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.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Alberts AW (1990) Lovastatin and simvastatin—inhibitors of HMG CoA reductase and cholesterol biosynthesis. Cardiology 77:14–21
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
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
Berger S, Braun S (2004) 200 and more NMR experiments: a practical course. Wiley–VCH, Weinhei
Bousquet P, Gayet JL (2003) Pharmacologic characteristics of rosuvastatin, a new HMG–CoA reductase inhibitor. Therapie 58:113–121
Chapman MJ, McTaggart F (2002) Optimizing the pharmacology of statins: characteristics of rosuvastatin. Atheroscler Suppl 2:33–36
Davidson MH (2002) Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drug 11:125–141
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
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
Ferris MJ (1990) Process for the preparation of 6-alpha-hydroxymethyl lovastatin derivatives. European Patent Application A1 0381478
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
Gunde-Cimerman N, Plemenitas A, Cimerman A (1993) Pleurotus fungi produce mevinolin, an inhibitor of HGM CoA reductase. FEMS Microbiol Lett 133:333–338
Hajjaj H, Niederberger P, Duboc P (2001) Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Environ Microbiol 67:2596–2602
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
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
Istvan E (2003) Statin inhibition of HMG–CoA reductase: a 3-dimensional view. Atheroscler Suppl l4:3–8
Istvan ES, Deisenhofer J (2007) Structural mechanism for statin inhibition of HMG–CoA reductase. Science 292:1160–1164
Jekkel A, Kónya A, Ilkóy E, Boros S, Horváth G, Sütó J (1997) Microbial conversion of mevinolin. J Antibiot 50:750–754
Joshua H, Schwartz MS, Wilson KE (1991) L-669, 262, a potent HMG–CoA reductase inhibitor. J Antibiot 44:366–370
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
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
Lorke DA (1983) New approach to practical acute toxicity testing. Arch Toxicol 54:275–287
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
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
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
Miyadoh S, Hamada M, Hotta K, Kudo T, Seino A, Vobis G, Yokota A (1997) Atlas of Actinomycetes. Asakura, Tokyo
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
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
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
Peng Y, Demain AL (2000) Bioconversion of compactin to pravastatin by Actinomadura sp. ATCC 55678. J Mol Catal B Enzym 10:151–156
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
Rosenson RS (2003) Rosuvastatin: a new inhibitor of HMG–CoA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 1:495–505
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
Terahara, Tanaka, Minoru (1985) Process for preparing 3-hydroxy-ML-236B derivatives known as M-4 and M-4′. US Patent 4,537,859
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
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
Williamson JM (1989) HMG–CoA reductase inhibitor produced by Nocardia sp.(MA6455). European Patent A20337548
Zhuge J, Fang HY, Yu H. (2004) Amycolatosis and biological conversion of lovastatin into wuxistatin thereby. Chinese Patent Zl 200410044893.6
We thank Prof. B. A. Prior (Department of Microbiology, University of Stellenbosch, South Africa) for the assistance in the revision of the manuscript.
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
- Amycolatopsis sp.
- HMG–CoA reductase