ, Yi DH, Kim YJ, Moon SH, Suh HH, Kang SM, Park YI (2003) Bioconversion of compactin into pravastatin by Streptomyces sp. Biotechnol Lett 25:1827–1831

  29. Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ (1990) Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG–CoA reductase inhibitors. J Lipid Res 31(7):1271–1282

  30. Peng Y, Demain AL (2000) Bioconversion of compactin to pravastatin by Actinomadura sp. ATCC 55678. J Mol Catal B Enzym 10:151–156

  31. Rainey FA, Ward-Rainey N, Kroppenstedt RM, Stackebrandt E (1996) The genus Nocardiopsis represents a phylogenetically coherent taxon and a distinct actinomycete lineage: proposal of Nocardiopsaceae fam. nov. Int J Syst Bacteriol 46:1088–1092

  32. Rosenson RS (2003) Rosuvastatin: a new inhibitor of HMG–CoA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 1:495–505

  33. Song H, Guo T, Zhang Y, Mi H, Zhang Q (1999) Studies on pharmacognostic identification and quality control standards for hongqu. Zhongguo Zhong Yao Za Zhi 24(5):262–265

  34. Terahara, Tanaka, Minoru (1985) Process for preparing 3-hydroxy-ML-236B derivatives known as M-4 and M-4′. US Patent 4,537,859

  35. Watanabe I, Serizawa N (1998) Molecular approaches for production of pravastatin, a HMG–CoA reductase inhibitor: transcriptional regulation of the cytochrome P450 sca gene from Streptomyces carbophilus by ML-236B sodium salt and phenobarbital. Gene 210:109–116

  36. Watanabe I, Nara F, Serizawa N (1995) Cloning, characterization and expression of the gene encoding cytochrome P-450sca-2 from Streptomyces carbophilus involved in the production of pravastatin, a specific HMG–CoA reductase inhibitor. Gene 163:81–85

  37. Williamson JM (1989) HMG–CoA reductase inhibitor produced by Nocardia sp.(MA6455). European Patent A20337548

  38. Zhuge J, Fang HY, Yu H. (2004) Amycolatosis and biological conversion of lovastatin into wuxistatin thereby. Chinese Patent Zl 200410044893.6

Download references

Acknowledgment

We thank Prof. B. A. Prior (Department of Microbiology, University of Stellenbosch, South Africa) for the assistance in the revision of the manuscript.

Author information

Correspondence to Jian Zhuge.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhuge, B., Fang, H.Y., Yu, H. et al. Bioconversion of lovastatin to a novel statin by Amycolatopsis sp.. Appl Microbiol Biotechnol 79, 209–216 (2008). https://doi.org/10.1007/s00253-008-1430-5

Download citation

Keywords

  • Amycolatopsis sp.
  • HMG–CoA reductase
  • Structure
  • Wuxistatin