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Microbial Statins

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Biotransformation of Waste Biomass into High Value Biochemicals

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Abstract

Statins are a class of antihypercholesterolemic (or cholesterol-lowering) drugs which act on the liver by reducing steroid biosynthesis by inhibiting the activity of HMG-CoA reductase, the enzyme responsible for the first step in the synthesis of cholesterol (and other biomolecules). This, in turn, causes the reduction of the concentration of LDL (low-density lipoproteins) associated with increased risk of coronary disease, stroke, and heart attack. The market for statins is around 25–30 billion dollars, with synthetic compounds such as atorvastatin having a large market share. However, microbial statins, such as lovastatin and pravastatin, have a market share around 10 %, while the semisynthetic simvastatin has a 50 % market. Extracts from Aspergillus terreus and Nocardia autotrophica, as well as raw biomass rich in statins from oyster mushroom or Monascus sp., are also sources of natural statins. This chapter describes briefly the action of statins, the market for these drugs, the potential for new microbial statins, and the production process for lovastatin and pravastatin.

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References

  • Ahmad A, Panda BP, Mujeeb M (2010) Screening of nutrient parameters for mevastatin production by Penicillium citrinum MTCC 1256 under submerged fermentation using the Plackett-Burman design. J Pharm Bioallied Sci 2:44–46

    Article  CAS  Google Scholar 

  • Arikan S, Bahceci M, Tuzcu A et al (2012) Postprandial hyperlipidemia in overt and subclinical hypothyroidism. Eur J Intern Med 12(6):e141–e145

    Article  Google Scholar 

  • Auclair K, Kennedy J, Richard C, Vederas JC (2001) Conversion of cyclic nonaketides to lovastatin and compactin by a lovC deficient mutant of Aspergillus terreus. Bioorg Med Chem Lett 11:1527–1531

    Article  CAS  Google Scholar 

  • Barrios-gonzález J, Miranda RU (2010) Biotechnological production and applications of statins. Appl Microbiol Biotechnol 85:869–883

    Article  Google Scholar 

  • Benedetti A, Manzoni M, Nichele M, Rollini M (2002) Process for the production of pravastatin and lovastatin. EP1266967.

    Google Scholar 

  • Berger C, Xia F, Maurer MH, Schwab S (2008) Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res Rev 58:48–56

    Article  CAS  Google Scholar 

  • Betteridge J (2010) Pitavastatin – results from phase III & IV. Atheroscler Suppl 11:8–14

    Article  CAS  Google Scholar 

  • Bizukojc M, Pawlowska B, Ledakowicz S (2007) Supplementation of the cultivation media with B-group vitamins enhances lovastatin biosynthesis by Aspergillus terreus. J Biotechnol 127:258–268

    Article  CAS  Google Scholar 

  • Bobek P, Galbavy S (1999) Hypocholesterolemic and antiatherogenic effect of oyster mushroom (Pleurotus ostreatus) in rabbits. Nahrung/Food 43:339–342

    Article  CAS  Google Scholar 

  • Borshch VN, Andreeva ER, Kuz’min SG, Vozovikov IN (2012) New medicines and approaches to treatment of atherosclerosis. Russ J Gen Chem 82:554–563

    Article  CAS  Google Scholar 

  • Bouraoui L, Cruz-Garcia L, Gutiérrez J et al (2012) Regulation of lipoprotein lipase gene expression by insulin and troglitazone in rainbow trout (Oncorhynchus mykiss) adipocyte cells in culture. Comp Biochem Physiol 161:83–88

    Article  CAS  Google Scholar 

  • Brown MS, Goldstein JL (2004) A tribute to Akira Endo, discoverer of a “Penicillin” for cholesterol. Atheroscler Suppl 5:13–16

    Article  Google Scholar 

  • Brull DJ, Sanders J, Rumley A et al (2001) Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 88:431–433

    Article  CAS  Google Scholar 

  • Campo VL, Carvalho I (2007) Estatinas hipolipidêmicas e novas tendências terapêuticas. Química Nova 30:425–430

    Article  CAS  Google Scholar 

  • Cantagrel V, Lefeber DJ, Ng BG et al (2010) SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142:203–217

    Article  CAS  Google Scholar 

  • Casas López J, Sánchez Pérez J, Fernández Sevilla J et al (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 33:270–277

    Article  Google Scholar 

  • Casey RG, Joyce M, Roche-Nagle G et al (2005) Pravastatin modulates early diabetic nephropathy in an experimental model of diabetic renal disease. J Surg Res 123:176–181

    Article  CAS  Google Scholar 

  • Catapano AL (2010) Pitavastatin – pharmacological profile from early phase studies. Atheroscler Suppl 11:3–7

    Article  CAS  Google Scholar 

  • Chapman MJ, Redfern JS, McGovern ME, Giral P (2010) Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 126:314–345

    Article  CAS  Google Scholar 

  • Chen G, Luo Y-C, Ji B-P et al (2011) Hypocholesterolemic effects of Auricularia auricula ethanol extract in ICR mice fed a cholesterol-enriched diet. J Food Sci Technol 48:692–698

    Article  CAS  Google Scholar 

  • Darwish IA, Obaid ARM, Malaq HA (2009) New highly sensitive enzyme immunoassay for the determination of pravastatin in human plasma. Talanta 79:1478–1483

    Article  CAS  Google Scholar 

  • Ellis JT, Kilpatrick DL, Consigny P et al (2010) Therapy considerations in drug-eluting stents. Crit Rev Ther Drug Carrier Syst 22:1–25

    Article  Google Scholar 

  • Fehr T, Kahlert C, Fierz W et al (2004) Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis 175:83–90

    Article  CAS  Google Scholar 

  • Findlay S, Gunawardena D, Newsome-Stewart K, Skinner G (2007) The statin drugs. Consum Rep Best Buy Drugs. October 2005 to December 2006

    Google Scholar 

  • Fukui M, Tanaka M, Toda H et al (2011) Risk factors for development of diabetes mellitus, hypertension and dyslipidemia. Diabetes Res Clin Pract 94:e15–e18

    Article  Google Scholar 

  • Gajendragadkar PR, Cooper DG, Walsh SR et al (2009) Novel uses for statins in surgical patients. Int J Surg (London) 7:285–290

    Article  CAS  Google Scholar 

  • Gu H, Tang C, Yang Y (2012) Psychological stress, immune response, and atherosclerosis. Atherosclerosis 223:69–77

    Article  CAS  Google Scholar 

  • Gururaja R, Goel A, Sridharan M et al (2003) Producing pravastatin sodium salt for use as antihyper-cholesterolemic agent, by fermentation under optimal fermentation parameters using new strain of Streptomyces flavovirens. WIPO WO2003027302

    Google Scholar 

  • Haytko PN, Wildman AS (1992) Process for purification of HMG-CoA reductase inhibitors. WIPO WO/1992/016276

    Google Scholar 

  • Hor SY, Farsi E, Yam MF et al (2011) Lipid-lowering effects of Coriolus versicolor extract in poloxamer 407-induced hypercholesterolaemic rats and high cholesterol-fed rats. J Med Plants Res 5:2261–2266

    Google Scholar 

  • Jia Z, Zhang X, Zhao Y, Cao X (2010) Enhancement of lovastatin production by supplementing polyketide antibiotics to the submerged culture of Aspergillus terreus. Biotechnol Appl Biochem 60:2014–2025

    Google Scholar 

  • Johannes BA, Mattheus PR, Piotr W (2009) Pravastatin extraction. WIPE WO 09728835

    Google Scholar 

  • Jones PH, Davidson MH, Stein EA et al (2003) Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 92:152–160

    Article  CAS  Google Scholar 

  • Kim JS, Youk YM, Ko HS, Kang DH (2011) PCR primer for detecting lovastatin-producing strain and a detection method using the same. Korean Patent Abstracts 1020110044613

    Google Scholar 

  • Klaassen P, Vollebregt AWH, Van den Berg MA, Meijrink B (2009) Improved statin production. United States Patent Application 20110223640

    Google Scholar 

  • Knopp RH (1999) Drug treatment of lipid disorders. N Engl J Med 12:498–511

    Google Scholar 

  • Koga J, Aikawa M (2012) Crosstalk between macrophages and smooth muscle cells in atherosclerotic vascular diseases. Vascul Pharmacol 57:24–28

    Article  CAS  Google Scholar 

  • Koh J-H, Kim J-M, Chang U-J, Suh H-J (2003) Hypocholesterolemic effect of hot-water extract from mycelia of Cordyceps sinensis. Biol Pharm Bull 26:84–87

    Article  CAS  Google Scholar 

  • Koh KK, Son JW, Ahn JY et al (2004) Vascular effects of diet and statin in hypercholesterolemic patients. Int J Cardiol 95:185–191

    Article  Google Scholar 

  • 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 42:407–412

    Article  CAS  Google Scholar 

  • Kumar A, Kaur H, Devi P, Mohan V (2009) Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther 124:259–268

    Article  CAS  Google Scholar 

  • Kumar MS, Jana SK, Senthil V et al (2000) Repeated fed-batch process for improving lovastatin production. Process Biochem 36:363–368

    Article  CAS  Google Scholar 

  • Kumar S, Srivastava N, Gomes J (2011) The effect of lovastatin on oxidative stress and antioxidant enzymes in hydrogen peroxide intoxicated rat. Food Chem Toxicol 49:898–902

    Article  CAS  Google Scholar 

  • Kumar Y, Thaper RK, Misra S et al (1998) Process for manufacturing simvastatin from lovastatin or mevinolinic acid. United States Patent 5763646

    Google Scholar 

  • Kzhyshkowska J, Neyen C, Gordon S (2012) Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217:492–502

    Article  CAS  Google Scholar 

  • Li JJ (2009) Triumph of the heart: the story of statins. Oxford University Press, New York

    Google Scholar 

  • Lisec B, Radež I, Žilnik LF (2012) Solvent extraction of lovastatin from a fermentation broth. Sep Purif Technol 96:187–193

    Article  CAS  Google Scholar 

  • Messner B, Bernhard D (2010) Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals 23:811–822

    Article  CAS  Google Scholar 

  • Minquan M, Xiaoming J, Xiaoliang G et al (2006) The microorganism and the process for preparation of pravastatin. WIPE 04738297

    Google Scholar 

  • Miyake T, Uchitomi K, Zhang MY et al (2006) Effects of the principal nutrients on lovastatin production by Monascus pilosus. Biosci Biotechnol Biochem 70:1154–1159

    Article  CAS  Google Scholar 

  • Morikawa S, Takabe W, Mataki C et al (2002) The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. J Ateroscler Thromb 9:178–183

    Article  CAS  Google Scholar 

  • Murphree R (2008) Pfizer ads come clean about lipitor, but is anyone paying attention? TAC Integr Healthcare 3:45–46

    Google Scholar 

  • Nirogi R, Mudigonda K, Kandikere V (2007) Chromatography-mass spectrometry methods for the quantitation of statins in biological samples. J Pharm Biomed Anal 44:379–387

    Article  CAS  Google Scholar 

  • Nobunari S, Shunshi K, Mutsuo S et al (2003) Method of purifying pravastatin. European Patent Office WO2001JP09045

    Google Scholar 

  • Nozue T, Yamamoto S, Tohyama S et al (2012) Comparison of arterial remodeling and changes in plaque composition between patients with progression versus regression of coronary atherosclerosis during statin therapy (from the TRUTH study). Am J Cardiol 109:1247–1253

    Article  Google Scholar 

  • Osman M, Khattab O, Zaghlol G, Abd El-Hameed R (2011) Screening for the production of cholesterol lowering drugs (lovastatin) by some fungi. Aust J Basic Appl Sci 5:698–703

    CAS  Google Scholar 

  • Ottosson M, Vikman-Adolfsson K, Enerbäck S et al (1994) The effects of cortisol on the regulation of lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab 79:820–825

    Article  CAS  Google Scholar 

  • Pater RM, Wnukowski P (2012) Crystalline form of pravastatine and process for the preparation thereof. WIPW WO/2012/085191

    Google Scholar 

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

    Article  CAS  Google Scholar 

  • Porcel EMR, López JLC, Pérez JAS, Christ Y (2008) Lovastatin production by Aspergillus. J Chem Technol Biotechnol 83:1236–1243

    Article  CAS  Google Scholar 

  • Riphagen IJ, van der Veer E, Muskiet FAJ, DeJongste MJL (2012) Myopathy during statin therapy in the daily practice of an outpatient cardiology clinic: prevalence, predictors and relation with vitamin D. Curr Med Res Opin 28:1247–1252

    Article  CAS  Google Scholar 

  • Rozman D, Monostory K (2010) Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther 127:19–40

    Article  CAS  Google Scholar 

  • Saha SA, Arora RR (2011) Hyperlipidaemia and cardiovascular disease: do fibrates have a role? Curr Opin Lipidol 22:270–276

    Article  CAS  Google Scholar 

  • Sakaki T (2012) Practical application of cytochrome P450. Biol Pharm Bull 35:844–849

    Article  CAS  Google Scholar 

  • Samiee SM, Moazamil N, Haghighi S et al (2003) Screening of lovastatin production by filamentous fungi. Iran Biomed J 7:29–33

    CAS  Google Scholar 

  • Santos LF, Zanatta AL, Soccol VT, Torres MF, Bonatto SJR, Rubel R, Soccol CR (2012) Hypolipidemic and antiatherosclerotic potential of Pleurotus ostreatus, cultived by submerged fermentation in the high-fat diet fed rats. Biotechnol Bioproc Eng 18(1):201–208

    Google Scholar 

  • Sayyad SA, Panda BP, Javed S, Ali M (2007) Optimization of nutrient parameters for lovastatin production by Monascus purpureus MTCC 369 under submerged fermentation using response surface methodology. Appl Microbiol Biotechnol 73:1054–1058

    Article  CAS  Google Scholar 

  • Schneider I, Kressel G, Meyer A et al (2011) Lipid lowering effects of oyster mushroom (Pleurotus ostreatus) in humans. J Funct Foods 3:17–24

    Article  CAS  Google Scholar 

  • Seenivas A, Subhagar S, Aravindan R, Viruthagiri T (2008) Microbial production and biomedical applications of lovastatin. Indian J Pharm Sci 70:701–709

    Article  Google Scholar 

  • Seraman S, Rajendran A, Thangavelu V (2010) Statistical optimization of anticholesterolemic drug lovastatin production by the red mold Monascus purpureus. Food Bioproducts Process 88:266–276

    Article  CAS  Google Scholar 

  • Serizawa N (1996) Biochemical and molecular approaches for production of pravastatin, a potent cholesterol-lowering drug. Biotechnol Annu Rev 2:373–389

    Article  CAS  Google Scholar 

  • Sorrentino F, Roy I, Keshavarz T (2010) Impact of linoleic acid supplementation on lovastatin production in Aspergillus terreus cultures. Appl Microbiol Biotechnol 88:65–73

    Article  CAS  Google Scholar 

  • Sripalakit P, Riunkesorn J, Saraphanchotiwitthaya A (2011) Utilisation of vegetable oils in the production of lovastatin by Aspergillus terreus ATCC 20542 in submerged cultivation. Maejo Int J Sci Technol 5:231–240

    CAS  Google Scholar 

  • Steinbrecher UP (1999) Receptors for oxidized low density lipoprotein. Biochim Biophys Acta 1436:279–298

    Article  CAS  Google Scholar 

  • Straathof AJJ (2011) The proportion of downstream costs in fermentative production processes. Compr Biotechnol 2:811–814

    Article  Google Scholar 

  • Strey CH, Young JM, Molyneux SL et al (2005) Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure. Atherosclerosis 179:201–206

    Article  CAS  Google Scholar 

  • Subhagar S, Aravindan R, Viruthagiri T (2009) Response surface optimization of mixed substrate solid state fermentation for the production of lovastatin by Monascus purpureus. Eng Life Sci 9:303–310

    Article  CAS  Google Scholar 

  • Subramanian S, Chait A (2012) Hypertriglyceridemia secondary to obesity and diabetes. Biochim Biophys Acta 1821:819–825

    Article  CAS  Google Scholar 

  • Szakács G, Morovján G, Tegendry RP (1998) Production of lovastatin by a wild strain of Aspergillus terreus. Biotechnol Lett 20:411–415

    Article  Google Scholar 

  • Talayero BG, Sacks FM (2011) The role of triglycerides in atherosclerosis. Curr Cardiol Rep 13:544–552

    Article  Google Scholar 

  • Teramoto T, Kashiwagi A, Ishibashi S et al (2012) Cross-sectional survey to assess the status of lipid management in high-risk patients with dyslipidemia: clinical impact of combination therapy with Ezetimibe. Ther Res Clin Exp 73:1–15

    Article  CAS  Google Scholar 

  • Tzotzas T, Karras S, Gautier T et al (2011) Exploring the contribution of plasma CETP to the modulation of HDL cholesterol during niacin administration in diabetic patients with dyslipidemia. Atherosclerosis Suppl 12:184

    Google Scholar 

  • Vaid S, Narula P (2006) Process for preparing simvastatin from lovastatin amine salts in three steps. WIPO Patent Application WO/2006/072963

    Google Scholar 

  • Valera HR, Gomes J, Lakshmi S et al (2005) Lovastatin production by solid state fermentation using Aspergillus flavipes. Enzyme Microb Technol 37:521–526

    Article  CAS  Google Scholar 

  • Vilches Ferrón MA, Casas López JL, Sánchez Pérez JA et al (2005) Rapid screening of Aspergillus terreus mutants for overproduction of lovastatin. World J Microbiol Biotechnol 21:123–125

    Article  Google Scholar 

  • Wagner M, Zollner G, Trauner M (2009) New molecular insights into the mechanisms of cholestasis. J Hepatol 51:565–580

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Weber MS, Steinman L, Zamvil SS (2007) Statins-treatment option for central nervous system autoimmune disease? Neurotherapeutics 4:693–700

    Article  CAS  Google Scholar 

  • Wexler BC (1971) Comparative aspects of hyperadrenocorticism and arteriosclerosis. Hum Pathol 2:180–181

    Article  CAS  Google Scholar 

  • Whigan DB, Ivashkiv E, Cohen AI (1989) Determination of pravastatin sodium and its isomeric metabolite in human urine by HPLC with UV detection. J Pharm Biomed Anal 7:907–912

    Article  CAS  Google Scholar 

  • Winkelnkemper T, Schuldt S, Schembecker G (2011) Systematic downstream process development for purification of baccatin III with key performance indicators. Sep Purif Technol 77:355–366

    Article  CAS  Google Scholar 

  • Zhong W-B, Hsu S-P, Ho P-Y et al (2011) Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway. Biochem Pharmacol 82:1663–1672

    Article  CAS  Google Scholar 

  • Østerud B, Bjørklid E (2003) Role of monocytes in atherogenesis. Physiol Rev 83:1069–1112

    Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology and Bioprocess Engineering, ACF Centro Politécnico, Federal University of Paraná – UFPR, Rua Cel. Francisco H dos Santos, 100, 19060, 81531-980, Curitiba, PR, Brazil

    Leandro F. dos Santos, Júlio C. de Carvalho, Rosália Rubel & Carlos Ricardo Soccol

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  1. Leandro F. dos Santos
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  2. Júlio C. de Carvalho
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  3. Rosália Rubel
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  4. Carlos Ricardo Soccol
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Correspondence to Júlio C. de Carvalho .

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Editors and Affiliations

  1. University of Québec INRS-ETE, Québec, Canada

    Satinder Kaur Brar

  2. University of Québec, University of Québec INRS-ETE, Québec, Québec, Canada

    Gurpreet Singh Dhillon

  3. Department of Chemical Engineering, Federal University of Parana Bioprocess Engineering and Biotechnology, Curitiba, Paraná, Brazil

    Carlos Ricardo Soccol

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dos Santos, L.F., de Carvalho, J.C., Rubel, R., Soccol, C.R. (2014). Microbial Statins. In: Brar, S., Dhillon, G., Soccol, C. (eds) Biotransformation of Waste Biomass into High Value Biochemicals. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8005-1_13

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