Applied Microbiology and Biotechnology

, Volume 85, Issue 4, pp 869–883 | Cite as

Biotechnological production and applications of statins

Mini-Review

Abstract

Statins are a group of extremely successful drugs that lower cholesterol levels in blood; decreasing the risk of heath attack or stroke. In recent years, statins have also been reported to have other biological activities and numerous potential therapeutic uses. Natural statins are lovastatin and compactin, while pravastatin is derived from the latter by biotransformation. Simvastatin, the second leading statin in the market, is a lovastatin semisynthetic derivative. Lovastatin is mainly produced by Aspergillus terreus strains, and compactin by Penicillium citrinum. Lovastatin and compactin are produced industrially by liquid submerged fermentation, but can also be produced by the emerging technology of solid-state fermentation, that displays some advantages. Advances in the biochemistry and genetics of lovastatin have allowed the development of new methods for the production of simvastatin. This lovastatin derivative can be efficiently synthesized from monacolin J (lovastatin without the side chain) by a process that uses the Aspergillus terreus enzyme acyltransferase LovD. In a different approach, A. terreus was engineered, using combinational biosynthesis on gene lovF, so that the resulting hybrid polyketide synthase is able to in vivo synthesize 2,2-dimethylbutyrate (the side chain of simvastatin). The resulting transformant strains can produce simvastatin (instead of lovastatin) by direct fermentation.

Keywords

Statins Biosynthesis and genetics Biotechnological production 

References

  1. Abe Y, Suzuki T, Ono C, Iwamoto K, Hosobuchi M, Yoshikawa H (2002) Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum. Mol Gen Genomics 267:636–646CrossRefGoogle Scholar
  2. Adibhatla RM, Hatcher JF (2008) Altered lipid metabolism in brain injury and disorders. Subcell Biochem 49:241–68CrossRefGoogle Scholar
  3. Alberts AW, Chen J, Kurov G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirschfield J, Hoofsteen KJ, Liesch J, Springer J (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957–3961CrossRefGoogle Scholar
  4. Askenazi M, Driggers EM, Holtzman DA, Norman TC, Iverson S, Zimmer DP, Boers ME, Blomquist PR, Martinez EJ, Monreal AW, Feibelman TP, Mayorga ME, Maxon ME, Sykes K, Tobin JV, Cordero E, Salama SR, Trueheart J, Royer JC, Madden KT (2003) Integrating transcriptional and metabolite profiles to direct the engineering of lovastatin-producing fungal strains. Nat Biotechnol 21:150–156CrossRefGoogle Scholar
  5. Baba S, Nihita T, Hosobuchi M (2008) Identification of the specific sequence recognized by MlcR, a GAL4-type transcriptional activator of ML-236B (compactin) biosynthetic genes. Fungal Genet Biol 45:1277–1283CrossRefGoogle Scholar
  6. Baba S, Abe Y, Suzuki T, Ono C, Iwamoto K, Nihira T, Hosobuchi M (2009) Improvement of compactin (ML-236B) production by genetic engineering in compactin high-producing Penicillium citrinum. Appl Microbiol Biotechnol 83:697–704CrossRefGoogle Scholar
  7. Balakrishna K, Pandey A (1996) Production of biologically active secondary metabolites in solid state fermentation. J Sci Ind Res 55:365–372Google Scholar
  8. Baños JG, Tomasini A, Szakács G, Barrios-González J (2009) High lovastatin production by Aspergillus terreus in solid-state fermentation on polyurethane foam: an artificial inert support. J Biosci Bioeng 108:105–110CrossRefGoogle Scholar
  9. Barrios-González J, Mejía A (1996) Secondary metabolites production by solid state fermentation. Biotechnol Annual Rev 2:85–121CrossRefGoogle Scholar
  10. Barrios-González J, Mejía A, Larroche C (2007) Production of antibiotics and other commercially valuable secondary metabolites. In: Pandey A, Soccol C (eds) Current Developments in Solid-State Fermentation. Asiatech Publishers, Inc, New Delhi, pp 262–296Google Scholar
  11. Barrios-González J, Fernández FJ, Tomasini A (2003) Production of microbial secondary metabolites and strain improvement. J Biotechnol Special Issue: Microbial Biotechnology 2:322–333Google Scholar
  12. Barrios-González J, Baños JG, Covarrubias AA, Garay-Arroyo A (2008) Lovastatin biosynthetic genes of Aspergillus terreus are differentially expressed in solid-state and in liquid submerged fermentation. Appl Microbiol Biotechnol 79:179–186CrossRefGoogle Scholar
  13. Becker C, Jick SS, Meier CR (2008) Use of statins and the risk of Parkinson’s disease: a retrospective case-control study in the UK. Drug Saf 31:399–407CrossRefGoogle Scholar
  14. Bigelis R, He H, Yang HY, Chang LP, Greenstein M (2006) Production of fungal antibiotics using polymeric solid supports in solid-state and liquid fermentation. J Ind Microbiol Biotechnol 33:815–826CrossRefGoogle Scholar
  15. Bizukojc M, Ledakowicz S (2008) Biosynthesis of lovastatin and (+)-geodin by Aspergillus terreus in batch and fed-batch culture in the stirred tank bioreactor. Biochem Eng J 42:198–207CrossRefGoogle Scholar
  16. Bizukojc M, Ledakowics S (2009) Physiological, morphological and kinetic aspects of lovastatin biosynthesis by Aspergillus terreus. Biotechnol J 4:647–664CrossRefGoogle Scholar
  17. Bonovas S, Filioussi K, Tsavaris N, Sitaras NM (2006) Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol 24:4808–4817CrossRefGoogle Scholar
  18. Buckland B, Gbewonyo K, Hallada T, Kaplan L, Musurekar P (1989) Production of lovastatin, an inhibitor of cholesterol accumulation in humans. In: Demain AL, Somkuti GA, Hunter-Cevera JC, Rossmoore HW (eds) Novel Microbial Products for Medicine and Agriculture. Elsevier, Amsterdam, pp 161–169Google Scholar
  19. Burr DA, Chen XB, Vederas JC (2007) Syntheses of conjugated pyrones for the enzymatic assay of lovastatin nonaketide synthase, an iterative polyketide synthase. Org Lett 9:161–164CrossRefGoogle Scholar
  20. Casas-López JL, Sánchez-Pérez JA, Fernández-Sevilla JM, Acién-Fernández FG, Molina-Grima E, Chisti Y (2003) Production of lovastatin by Aspergillus terreus: effects of the C:N ratio and the principal nutrients on growth and metabolite production. Enzyme Microb Technol 33:270–277CrossRefGoogle Scholar
  21. Casas-López JL, Sánchez-Pérez JA, Fernández-Sevilla JM, Acién-Fernández FG, Molina-Grima E, Chisti Y (2004) Fermentation optimization for the production of lovastatin by Aspergillus terreus: use of response surface methodology. J Chem Technol Biotechnol 79:1119–1126CrossRefGoogle Scholar
  22. Casas-López JL, Sánchez-Pérez JA, Fernández-Sevilla JM, Rodríguez-Porcel EM, Chisti Y (2005) Pellet morphology, culture rheology and lovastatin production in cultures of Aspergillus terreus. J Biotechnol 116:61–77CrossRefGoogle Scholar
  23. Chakravarti R, Sahai1 V (2004) Compactin—a review. Appl Microbiol Biotechnol 64:618–624Google Scholar
  24. Chan JK, Moore RN, Nalashima TT, Vederas JC (1983) Biosynthesis of mevinolin. Spectral assignment by double-quantum coherence NMR after high carbon-13 incorporation. J Am Chem Soc 105:3334–3336CrossRefGoogle Scholar
  25. Chen CH, Hu HY, Cho YC, Hsu WH (2006) Screening of compactin-resistant microorganisms capable of converting compactin to pravastatin. Curr Microbiol 53:108–112CrossRefGoogle Scholar
  26. Couch RD, Gaucher GM (2004) Rational elimination of Aspergillus terreus sulochrin production. J Biotechnol 108:171–177CrossRefGoogle Scholar
  27. Cummings SR, Bauer DC (2000) Do statins prevent both cardiovascular disease and fracture? JAMA 283:3255–3257CrossRefGoogle Scholar
  28. Davignon J, Leiter LA (2005) Ongoing clinical trials of the pleiotropic effects of statins. Vasc Health Risk Manag 1:29–40CrossRefGoogle Scholar
  29. Dulak J, Józkowicz A (2005) Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr Cancer Drug Targets 5:579–594CrossRefGoogle Scholar
  30. Durand A (2003) Bioreactor designs for solid state fermentation. Biochem Eng J 13:113–125CrossRefGoogle Scholar
  31. Edwards CJ, Spector TD (2002) Statins as modulators of bone formation. Arthritis Res 4:151–153CrossRefGoogle Scholar
  32. Endo A, Kuroda M, Tanzawa K (1976) Competitive inhibition of 3-hydroxy-3methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites having hypocholesterolemic activity. FEBS Lett 72:323–326CrossRefGoogle Scholar
  33. Endo A, Negishi Y, Iwashita T, Mizukawa K, Hirama M (1985) Biosynthesis of ML-236B (compactin) and monacolin K. J Antibiot (Tokyo) 38:444–448Google Scholar
  34. Endo A, Terahara A, kitano N, Ogiso A, Mitsui S (1979) ML236B carboxylic acid derivatives and their use as antihyperlipidemic agents. U.S. Patent 4,137,322Google Scholar
  35. Farnier M, Davignon J (1998) Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol 82:3J–10CrossRefGoogle Scholar
  36. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 98:5856–5861CrossRefGoogle Scholar
  37. Furberg CD (1999) Natural statins and stroke risk. Circulation 99:185–188Google Scholar
  38. Galán M, Taix F, Carrascosa F (2004) Estatinas: eficacia, seguridad e indicaciones. Inf Ter Sist Nac Salud 28:89–100Google Scholar
  39. Giovannozzi S, Tiso N (2007) Aspects of design of bioreactors in SSF. In: Pandey A, Larroche C, Soccol CR (eds) Current Developments in Solid-State Fermentation. Asiatech Publishers, Inc, New Delhi, pp 117–144Google Scholar
  40. Glynn SA, O'Sullivan D, Eustace AJ, Clynes M, O'Donovan N (2008) The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells. BMC Cancer 8:9. doi:10.1186/1471-2407-8-9 CrossRefGoogle Scholar
  41. Greenspan MD, Yudrovitz JB (1985) Mevinolinic acid biosynthesis by Aspergillus terreus and its relationship to fatty acid biosynthesis. J Bacteriol 162:704–707Google Scholar
  42. Hendrickson L, Davis CR, Roach C, Nguyen DK, Aldrich T, McAda PC, Reeves CD (1999) Lovastatin biosynthesis in Aspergillus terreus: characterization of blocked mutants, enzyme activities and multifunctional polyketide synthase gene. Chem Biol 6:429–439CrossRefGoogle Scholar
  43. Herold S (2007) Prescriptions for Cholesterol Drugs Rise with New Generics. In: Consumers Reports. Best Buy Drugs. The Statins. Available on line. http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/Statins. Accessed Feruary 13, 2007
  44. Hesseltine CW (1977a) Solid-state fermentation. Part 1. Proc Biochem 12:24–27Google Scholar
  45. Hesseltine CW (1977b) Solid-state fermentation. Part 2. Proc Biochem 12:29–32Google Scholar
  46. Höglund K, Wiklund O, Vanderstichele H et al (2004) Plasma levels of β-amyloid (1–40), β-amyloid (1–42), and total β- amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol 61:333–337CrossRefGoogle Scholar
  47. Hölke U, Höfer M, Lenz J (2004) Biotechnological advantages of laboratory-scale solid-state fermentation with fungi. Appl Microbiol Biotechnol 64:175–186 Hesseltine 1977a; 1977bCrossRefGoogle Scholar
  48. Hölker U, Lenz J (2005) Solid-state fermentation—are there any biotechnological advantages? Current Opinion in Microbiology 8:301–306CrossRefGoogle Scholar
  49. Hosobuchi M, Shiori T, Ohyama J, Arai M, Iwado S, Yoshikawa H (1993a) Production of ML-236B, and inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, by Penicillium citrinum: improvement of strain and culture conditions. Biosci Biotechnol Biochem 57:1414–1419CrossRefGoogle Scholar
  50. Hosobuchi M, Kurosawa K, Yoshikawa H (1993b) Application of computer to monitoring and control of fermentation process: microbial conversion of ML-236B to pravastatin. J Ferment Bioeng 76:482–486CrossRefGoogle Scholar
  51. Hosobuchi M, Ogawa K, Yoshikawa H (1993c) Morphology study in production of ML-236B, a precursor of pravastatin sodium by Penicillium citrinum. J Ferment Bioeng 76:470–475CrossRefGoogle Scholar
  52. Huang X, Chen H, Miller WC et al (2007) Lower low-density lipoprotein cholesterol levels are associated with Parkinson´s disease. Mov Disord 22:377–81CrossRefGoogle Scholar
  53. Hutchinson CR, Kennedy J, Park C, Kendrew G, Auclair K, Vederas JC (2000) Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases. Antonie van Leeuwenhoek 78:287–295CrossRefGoogle Scholar
  54. Jick SS, Choi H, Li L, McInnes IB, Sattar N (2009) Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann Rheum Dis 68:546–551CrossRefGoogle Scholar
  55. Kannel WB, Dawber TR, Kaban A, Revotskie SJL (1961) Factors of risk in the development of coronary heart disease —six year follow up experience; the Farmingham Study. Ann Intern Med 40:602–609Google Scholar
  56. Keller NP, Hohn TM (1997) Metabolic pathway gene clusters in filamentous fungi. Fungal Genet Biol 21:17–29CrossRefGoogle Scholar
  57. Kennedy J, Auclair K, Kendrew G, Cheonseok P, Vederas JC, Hutchinson CR (1999) Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284:1368–1372CrossRefGoogle Scholar
  58. Kidd J (2006) Life after statin patent expiries. Nature Revs/Drug Discovery 5:813–814CrossRefGoogle Scholar
  59. Kimura K, Komagata D, Murakawa S, Endo A (1990) Biosynthesis of monacolins: conversion of monacolin J to monacolin K (mevilonil). J Antibiot (Tokyo) 43:1621–1622Google Scholar
  60. Kodaman PH, Duleba AJ (2008) Statins in the treatment of polycystic ovary syndrome. Semin Reprod Med 26(1):127–38CrossRefGoogle Scholar
  61. Komagata D, Shimada H, Murakawa S, Endo A (1989) Biosynthesis of monacolins: conversion of monacolin L to monacolin J by a monooxygenase of Monascus ruber. J Antibiot (Tokyo) 42:407–412Google Scholar
  62. Kumar MS, Jana SK, Senthil V, Shashanka V, Kumar SV, Sadhukhan (2000) Repeated fed-batch process for improving lovastatin production. Process Biochem 36:363–368CrossRefGoogle Scholar
  63. Lai LST, Pan CC, Tzeng BK (2003) The influence of medium design on lovastatin production and pellet formation with a high producing mutant of Aspergillus terreus in submerged cultures. Process Biochem 38:1317–1326CrossRefGoogle Scholar
  64. Leung BP, Sattar N, Crilly A et al (2003) A Novel Anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170:1524–1530Google Scholar
  65. Lin YL, Wang TH, Lee MH, Su NW (2008) Biologically active components and nutraceuticals in the Monascus-fermented rice: a review. Appl Microbiol Biotechnol 77:965–973CrossRefGoogle Scholar
  66. Ma SM, Tang Y (2007) Biochemical characterization of the minimal polyketide synthase domains in the lovastatin nonaketide synthase LovB. FEBS Journal 274:2854–28CrossRefGoogle Scholar
  67. Manzoni M, Rollini M (2002) Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol 58:555–564CrossRefGoogle Scholar
  68. Manzoni M, Rollini M, Bergomi S, Cavazzoni V (1998) Production and purification of statins from Aspergillus terreus strains. Biotechnol Techniques 12:529–532CrossRefGoogle Scholar
  69. Maron DJ, Fazio S, Linton MF (2000) Current perspective on statins. Circulation 101:207–213Google Scholar
  70. Masahiko H, Ogawa K, Yoshikawa H (1993) Application of computer to monitoring and control of fermentation process: microbiological conversion of ML-236B Na to pravastatin. Biotechnol Bioeng 42:815–820CrossRefGoogle Scholar
  71. Metkinen (2009) Available on line. http://www.metkinen.fi/. Accessed September 1, 2009
  72. Mistry K (2007) Statins have once again hit the news. Yale Scientific Magazine 81.2.Google Scholar
  73. Monaghan R, Alberts L, Hoffman AW, Carl H, Albers-Schonberg G (1981) Hypocholesteremic fermentation products and process of preparation. US Patent 4294926Google Scholar
  74. Massy ZA, Guijarro C (2001) Statins: effects beyond cholesterol lowering. Nephrol Dial Transplant 16:1738–1741CrossRefGoogle Scholar
  75. McCarey DW, Sattar N, McInnes IB (2005) Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases? Arthritis Res Ther 7:55–61CrossRefGoogle Scholar
  76. Moore RN, Bigam G, Chan JK, Hogg AM, Nakashima TT, Vederas JC (1985) Biosynthesis of the hypocholesterolemic agent mevinolin by by Aspergillus terreus. Determination of the origin of carbon, hydrogen, and oxygen atoms by 13C NMR and mass spectrometry. J Am Chem Soc 107:3694–3701CrossRefGoogle Scholar
  77. Moride Y, Hegele RA, Langer A, McPherson R, Miller DB, Rinfret S (2008) Clinical and public health assessment of benefits and risks of statins in primary prevention of coronary events: Resolved and unresolved issues. Can J Cardiol 24:293–300Google Scholar
  78. Mundy G, Garrett R, Harris S et al (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949CrossRefGoogle Scholar
  79. Nash DT (2005) Relationship of C-reactive protein, metabolic syndrome and diabetes mellitus: potential role of statins. J Natl Med Assoc 97:1600–1607Google Scholar
  80. Negishi S, Huang ZC, Hasumi K, Murakawa S, Endo A (1986) Productivity of monacolin K (mevinolin) in the genus Monascus. J Fement Eng 64:509–511Google Scholar
  81. Neuhaus O, Hartung HP (2007) Evaluation of atorvastatin and simvastatin for treatment of multiple sclerosis. Expert Rev Neurother 7:547–56CrossRefGoogle Scholar
  82. Novak N, Gerdin S, Berovic M (1997) Increased lovastatin formation by Aspergillus terreus using repeated fed-batch process. Biotechnol Lett 19:947–948CrossRefGoogle Scholar
  83. Ooijkaas LP, Weber FJ, Buitelaar RM, Tramper J, Rinzema A (2000) Defined media and inert supports: their potential as solid-state fermentation production systems. Trends Biotechnol 18:356–360CrossRefGoogle Scholar
  84. Pahan K (2006) Lipid-lowering drugs. Cell Mol Life Sci 63:1165–1178CrossRefGoogle Scholar
  85. Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary ostrocytes, microglia, and macrophages. J Clin Invest 100:2671–9CrossRefGoogle Scholar
  86. Pandey A, Larroche C, Soccol C (2007) General considerations about solid-state fermentation processes. In: Pandey A, Larroche C, Soccol CR (eds) Current Developments in Solid-State Fermentation. New Delhi, Asiatech Publishers Inc, pp 13–25Google Scholar
  87. 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 25:1827–1831CrossRefGoogle Scholar
  88. Pedrini S, Carter TL, Prendergast G et al (2005) Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLos Med 2(1):e81. doi:10.1371/journal.pmed.0020018 CrossRefGoogle Scholar
  89. Robinson T, Singh D, Nigam P (2001) Solid-state fermentation a promising microbial technology for secondary metabolite production. Appl Microbiol Biotechnol 55:284–289CrossRefGoogle Scholar
  90. Rodríguez-Porcel EM, Casas-López JL, Sánchez-Pérez JA, Fernández-Sevills JM, Chisti Y (2005) Effects of pellet morphology on broth rheology in fermentations of Aspergillus terreus. Biochem Eng J 26:139–144CrossRefGoogle Scholar
  91. Rodríguez-Porcel EM, Casas-López JL, Sánchez-Pérez JA, Chisti Y (2007) Enhanced production of lovastatin in a bubble column by Aspergillus terreus using two-stage feeding strategy. J Chem Technol Biotechnol 82:58–64CrossRefGoogle Scholar
  92. Seenivasan A, Subhagar S, Aravindan R, Viruthagiri T (2008) Microbial production and biomedical applications of lovastatin. Indian J Pharm Sci 70:701–709CrossRefGoogle Scholar
  93. Serizawa N, Nakagawa K, Hamano K, Tsujita Y, Terahara A, Kuwano H (1983) Microbial hydroxylation of ML-236B (compactin) and monacolin K (MB-530 B). J Antibiot 36:604–607Google Scholar
  94. Serizawa N, Watanabe I (1997) Actinomycete promoter. European Patent EP0776974 (A2)Google Scholar
  95. Shaligram S, Sudheer KS, Rekha SS, Szakacs G, Pandey A (2008) Compactin production in solid-state fermentation using orthogonal array method by P. brevicompactum. Biochem Eng J 41:295–300CrossRefGoogle Scholar
  96. Shiao M, Don H (1987) Biosynthesis of mevinolin, a hypocholesterolemic fungal metabolite, in Aspergillus terreus. Proc Nat Sci Counc 11:223–231Google Scholar
  97. Staunton J, Weissman KJ (2001) Polyketide biosynthesis: a millennium review. Nat Prod Rep 18:380–416CrossRefGoogle Scholar
  98. Suryanarayan S (2003) Current industrial practice in solid state fermentations for secondary metabolite production: the Biocon India experience. Biochem Eng J 13:189–195CrossRefGoogle Scholar
  99. Turesson C, Jacobsson LTH, Matteson EL (2008) Cardiovascular co-morbidity in rheumatic diseases. Vasc Heal Risk Manag 4:605–614Google Scholar
  100. Van den Berg MA, Hans M, Streekstra H (2007) Metod for the production of simvastatin. International Patent WO 2007147801 A1Google Scholar
  101. Vinci VA, Hoerner TD, Coffman AD, Schimmel TG, Dabora RL, Kirpekar AC, Ruby CL, Stieber RW (1999) Mutants of a lovastatin-hyperproducing Aspergillus terreus deficient in the production of sulochrin. J Ind Micro 8:113–120CrossRefGoogle Scholar
  102. Wang CY, Liu PY, Liao JK (2008) Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 14:37–44CrossRefGoogle Scholar
  103. Wolozin B (2002) Cholesterol and Alzheimer´s disease. Biochem Soc Trans 30:525–529CrossRefGoogle Scholar
  104. Xie X, Watanabe K, Wojcicki WA, Wand CC, Tang Y (2006) Biosynthesis of lovastatin analogs with a broad specificity acyltransferase. Chem Biol 13:1161–1169CrossRefGoogle Scholar
  105. Xie X, Tang Y (2007) Efficient synthesis of simvastatin using whole-cell biocatalysis. Appl Environ Microbiol 73:2054–2060CrossRefGoogle Scholar
  106. Xie X, Wong W, Tang Y (2007) Improving simvastatin bioconversion in Escherichia coli by deletion of bioH. Metabol Eng 9:379–386CrossRefGoogle Scholar
  107. Xie X, Pashkov I, Gao X, Guerrero JL, Yeates TO, Tang Y (2009a) Rational improvement of simvastatin synthase solubility in Escherichia coli leads to higher whole-cell biocatalyctic activity. Biotechnol Bioeng 102:20–28CrossRefGoogle Scholar
  108. Xie X, Meehan MJ, Xu W, Dorrestein PC, Tang Y (2009b) Acyltransferase-mediated polyketide release from a fungal megasynthase. J Am Chem Soc 131:8388–8389CrossRefGoogle Scholar
  109. Ykema A, Streekstra H, Luiten RGM (1999) Statin production by fermentation. International Patent WO/1999/010499Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Departamento de BiotecnologíaUniversidad Autónoma MetropolitanaIztapalapaMexico

Personalised recommendations