Biotechnological Production of Statins: Metabolic Aspects and Genetic Approaches

Roberval 	   N.M.   Neto; Edelvio   de   Barros Gomes; Lucas      Weba-Soares; Léo 	   R.L.   Dias; Luís 	   C.N.   da Silva; Rita de    C.M.   de Miranda
Abstract

Statins are drugs used for people with abnormal lipid levels (hyperlipidemia) and are among the best-selling medications in the United States. Thus, the aspects related to the production of these drugs are of extreme importance for the pharmaceutical industry. Herein, we provide a non-exhaustive review of fungal species used to produce statin and highlighted the major factors affecting the efficacy of this process. The current biotechnological approaches and the advances of a metabolic engineer to improve statins production are also emphasized. The biotechnological production of the main statins (lovastatin, pravastatin and simvastatin) uses different species of filamentous fungi, for example Aspergillus terreus. The statins production is influenced by different types of nutrients available in the medium such as the carbon and nitrogen sources, and several researches have focused their efforts to find the optimal cultivation conditions. Enzymes belonging to Lov class, play essential roles in statin production and have been targeted to genetic manipulations in order to improve the efficiency for Lovastatin and Simvastatin production. For instance, Escherichia coli strains expressing the LovD have been successfully used for lovastatin production. Other examples include the use of iRNA targeting LovF of A. terreus. Therefore, fungi are important allies in the fight against hyperlipidemias. Although many studies have been conducted, investigations on bioprocess optimization (using both native or genetic- modified strains) still necessary.
Keywords: Hyperlipidemia, microbial secondary metabolites, polyketides, fermentation processes, genetic manipulation, heterologous expression.
Graphical Abstract

[1] 
Finn, A.K.; Nakano, M.; Narula, J.; Kolodgie, F.D.; Virmani, R. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol.,  2010, 30(7), 1282-1292.
[http://dx.doi.org/10.1161/ATVBAHA.108.179739] [PMID:  20554950] 
[2] 
Tziomalos, K.; Athyros, V.G.; Karagiannis, A.; Mikhailidis, D.P. Dyslipidemia as a risk factor for ischemic stroke. Curr. Top. Med. Chem.,  2009, 9(14), 1291-1297.
[http://dx.doi.org/10.2174/156802609789869628] [PMID:  19849661] 
[3] 
Zimny, S.; Pohl, R.; Rein-Fischboeck, L.; Haberl, E.M.; Krautbauer, S.; Weiss, T.S.; Buechler, C. Chemokine (CC-motif) receptor-like 2 mRNA is expressed in hepatic stellate cells and is positively associated with characteristics of non-alcoholic steatohepatitis in mice and men. Exp. Mol. Pathol.,  2017, 103(1), 1-8.
[http://dx.doi.org/10.1016/j.yexmp.2017.06.001] [PMID:  28600126] 
[4] 
Rashidi, O.M.; H. Nazar, F.A.; Alama, M.N.; Awan, Z.A. Interpreting the mechanism of APOE (p. Leu167del) mutation in the incidence of familial hypercholesterolemia; an in-silico approach. Open Cardiovasc. Med. J.,  2017, 11, 84-93.
[http://dx.doi.org/10.2174/1874192401711010084] [PMID:  29204218] 
[5] 
Omer, L.; Hudson, E.A.; Zheng, S.; Hoying, J.B.; Shan, Y.; Boyd, N.L. CRISPR Correction of a homozygous low-density lipoprotein receptor mutation in familial hypercholesterolemia induced pluripotent stem cells. Hepatol. Commun,  2017, 1(9), 886-898.
[http://dx.doi.org/10.1002/hep4.1110] [PMID:  29130076] 
[6] 
Last, A.R.; Ference, J.D.; Menzel, E.R. Hyperlipidemia: Drugs for cardiovascular risk reduction in adults. Am. Fam. Physician,  2017, 95(2), 78-87.
[PMID:  28084704] 
[7] 
Profumo, E.; Buttari, B.; Saso, L.; Rigano, R. Pleiotropic effects of statins in atherosclerotic disease: Focus on the antioxidant activity of atorvastatin. Curr. Top. Med. Chem.,  2014, 14(22), 2542-2551.
[http://dx.doi.org/10.2174/1568026614666141203130324] [PMID:  25478882] 
[8] 
Romana, B.; Batger, M.; Prestidge, C.A.; Colombo, G.; Sonvico, F. Expanding the therapeutic potential of statins by means of nanotechnology enabled drug delivery systems. Curr. Top. Med. Chem.,  2014, 14(9), 1182-1193.
[http://dx.doi.org/10.2174/1568026614666140329232252] [PMID:  24678704] 
[9] 
Scharnagl, H.; März, W. New lipid-lowering agents acting on LDL receptors. Curr. Top. Med. Chem.,  2005, 5(3), 233-242.
[http://dx.doi.org/10.2174/1568026053544524] [PMID:  15857307] 
[10] 
Pertzov, B.; Eliakim-Raz, N.; Atamna, H.; Trestioreanu, A.Z.; Yahav, D.; Leibovici, L. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - a systematic review and meta-analysis. Clin. Microbiol. Infect., 2018.
[PMID:  30472427] 
[11] 
Raparelli, V.; Pannitteri, G.; Todisco, T.; Toriello, F.; Napoleone, L.; Manfredini, R.; Basili, S. Treatment and response to statins: Gender-related Differences. Curr. Med. Chem.,  2017, 24(24), 2628-2638.
[http://dx.doi.org/10.2174/0929867324666161118094711] [PMID:  28552051] 
[12] 
Chatelin, J.; Stathopoulou, M.G.; Arguinano, A.A.; Xie, T.; Visvikis-Siest, S. Pharmacogenomic challenges in cardiovascular diseases: Examples of drugs and considerations for future integration in clinical practice. Curr. Pharm. Biotechnol.,  2017, 18(3), 231-241.
[http://dx.doi.org/10.2174/1389201018666170123153626] [PMID:  28117005] 
[13] 
Wiewel, M.A.; Scicluna, B.P.; van Vught, L.A.; Hoogendijk, A.J.; Zwinderman, A.H.; Lutter, R.; Horn, J.; Cremer, O.L.; Bonten, M.J.; Schultz, M.J.; van der Poll, T. The host response in critically ill sepsis patients on statin therapy: A prospective observational study. Ann. Intensive Care,  2018, 8(1), 9.
[http://dx.doi.org/10.1186/s13613-017-0349-3] [PMID:  29349709] 
[14] 
Iarrobino, N.A.; Gill, B.; Bernard, M.E.; Mishra, M.V.; Champ, C.E. Targeting tumor metabolism with statins during treatment for advanced-stage pancreatic cancer. Am. J. Clin. Oncol., 2018.
[http://dx.doi.org/10.1097/COC.0000000000000433] [PMID:  29509593] 
[15] 
Schultz, B.G.; Patten, D.K.; Berlau, D.J. The role of statins in both cognitive impairment and protection against dementia: A tale of two mechanisms. Transl. Neurodegener.,  2018, 7, 5.
[http://dx.doi.org/10.1186/s40035-018-0110-3] [PMID:  29507718] 
[16] 
Cunnington, A.; Nadel, S. New therapies for sepsis. Curr. Top. Med. Chem.,  2008, 8(7), 603-614.
[http://dx.doi.org/10.2174/156802608783955601] [PMID:  18473886] 
[17] 
Reis, P.A.; Alexandre, P.C.B.; D’Avila, J.C.; Siqueira, L.D.; Antunes, B.; Estato, V.; Tibiriça, E.V.; Verdonk, F.; Sharshar, T.; Chrétien, F.; Castro-Faria-Neto, H.C.; Bozza, F.A. Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction. Brain Behav. Immun.,  2017, 60, 293-303.
[http://dx.doi.org/10.1016/j.bbi.2016.11.006] [PMID:  27833044] 
[18] 
Ribeiro, N.Q.; Costa, M.C.; Magalhães, T.F.F.; Carneiro, H.C.S.; Oliveira, L.V.; Fontes, A.C.L.; Santos, J.R.A.; Ferreira, G.F.; Araujo, G.R.S.; Alves, V.; Frases, S.; Paixão, T.A.; de Resende Stoianoff, M.A.; Santos, D.A. Atorvastatin as a promising anticryptococcal agent. Int. J. Antimicrob. Agents,  2017, 49(6), 695-702.
[http://dx.doi.org/10.1016/j.ijantimicag.2017.04.005] [PMID:  28450174] 
[19] 
Braga Filho, J.A.F.; Abreu, A.G.; Rios, C.E.P.; Trovão, L.O.; Silva, D.L.F.; Cysne, D.N.; Nascimento, J.R.; Fortes, T.S.; Silva, L.A.; Guerra, R.N.M.; Maciel, M.C.G.; Serezani, C.H.; Nascimento, F.R.F. Prophylactic treatment with simvastatin modulates the immune response and increases animal survival following lethal sepsis infection. Front. Immunol.,  2018, 9, 2137.
[http://dx.doi.org/10.3389/fimmu.2018.02137] [PMID:  30298072] 
[20] 
Kaminska, M.; Aliko, A.; Hellvard, A.; Bielecka, E.; Binder, V.; Marczyk, A.; Potempa, J.; Delaleu, N.; Kantyka, T.; Mydel, P. Effects of statins on multispecies oral biofilm identify simvastatin as a drug candidate targeting Porphyromonas gingivalis. J. Periodontol., 2018.
[PMID:  30506795] 
[21] 
Parihar, S.P.; Guler, R.; Brombacher, F. Statins: A viable candidate for host-directed therapy against infectious diseases. Nat. Rev. Immunol., 2018.
[PMID:  30487528] 
[22] 
Spychalowicz, A.; Wilk, G.; Śliwa, T.; Ludew, D.; Guzik, T.J. Novel therapeutic approaches in limiting oxidative stress and inflammation. Curr. Pharm. Biotechnol.,  2012, 13(13), 2456-2466.
[http://dx.doi.org/10.2174/1389201011208062456] [PMID:  22280420] 
[23] 
Smelser, L.K.; Walker, C.; Burns, E.M.; Curry, M.; Black, N.; Metzler, J.A.; McDowell, S.A.; Bruns, H.A. Short term, low dose simvastatin pretreatment alters memory immune function following secondary Staphylococcus aureus infection. Curr. Pharm. Biotechnol.,  2016, 17(10), 886-893.
[http://dx.doi.org/10.2174/1389201017666160301122330] [PMID:  26927218] 
[24] 
McDowell, S.A.; Ma, Y.; Kusano, R.; Akinbi, H.T. Simvastatin is protective during Staphylococcus aureus pneumonia. Curr. Pharm. Biotechnol.,  2011, 12(9), 1455-1462.
[http://dx.doi.org/10.2174/138920111798281027] [PMID:  21401521] 
[25] 
Ansquer, J.C.; Crimet, D.; Foucher, C. Fibrates and statins in the treatment of diabetic retinopathy. Curr. Pharm. Biotechnol.,  2011, 12(3), 396-405.
[http://dx.doi.org/10.2174/138920111794480570] [PMID:  20939802] 
[26] 
Licata, A.; Giammanco, A.; Minissale, M.G.; Pagano, S.; Petta, S.; Averna, M. Liver and statins: A critical appraisal of the evidence. Curr. Med. Chem.,  2018, 25(42), 5835-5846.
[http://dx.doi.org/10.2174/0929867325666180327095441] [PMID:  29589533] 
[27] 
Manzoni, M.; Rollini, M. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl. Microbiol. Biotechnol.,  2002, 58(5), 555-564.
[http://dx.doi.org/10.1007/s00253-002-0932-9] [PMID:  11956737] 
[28] 
Javed, S.; Bukhari, S.A.; Zovia, I.; Meraj, M. Screening of indigenously isolated fungi for lovastatin production and its in vivo evaluation. Curr. Pharm. Biotechnol.,  2014, 15(4), 422-427.
[http://dx.doi.org/10.2174/1389201015666140528152138] [PMID:  24894549] 
[29] 
Endo, A.; Hasumi, K.; Yamada, A.; Shimoda, R.; Takeshima, H. The synthesis of compactin (ML-236B) and monacolin K in fungi. J. Antibiot. (Tokyo),  1986, 39(11), 1609-1610.
[http://dx.doi.org/10.7164/antibiotics.39.1609] [PMID:  3793631] 
[30] 
Nissen, S.E.; Nicholls, S.J.; Sipahi, I.; Libby, P.; Raichlen, J.S.; Ballantyne, C.M.; Davignon, J.; Erbel, R.; Fruchart, J.C.; Tardif, J.C.; Schoenhagen, P.; Crowe, T.; Cain, V.; Wolski, K.; Goormastic, M.; Tuzcu, E.M.; Investigators, A. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID trial. JAMA,  2006, 295(13), 1556-1565.
[http://dx.doi.org/10.1001/jama.295.13.jpc60002] [PMID:  16533939] 
[31] 
Neuvonen, P.J.; Backman, J.T.; Niemi, M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin. Pharmacokinet.,  2008, 47(7), 463-474.
[http://dx.doi.org/10.2165/00003088-200847070-00003] [PMID:  18563955] 
[32] 
Endo, A.; Kuroda, M.; Tsujita, Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J. Antibiot. (Tokyo),  1976, 29(12), 1346-1348.
[http://dx.doi.org/10.7164/antibiotics.29.1346] [PMID:  1010803] 
[33] 
Barrios-González, J.; Baños, J.G.; Covarrubias, A.A.; Garay-Arroyo, A. Lovastatin biosynthetic genes of Aspergillus terreus are expressed differentially in solid-state and in liquid submerged fermentation. Appl. Microbiol. Biotechnol.,  2008, 79(2), 179-186.
[http://dx.doi.org/10.1007/s00253-008-1409-2] [PMID:  18414850] 
[34] 
Endo, A.; Monacolin, K. Monacolin K, a new hypocholesterolemic agent produced by a Monascus species. J. Antibiot. (Tokyo),  1979, 32(8), 852-854.
[http://dx.doi.org/10.7164/antibiotics.32.852] [PMID:  500505] 
[35] 
Huang, J.; Liao, N.; Li, H. Linoleic acid enhance the production of moncolin K and red pigments in Monascus ruber by activating mokH and mokA, and by accelerating cAMP-PkA pathway. Int. J. Biol. Macromol.,  2018, 109, 950-954.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.11.074] [PMID:  29162465] 
[36] 
Kimura, K.; Komagata, D.; Murakawa, S.; Endo, A. Biosynthesis of monacolins: Conversion of monacolin J to monacolin K (mevinolin). J. Antibiot. (Tokyo),  1990, 43(12), 1621-1622.
[http://dx.doi.org/10.7164/antibiotics.43.1621] [PMID:  2276983] 
[37] 
McLean, K.J.; Hans, M.; Meijrink, B.; van Scheppingen, W.B.; Vollebregt, A.; Tee, K.L.; van der Laan, J.M.; Leys, D.; Munro, A.W.; van den Berg, M.A. Single-step fermentative production of the cholesterol-lowering drug pravastatin via reprogramming of Penicillium chrysogenum. Proc. Natl. Acad. Sci. USA,  2015, 112(9), 2847-2852.
[http://dx.doi.org/10.1073/pnas.1419028112] [PMID:  25691737] 
[38] 
Tobert, J.A. Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov.,  2003, 2(7), 517-526.
[http://dx.doi.org/10.1038/nrd1112] [PMID:  12815379] 
[39] 
Endo, A.; Tsujita, Y.; Kuroda, M.; Tanzawa, K. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Eur. J. Biochem.,  1977, 77(1), 31-36.
[http://dx.doi.org/10.1111/j.1432-1033.1977.tb11637.x] [PMID:  908337] 
[40] 
Brown, M.S.; Faust, J.R.; Goldstein, J.L.; Kaneko, I.; Endo, A. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J. Biol. Chem.,  1978, 253(4), 1121-1128.
[PMID:  624722] 
[41] 
Terahara, A.; Tanaka, M. ML-236B Derivatives and their preparation. U.S. Patent 4346227A.  1982.
[42] 
Arai, M. Pravastatin sodium (CS-154), a novel cholesterol-lowering agent which inhibits HMG-CoA reductase. Sankyo Kenkyusyo Nempo,  1988, 40, 1-38.
[43] 
Tobert, J.A.; Hitzenberger, G.; Kukovetz, W.R.; Holmes, I.B.; Jones, K.H. Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase. Atherosclerosis,  1982, 41(1), 61-65.
[http://dx.doi.org/10.1016/0021-9150(82)90070-3] [PMID:  6918220] 
[44] 
Bilheimer, D.W.; Grundy, S.M.; Brown, M.S.; Goldstein, J.L. Mevinolin stimulates receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Trans. Assoc. Am. Physicians,  1983, 96, 1-9.
[http://dx.doi.org/10.1073/pnas.80.13.4124] [PMID:  6388097] 
[45] 
Illingworth, D.R.; Sexton, G.J. Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia. J. Clin. Invest.,  1984, 74(6), 1972-1978.
[http://dx.doi.org/10.1172/JCI111618] [PMID:  6569064] 
[46] 
Gonyeau, M.J. Statins and osteoporosis: A clinical review. Pharmacotherapy,  2005, 25(2), 228-243.
[http://dx.doi.org/10.1592/phco.25.2.228.56954] [PMID:  15767237] 
[47] 
Sparks, D.L. Alzheimer disease: statins in the treatment of Alzheimer disease. Nat. Rev. Neurol.,  2011, 7(12), 662-663.
[http://dx.doi.org/10.1038/nrneurol.2011.165] [PMID:  22009281] 
[48] 
Hindler, K.; Cleeland, C.S.; Rivera, E.; Collard, C.D. The role of statins in cancer therapy. Oncologist,  2006, 11(3), 306-315.
[http://dx.doi.org/10.1634/theoncologist.11-3-306] [PMID:  16549815] 
[49] 
Lam, Y.S.; Okello, E.J. Determination of lovastatin, β-glucan, total polyphenols, and antioxidant activity in raw and processed oyster culinary-medicinal mushroom, Pleurotus ostreatus (Higher Basidiomycetes). Int. J. Med. Mushrooms,  2015, 17(2), 117-128.
[http://dx.doi.org/10.1615/IntJMedMushrooms.v17.i2.30] [PMID:  25746617] 
[50] 
Pattanagul, P.; Pinthong, R.; Phianmongkhol, A.; Leksawasdi, N. Review of angkak production (Monascus purpureus). Warasan Khana Witthayasat Maha Witthayalai Chiang Mai,  2007, 34(3), 319-328.
[51] 
Pattanagul, P.; Pinthong, R.; Phianmongkhol, A.; Tharatha, S. Mevinolin, citrinin and pigments of adlay angkak fermented by Monascus sp. Int. J. Food Microbiol.,  2008, 126(1-2), 20-23.
[http://dx.doi.org/10.1016/j.ijfoodmicro.2008.04.019] [PMID:  18538878] 
[52] 
Rahim, M.H.A.; Harith, H.H.; Montoya, A.; Abbas, A. Growth and lovastatin production by Aspergillus terreus under different carbohyrates as carbon sources. Biocatal. Agric. Biotechnol., 2017.
[http://dx.doi.org/10.1016/j.bcab.2017.04.011] 
[53] 
Bizukojc, M.; Ledakowicz, S. Bioprocess engineering aspects of the cultivation of a lovastatin producer Aspergillus terreus. Adv. Biochem. Eng. Biotechnol.,  2015, 149, 133-170.
[http://dx.doi.org/10.1007/10_2014_302] [PMID:  25633258] 
[54] 
Alarcón, J.; Aguila, S. Lovastatin production by Pleurotus ostreatus: Effects of the C:N ratio. Z. Natforsch. C J. Biosci.,  2006, 61(1-2), 95-98.
[http://dx.doi.org/10.1515/znc-2006-1-217] [PMID:  16610224] 
[55] 
Atlı, B.; Yamaç, M.; Yıldız, Z.; Isikhuemnen, O.S. Enhanced production of lovastatin by Omphalotus olearius (DC.) Singer in solid state fermentation. Rev. Iberoam. Micol.,  2015, 32(4), 247-251.
[http://dx.doi.org/10.1016/j.riam.2014.06.008] [PMID:  25618184] 
[56] 
Atli, B.; Yamac, M. Screening of medicinal higher Basidiomycetes mushrooms from Turkey for lovastatin production. Int. J. Med. Mushrooms,  2012, 14(2), 149-159.
[http://dx.doi.org/10.1615/IntJMedMushr.v14.i2.30] [PMID:  22506575] 
[57] 
Jia, Z.; Zhang, X.; Zhao, Y.; Cao, X. Enhancement of lovastatin production by supplementing polyketide antibiotics to the submerged culture of Aspergillus terreus. Appl. Biochem. Biotechnol.,  2010, 160(7), 2014-2025.
[http://dx.doi.org/10.1007/s12010-009-8762-1] [PMID:  19728167] 
[58] 
Kumar, M.S.; Jana, S.K.; Senthil, V.; Shashanka, V.; Kumar, S.V.K. S.A., Repeated fed-batch process for improving lovastatin production. Process Biochem.,  2000, 36(4), 363-368.
[http://dx.doi.org/10.1016/S0032-9592(00)00222-3] 
[59] 
Hendrickson, L.; Davis, C.R.; Roach, C.; Nguyen, D.K.; Aldrich, T.; McAda, P.C.; Reeves, C.D. Lovastatin biosynthesis in Aspergillus terreus: Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene. Chem. Biol.,  1999, 6(7), 429-439.
[http://dx.doi.org/10.1016/S1074-5521(99)80061-1] [PMID:  10381407] 
[60] 
Kennedy, J.; Auclair, K.; Kendrew, S.G.; Park, C.; Vederas, J.C.; Hutchinson, C.R. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science,  1999, 284(5418), 1368-1372.
[http://dx.doi.org/10.1126/science.284.5418.1368] [PMID:  10334994] 
[61] 
Barriuso, J.; Nguyen, D.T.; Li, J.W.; Roberts, J.N.; MacNevin, G.; Chaytor, J.L.; Marcus, S.L.; Vederas, J.C.; Ro, D.K. Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin J by a single cytochrome P450 monooxygenase, LovA. J. Am. Chem. Soc.,  2011, 133(21), 8078-8081.
[http://dx.doi.org/10.1021/ja201138v] [PMID:  21495633] 
[62] 
Baños, J.G.; Tomasini, A.; Szakács, G.; Barrios-González, J. High lovastatin production by Aspergillus terreus in solid-state fermentation on polyurethane foam: An artificial inert support. J. Biosci. Bioeng.,  2009, 108(2), 105-110.
[http://dx.doi.org/10.1016/j.jbiosc.2009.03.006] [PMID:  19619855] 
[63] 
Xu, W.; Chooi, Y.H.; Choi, J.W.; Li, S.; Vederas, J.C.; Da Silva, N.A.; Tang, Y.; Lov, G. LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis. Angew. Chem. Int. Ed. Engl.,  2013, 52(25), 6472-6475.
[http://dx.doi.org/10.1002/anie.201302406] [PMID:  23653178] 
[64] 
Gao, X.; Xie, X.; Pashkov, I.; Sawaya, M.R.; Laidman, J.; Zhang, W.; Cacho, R.; Yeates, T.O.; Tang, Y. Directed evolution and structural characterization of a simvastatin synthase. Chem. Biol.,  2009, 16(10), 1064-1074.
[http://dx.doi.org/10.1016/j.chembiol.2009.09.017] [PMID:  19875080] 
[65] 
Sorensen, J.L.; Auclair, K.; Kennedy, J.; Hutchinson, C.R.; Vederas, J.C. Transformations of cyclic nonaketides by Aspergillus terreus mutants blocked for lovastatin biosynthesis at the lovA and lovC genes. Org. Biomol. Chem.,  2003, 1(1), 50-59.
[http://dx.doi.org/10.1039/b207721c] [PMID:  12929390] 
[66] 
Bhargavi, S.D.; Praveen, V.K.; Anil Kumar, M.; Savitha, J. Comparative study on whole genome sequences of Aspergillus terreus (soil fungus) and Diaporthe ampelina (endophytic fungus) with reference to lovastatin production. Curr. Microbiol.,  2018, 75(1), 84-91.
[http://dx.doi.org/10.1007/s00284-017-1353-4] [PMID:  28879444] 
[67] 
Miranda, R.U.; Gómez-Quiroz, L.E.; Mendoza, M.; Pérez-Sánchez, A.; Fierro, F.; Barrios-González, J. Reactive oxygen species regulate lovastatin biosynthesis in Aspergillus terreus during submerged and solid-state fermentations. Fungal Biol.,  2014, 118(12), 979-989.
[http://dx.doi.org/10.1016/j.funbio.2014.09.002] [PMID:  25457945] 
[68] 
Xie, X.; Watanabe, K.; Wojcicki, W.A.; Wang, C.C.; Tang, Y. Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem. Biol.,  2006, 13(11), 1161-1169.
[http://dx.doi.org/10.1016/j.chembiol.2006.09.008] [PMID:  17113998] 
[69] 
Xie, X.; Tang, Y. Efficient synthesis of simvastatin by use of whole-cell biocatalysis. Appl. Environ. Microbiol.,  2007, 73(7), 2054-2060.
[http://dx.doi.org/10.1128/AEM.02820-06] [PMID:  17277201] 
[70] 
Jiménez-Osés, G.; Osuna, S.; Gao, X.; Sawaya, M.R.; Gilson, L.; Collier, S.J.; Huisman, G.W.; Yeates, T.O.; Tang, Y.; Houk, K.N. The role of distant mutations and allosteric regulation on LovD active site dynamics. Nat. Chem. Biol.,  2014, 10(6), 431-436.
[http://dx.doi.org/10.1038/nchembio.1503] [PMID:  24727900] 
[71] 
Vinci, V.A.; Hoerner, T.D.; Coffman, A.D.; Schimmel, T.G.; Dabora, R.L.; Kirpekal, A.C.; Ruby, C.L.; Stieber, R.W. Mutants of a lovastatin-hyperproducing Aspergillus terreus deficient in the production of sulochrin. Appl. Microbiol. Biotechnol.,  2010, 85, 869-883.
[72] 
Bizukojc, M.; Ledakowicz, S. Biosynthesis of lovastatin and (+)-geodin by Aspergillus terreus in batch and fed-batch culture in the stirred tank bioreactor. Biochem. Eng. J.,  2008, 42(3), 198-207.
[http://dx.doi.org/10.1016/j.bej.2008.06.022] 
[73] 
Bizukojc, M.; Ledakowicz, S. Physiological, morphological and kinetic aspects of lovastatin biosynthesis by Aspergillus terreus. Biotechnol. J.,  2009, 4(5), 647-664.
[http://dx.doi.org/10.1002/biot.200800289] [PMID:  19452466] 
[74] 
López, J.L.C.; Pérez, J.A.S.; Sevilla, J.M.F.; Fernández, F.G.A.; Grimaa, Y.; Chisti, E.M. Production of lovastatin by Aspergillus terreus: effects of the C:N ratio and the principal nutrients on growth and metabolite production. Enzyme Microb. Technol.,  2003, 33(2-3), 270-277.
[http://dx.doi.org/10.1016/S0141-0229(03)00130-3] 
[75] 
Bizukojc, M.; Gonciarz, J. Influence of oxygen on lovastatin biosynthesis by Aspergillus terreus ATCC 20542 quantitatively studied on the level of individual pellets. Bioprocess Biosyst. Eng.,  2015, 38(7), 1251-1266.
[http://dx.doi.org/10.1007/s00449-015-1366-y] [PMID:  25627471] 
[76] 
Arora, S.; Rani, R.; Ghosh, S. Bioreactors in solid state fermentation technology: Design, applications and engineering aspects. J. Biotechnol.,  2018, 269, 16-34.
[http://dx.doi.org/10.1016/j.jbiotec.2018.01.010] [PMID:  29408199] 
[77] 
Mulder, K.C.; Mulinari, F.; Franco, O.L.; Soares, M.S.; Magalhães, B.S.; Parachin, N.S. Lovastatin production: From molecular basis to industrial process optimization. Biotechnol. Adv.,  2015, 33(6 Pt 1), 648-665.
[http://dx.doi.org/10.1016/j.biotechadv.2015.04.001] [PMID:  25868803] 
[78] 
Zhang, B.B.; Lu, L.P.; Xu, G.R. Why solid-state fermentation is more advantageous over submerged fermentation for converting high concentration of glycerol into Monacolin K by Monascus purpureus 9901: A mechanistic study. J. Biotechnol.,  2015, 206, 60-65.
[http://dx.doi.org/10.1016/j.jbiotec.2015.04.011] [PMID:  25931192] 
[79] 
Suraiya, S.; Kim, J-H.; Tak, J.Y.; Siddique, M.P.; Young, C.J.; Kim, J.K.; Kong, I-S. Influences of fermentation parameters on lovastatin production by Monascus purpureus using Saccharina japonica as solid fermented substrate. LWT,  2018, 92, 1-9.
[http://dx.doi.org/10.1016/j.lwt.2018.02.013] 
[80] 
Reddy, D.S.; Latha, D.P.; Latha, K.P.J.H. Poduction of lovastatin by solid state fermentation by Penicillium funiculosum NCM 1174. Drug Invention Today,  2011, 3(6), 75-77.
[81] 
Chanakya, P.; Latha, P.M.; Srikanth, M. Solid state fermentation for the production of lovastatin by Aspergillus fischerii. Res. J. Pharma. Sci. Bioctechnol.,  2011, 1(1), 9-13.
[82] 
Sorrentino, F.; Roy, I.; Keshavarz, T. Impact of linoleic acid supplementation on lovastatin production in Aspergillus terreus cultures. Appl. Microbiol. Biotechnol.,  2010, 88(1), 65-73.
[http://dx.doi.org/10.1007/s00253-010-2722-0] [PMID:  20571794] 
[83] 
Osman, M.E.; Khattab, O.H.; Zghlol, G.M.; El-Hameed, R.M. Optimization of some physical and chemical factors for lovastatin productivity by local strain of Aspergillus terreus. Aust. J. Basic Appl. Sci.,  2011, 5(6), 718-732.
[84] 
Pecyna, M.; Bizukojc, M. Lovastatin biosynthesis by Aspergillus terreus with the simultaneous use of lactose and glycerol in a discontinuous fed-batch culture. J. Biotechnol.,  2011, 151(1), 77-86.
[http://dx.doi.org/10.1016/j.jbiotec.2010.10.079] [PMID:  21056601] 
[85] 
Samiee, S.M.; Moazami, N.; Haghighui, S.; Mohseni, F.A.; Mirdamadi, S.; Bakhtiari, M.R. Screening of lovastatin production by filamentous fungi. Iran. Biomed. J.,  2001, 7(1), 29-33.
[86] 
Jaivel, N.; Marimuthu, P. Optimization of lovastatin production in solid state fermentation by Aspergillus terreus. Int. J. Eng. Sci. Technol.,  2010, 2(7), 2730-2733.
[87] 
Prabhakar, M.; Lingappa, K.; Vivek, B.; Amena, S.; Vishalakshi, N.; Mahesh, D. Characterization of physical factors for optimum lovastatin production by Aspergillus terreus KLVB28mu21 under solid state fermentation. J. Recent Adv. Appl. Sci.,  2011, 27, 1-5.
[88] 
Pie-Lien, W.; Zhi-nan, X.C.P. Lovastatin production by Aspergillus terreus in solid-state fermentation. J. Zhejiang Univ. Sci.,  2007, 8(9), 1521-1526.
[http://dx.doi.org/10.1631/jzus.2007.A1521] 
[89] 
Pansuriya, R.C.; Singhal, R.S. Response surface methodology for optimization of production of lovastatin by solid state fermentation. Braz. J. Microbiol.,  2010, 41(1), 164-172.
[http://dx.doi.org/10.1590/S1517-838220100001000024] [PMID:  24031477] 
[90] 
Valera, H.R.; Gomes, J.; Lakshmi, S.; Gururaja, R.; Suryanarayan, S.; Kumar, D. Lovastatin production by solid state fermentation using Aspergillus flavipes. Enzyme Microb. Technol.,  2005, 37(5), 521-526.
[http://dx.doi.org/10.1016/j.enzmictec.2005.03.009] 
[91] 
Trenin, A.S. Microbial metabolites that inhibit sterol biosynthesis, their chemical diversity and characteristics of mode of action. Bioorg. Khim.,  2013, 39(6), 633-657.
[PMID:  25696927] 
[92] 
Javed, S.; Bukhari, S.A.; Ali, M. Sajjad-ur-Rehman. Estimation of antifungal activity of mevastatin produced by Aspergillus terreus GCBL-03 on pretreated substrate in solid state fermentation. Curr. Pharm. Biotechnol.,  2016, 17(3), 291-298.
[http://dx.doi.org/10.2174/138920101703160206151242] [PMID:  26873078] 
[93] 
Sayyad, S.A.; Panda, B.P.; Javed, S.; Ali, M. Optimization of nutrient parameters for lovastatin production by Monascus purpureus MTCC 369 under submerged fermentation using response surface methodology. Appl. Microbiol. Biotechnol.,  2007, 73(5), 1054-1058.
[http://dx.doi.org/10.1007/s00253-006-0577-1] [PMID:  17019609] 
[94] 
Seraman, S.; Aravindan, R.; Viruthagi, T. Statistical optimization of anticholesterolemic drug lovastatin production by the red mold Monascus purpureus. Food Bioprod. Process.,  2010, 88(2-3), 266-276.
[http://dx.doi.org/10.1016/j.fbp.2010.01.006] 
[95] 
Praveen, V.K.; Bhargavi, S.D.; Savitha, J. Lovastatin production by Aspergillus terreus (KM017963) in submerged and solid state fermentation: A comparative study. Amer. J. Pharmacol. Health Res.,  2015, 3(7), 116-126.
[96] 
Gonciarz, J.; Kowalska, A.; Bizukojc, M. Application of microparticle-enhanced cultivation to increase the access of oxygen to Aspergillus terreus ATCC 20542 mycelium and intensify lovastatin biosynthesis in batch and continuous fed-batch stirred tank bioreactors. Biochem. Eng. J.,  2016, 109, 178-188.
[http://dx.doi.org/10.1016/j.bej.2016.01.017] 
[97] 
Miranda, R.U.; Gómez-Quiroz, L.E.; Mejía, A.; Barrios-González, J. Oxidative state in idiophase links Reactive Oxygen Species (ROS) and lovastatin biosynthesis: Differences and similarities in submerged- and solid-state fermentations. Fungal Biol.,  2013, 117(2), 85-93.
[http://dx.doi.org/10.1016/j.funbio.2012.12.001] [PMID:  23452946] 
[98] 
Pérez-Sánchez, A.; Uribe-Carvajal, S.; Cabrera-Orefice, A.; Barrios-González, J. Key role of alternative oxidase in lovastatin solid-state fermentation. Appl. Microbiol. Biotechnol.,  2017, 101(19), 7347-7356.
[http://dx.doi.org/10.1007/s00253-017-8452-9] [PMID:  28791446] 
[99] 
Xu, B.; Wang, Q.; Jia, X.; Sung, C. Enhanced lovastatin production by solid state fermentation of Monascus ruber. Biotechnology Biochem. Eng,  2005, 10, 78-84.
[100] 
Mouafi, F.E.; Ibrahim, G.S.; Abo Elsoud, M.M. Optimization of lovastatin production from Aspergillus fumigatus. J. Genet. Eng. Biotechnol.,  2016, 14(2), 253-259.
[http://dx.doi.org/10.1016/j.jgeb.2016.10.006] [PMID:  30647623] 
[101] 
Bizukojc, M.; Pawlak, M.; Boruta, T.; Gonciarz, J. Effect of pH on biosynthesis of lovastatin and other secondary metabolites by Aspergillus terreus ATCC 20542. J. Biotechnol.,  2012, 162(2-3), 253-261.
[http://dx.doi.org/10.1016/j.jbiotec.2012.09.007] [PMID:  22995742] 
[102] 
P.A., Belter; E.L., Cussler; and W.S., Hu A Review of: “Bioseparations” In: Downstream Processing for Biotechnology; Wiley Interscience: New York, 1988; Vol.18, pp. (3)375-376.
[103] 
Martins, S.; Aguilar, C.N.; Teixeira, J.A.; Mussatto, S.I. Bioactive compounds (phytoestrogens) recovery from Larrea tridentata leaves by solvents extraction. Separ. Purif. Tech.,  2012, 88, 163-167.
[http://dx.doi.org/10.1016/j.seppur.2011.12.020] 
[104] 
Lisec, B.; Radez, I.; Zilnik, L.F. Solvent extraction of lovastatin from a fermentation broth. Separ. Purif. Tech.,  2012, 96, 187-193.
[http://dx.doi.org/10.1016/j.seppur.2012.06.006] 
[105] 
Alberts, A.W.; Chen, J.; Kuron, 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.; Hirshfield, J.; Hoogsteen, K.; Liesch, J.; Springer, J. Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA,  1980, 77(7), 3957-3961.
[http://dx.doi.org/10.1073/pnas.77.7.3957] [PMID:  6933445] 
[106] 
Endo, A.; Monacolin, K. Monacolin K, a new hypocholesterolemic agent that specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. J. Antibiot. (Tokyo),  1980, 33(3), 334-336.
[http://dx.doi.org/10.7164/antibiotics.33.334] [PMID:  7380744] 
[107] 
Hajjaj, H.; Niederberger, P.; Duboc, P. Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl. Environ. Microbiol.,  2001, 67(6), 2596-2602.
[http://dx.doi.org/10.1128/AEM.67.6.2596-2602.2001] [PMID:  11375168] 
[108] 
Hoffman, W.F.; Alberts, A.W.; Anderson, P.S.; Chen, J.S.; Smith, R.L.; Willard, A.K. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. 4. Side chain ester derivatives of mevinolin. J. Med. Chem.,  1986, 29(5), 849-852.
[http://dx.doi.org/10.1021/jm00155a040] [PMID:  3634830] 
[109] 
Huang, X.; Liang, Y.; Yang, Y.; Lu, X. Single-step production of the simvastatin precursor monacolin J by engineering of an industrial strain of Aspergillus terreus. Metab. Eng.,  2017, 42, 109-114.
[http://dx.doi.org/10.1016/j.ymben.2017.06.005] [PMID:  28619444] 
[110] 
Weng, T.C.; Yang, Y.H.; Lin, S.J.; Tai, S.H. A systematic review and meta-analysis on the therapeutic equivalence of statins. J. Clin. Pharm. Ther.,  2010, 35(2), 139-151.
[http://dx.doi.org/10.1111/j.1365-2710.2009.01085.x] [PMID:  20456733] 
[111] 
Syed, M.B.; Rajasimman, M. Fermentative production and optimization of mevastatin in submerged fermentation using Aspergillus terreus. Biotechnol. Rep. (Amst.),  2015, 6, 124-128.
[http://dx.doi.org/10.1016/j.btre.2015.04.002] [PMID:  28435810] 
[112] 
Hatanaka, T.; Honda, S.; Sasaki, S.; Katayama, K.; Koizumi, T. Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin. J. Pharmacokinet. Biopharm.,  1998, 26(3), 329-347.
[http://dx.doi.org/10.1023/A:1023237510458] [PMID:  10098103] 
[113] 
Ditschuneit, H.H.; Kuhn, K.; Ditschuneit, H. Comparison of different HMG-CoA reductase inhibitors. Eur. J. Clin. Pharmacol.,  1991, 40(Suppl. 1), S27-S32.
[http://dx.doi.org/10.1007/BF03216285] [PMID:  1904357] 
[114] 
Barrios-González, J.; Miranda, R.U. Biotechnological production and applications of statins. Appl. Microbiol. Biotechnol.,  2010, 85(4), 869-883.
[http://dx.doi.org/10.1007/s00253-009-2239-6] [PMID:  19820926] 
[115] 
Seydametova, E. Production of pravastatin by filamentous fungi isolated from soil, 2013.http://umpir.ump.edu.my/id/eprint/7293/1/CD7797.pdf
[116] 
Seydametova, E. Novel pravastatin-producing Penicillium janthinellum strain isolated from soil. Int. J. Biosci. Biochem. Bioinform.,  2015, 5(2), 80.
[http://dx.doi.org/10.17706/ijbbb.2015.5.2.80-90] 
[117] 
Hosobuchi, M.; Kurosawa, K.; Yoshikawa, H. Application of computer to monitoring and control of fermentation process: Microbial conversion of ML-236B Na to pravastatin. Biotechnol. Bioeng.,  1993, 42(7), 815-820.
[http://dx.doi.org/10.1002/bit.260420705] [PMID:  18613128] 
[118] 
Syed, M.B.; Ponnusamy, T. Bioconversion of mevastatin to pravastatin by various microorganisms and its application - A review. Biocatal. Agric. Biotechnol.,  2017, 13, 62-74.
[http://dx.doi.org/10.1016/j.bcab.2017.11.002] 
[119] 
Shaligram, N.S.; Singh, S.K.; Singhal, R.S.; Szakacs, G.; Pandey, A. Effect of precultural and nutritional parameters on compactin production by solid-state fermentation. J. Microbiol. Biotechnol.,  2009, 19(7), 690-697.
[PMID:  19652517] 
[120] 
Dzhavakhiya, V.V.; Voinova, T.M.; Glagoleva, E.V.; Petukhov, D.V.; Ovchinnikov, A.I.; Kartashov, M.I.; Kuznetsov, B.B.; Skryabin, K.G. Strain improvement of Streptomyces xanthochromogenes RIA 1098 for enhanced pravastatin production at high compactin concentrations. Indian J. Microbiol.,  2015, 55(4), 440-446.
[http://dx.doi.org/10.1007/s12088-015-0537-5] [PMID:  26543270] 
[121] 
Jekkel, A.; Konya, A.; Barta, I.; Ilkoy, E.; Somogyi, G.; Ambrus, G. Microbial process for pravastatin. US Patent 6,750,366 B2. 2004.
[122] 
Lin, C.L.; Tang, Y.L.; Lin, S.M. Efficient bioconversion of compactin to pravastatin by the quinoline-degrading microorganism Pseudonocardia carboxydivorans isolated from petroleum-contaminated soil. Bioresour. Technol.,  2011, 102(22), 10187-10193.
[http://dx.doi.org/10.1016/j.biortech.2011.09.029] [PMID:  21974888] 
[123] 
Talan, D.A.; Krishnadasan, A.; Gorwitz, R.J.; Fosheim, G.E.; Limbago, B.; Albrecht, V.; Moran, G.J.; Group, E.M.I.N.S. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin. Infect. Dis.,  2011, 53(2), 144-149.
[http://dx.doi.org/10.1093/cid/cir308] [PMID:  21690621] 
[124] 
Ames, B.D.; Nguyen, C.; Bruegger, J.; Smith, P.; Xu, W.; Ma, S.; Wong, E.; Wong, S.; Xie, X.; Li, J.W.; Vederas, J.C.; Tang, Y.; Tsai, S.C. Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis. Proc. Natl. Acad. Sci. USA,  2012, 109(28), 11144-11149.
[http://dx.doi.org/10.1073/pnas.1113029109] [PMID:  22733743] 
[125] 
Mukhtar, H.; Ijaz, S.S. Ikram-ul-Haq. Upstream and downstream processing of lovastatin by Aspergillus terreus. Cell Biochem. Biophys.,  2014, 70(1), 309-320.
[http://dx.doi.org/10.1007/s12013-014-9914-7] [PMID:  24671671] 
[126] 
Kaur, H.; Kaur, A.; Saini, H.S.; Chadha, B.S. Screening and selection of lovastatin hyper-producing mutants of Aspergillus terreus using cyclic mutagenesis. Acta Microbiol. Immunol. Hung.,  2009, 56(2), 169-180.
[http://dx.doi.org/10.1556/AMicr.56.2009.2.5] [PMID:  19621768] 
[127] 
El-Sayed, A.S.A.; Abdel-Ghany, S.E.; Ali, G.S. Genome editing approaches: Manipulating of lovastatin and taxol synthesis of filamentous fungi by CRISPR/Cas9 system. Appl. Microbiol. Biotechnol.,  2017, 101(10), 3953-3976.
[http://dx.doi.org/10.1007/s00253-017-8263-z] [PMID:  28389711] 
[128] 
Katayama, T.; Tanaka, Y.; Okabe, T.; Nakamura, H.; Fujii, W.; Kitamoto, K.; Maruyama, J. Development of a genome editing technique using the CRISPR/Cas9 system in the industrial filamentous fungus Aspergillus oryzae. Biotechnol. Lett.,  2016, 38(4), 637-642.
[http://dx.doi.org/10.1007/s10529-015-2015-x] [PMID:  26687199] 
[129] 
Li, N.; Li, M.; Yu, Z.; Zhou, J.; Huang, J. One-step fermentation for producing simvastatin via RNAi silencing of lovF gene in Aspergillus terreus. Sheng Wu Gong Cheng Xue Bao,  2016, 32(4), 478-486.
[PMID:  28853269] 
[130] 
Li, M.; Zhang, Z.J.; Kong, X.D.; Yu, H.L.; Zhou, J.; Xu, J.H. Engineering Streptomyces coeli color carbonyl reductase for efficient atorvastatin precursor synthesis. Appl. Environ. Microbiol.,  2017, 83(12), e00603-e00617.
[http://dx.doi.org/10.1128/AEM.00603-17] [PMID:  28389544] 
[131] 
Fujii, Y.; Norihisa, K.; Fujii, T.; Aritoku, Y.; Kagawa, Y.; Sallam, K.I.; Johdo, O.; Arisawa, A.; Tamura, T. Construction of a novel expression vector in Pseudonocardia autotrophica and its application to efficient biotransformation of compactin to pravastatin, a specific HMG-CoA reductase inhibitor. Biochem. Biophys. Res. Commun.,  2011, 404(1), 511-516.
[http://dx.doi.org/10.1016/j.bbrc.2010.12.013] [PMID:  21144838] 
[132] 
Chen, C.H.; Hu, H.Y.; Cho, Y.C.; Hsu, W.H. Screening of compactin-resistant microorganisms capable of converting compactin to pravastatin. Curr. Microbiol.,  2006, 53(2), 108-112.
[http://dx.doi.org/10.1007/s00284-005-0276-7] [PMID:  16802209] 
[133] 
Basu, S.; Bose, C.; Ojha, N.; Das, N.; Das, J.; Pal, M.; Khurana, S. Evolution of bacterial and fungal growth media. Bioinformation,  2015, 11(4), 182-184.
[http://dx.doi.org/10.6026/97320630011182] [PMID:  26124557] 
[134] 
Xie, X.; Wong, W.W.; Tang, Y. Improving simvastatin bioconversion in Escherichia coli by deletion of bioH. Metab. Eng.,  2007, 9(4), 379-386.
[http://dx.doi.org/10.1016/j.ymben.2007.05.006] [PMID:  17625941] 
[135] 
Xie, X.; Pashkov, I.; Gao, X.; Guerrero, J.L.; Yeates, T.O.; Tang, Y. Rational improvement of simvastatin synthase solubility in Escherichia coli leads to higher whole-cell biocatalytic activity. Biotechnol. Bioeng.,  2009, 102(1), 20-28.
[http://dx.doi.org/10.1002/bit.22028] [PMID:  18988191] 
[136] 
Bilheimer, D.W.; Grundy, S.M.; Brown, M.S.; Goldstein, J.L. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc. Natl. Acad. Sci. USA,  1983, 80(13), 4124-4128.
[http://dx.doi.org/10.1073/pnas.80.13.4124] [PMID:  6575399] 
[137] 
Thompson, G.R.; Ford, J.; Jenkinson, M.; Trayner, I. Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolaemia. Q. J. Med.,  1986, 60(232), 803-811.
[PMID:  3640503] 
[138] 
Bradford, R.H.; Shear, C.L.; Chremos, A.N.; Dujovne, C.; Downton, M.; Franklin, F.A.; Gould, A.L.; Hesney, M.; Higgins, J.; Hurley, D.P. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch. Intern. Med.,  1991, 151(1), 43-49.
[http://dx.doi.org/10.1001/archinte.1991.00400010067008] [PMID:  1985608] 
[139] 
Steinberg, D.; Gotto, A.M., Jr Preventing coronary artery disease by lowering cholesterol levels: Fifty years from bench to bedside. JAMA,  1999, 282(21), 2043-2050.
[http://dx.doi.org/10.1001/jama.282.21.2043] [PMID:  10591387] 
[140] 
Davey Smith, G.; Pekkanen, J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ,  1992, 304(6824), 431-434.
[http://dx.doi.org/10.1136/bmj.304.6824.431] [PMID:  1532138] 
[141] 
Greenspan, M.D.; Yudkovitz, J.B. Mevinolinic acid biosynthesis by Aspergillus terreus and its relationship to fatty acid biosynthesis. J. Bacteriol.,  1985, 162(2), 704-707.
[PMID:  3988710] 
[142] 
Novak, N.; Gerdin, S.; Berovic, M. Increased lovastatin formation by Aspergillus terreus using repeated fed-batch process. Biotechnol. Lett.,  1997, 19(10), 947-948.
[http://dx.doi.org/10.1023/A:1018322628333] 
[143] 
Gunde-Cimerman, N.; Cimerman, A. Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-lovastatin. Exp. Mycol.,  1995, 19(1), 1-6.
[http://dx.doi.org/10.1006/emyc.1995.1001] [PMID:  7614366] 
[144] 
Serizawa, N.; Hosobuchi, M.; Yoshikawa, H. Biochemical and fermentation technological approaches to production of pravastatin, a HMG-CoA reductase inhibitor; Drugs Pharmaceut. Sci, 1997. 
[145] 
Matsuoka, T.; Miyakoshi, S.; Tanzawa, K.; Nakahara, K.; Hosobuchi, M.; Serizawa, N. Purification and characterization of cytochrome P-450sca from Streptomyces carbophilus. ML-236B (compactin) induces a cytochrome P-450sca in Streptomyces carbophilus that hydroxylates ML-236B to pravastatin sodium (CS-514), a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase. Eur. J. Biochem.,  1989, 184(3), 707-713.
[http://dx.doi.org/10.1111/j.1432-1033.1989.tb15070.x] [PMID:  2509201] 
[146] 
Novák, P.; Müller, K.; Santhanam, K.S.; Haas, O. Electrochemically active polymers for rechargeable batteries. Chem. Rev.,  1997, 97(1), 207-282.
[http://dx.doi.org/10.1021/cr941181o] [PMID:  11848869] 
[147] 
Bizukojc, M.; Ledakowicz, S. A macrokinetic modelling of the biosynthesis of lovastatin by Aspergillus terreus. J. Biotechnol.,  2007, 130(4), 422-435.
[http://dx.doi.org/10.1016/j.jbiotec.2007.05.007] [PMID:  17602773] 
[148] 
Mouafi, F.E.; Abo Elsoud, M.M.; Moharam, M.E. Optimization of biosurfactant production by Bacillus brevis using response surface methodology. Biotechnol. Rep. (Amst.),  2016, 9, 31-37.
[http://dx.doi.org/10.1016/j.btre.2015.12.003] [PMID:  28352589] 
[149] 
Seenivasan, A.; Subhagar, S.; Aravindan, R.; Viruthagiri, T. Microbial production and biomedical applications of lovastatin. Indian J. Pharm. Sci.,  2008, 70(6), 701-709.
[http://dx.doi.org/10.4103/0250-474X.49087] [PMID:  21369428] 
[150] 
Arai, H. Foxing caused by fungi: twenty-five years of study. Int. Biodeterior. Biodegradation,  2000, 46(3), 181-188.
[http://dx.doi.org/10.1016/S0964-8305(00)00063-9] 
[151] 
Istvan, E.S.; Deisenhofer, J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science,  2001, 292(5519), 1160-1164.
[http://dx.doi.org/10.1126/science.1059344] [PMID:  11349148] 
[152] 
Oberlin, A.; Endo, M.; Koyama, T. Filamentous growth of carbon through benzene decomposition. J. Cryst. Growth,  1976, 32(3), 335-349.
[http://dx.doi.org/10.1016/0022-0248(76)90115-9] 
[153] 
Syed, M.B.; Ponnusamy, T. Bioconversion of mevastatin to pravastatin by various microorganisms and its applications-A review. Biocatal. Agric. Biotechnol.,  2018, 13, 62-74.
[http://dx.doi.org/10.1016/j.bcab.2017.11.002] 
[154] 
Yamamoto, A.; Sudo, H.; Endo, A. Therapeutic effects of ML-236B in primary hypercholesterolemia. Atherosclerosis,  1980, 35(3), 259-266.
[http://dx.doi.org/10.1016/0021-9150(80)90124-0] [PMID:  7362699] 
[155] 
Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S.M.; Ahmad, M.; Alnemri, E.S.; Wang, X. Cytochrome C and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell,  1997, 91(4), 479-489.
[http://dx.doi.org/10.1016/S0092-8674(00)80434-1] [PMID:  9390557] 
[156] 
Samiee, S.M.; Moazami, N.; Haghighi, S.; Aziz Mohseni, F.; Mirdamadi, S.; Bakhtiari, M.R. Screening of lovastatin production by filamentous fungi. Iran. Biomed. J.,  2003, 7(1), 29-33.
[157] 
Jaivel, N.; Marimuthu, P. Isolation and screening of lovastatin producing microorganisms. Int. J. Eng. Sci. Technol.,  2010, 2(7), 2607-2611.
[158] 
Suraya, N.; Owolabi, F.; Khalil, H.A.; Saurabh, C.K.; Paridah, M.; Asniza, M.; Samsul, R. Synergistic effect of oil palm based pozzolanic materials/oil palm waste on polyester hybrid composite. J. Polym. Environ.,  2018, 26(10), 4063-4072.
[http://dx.doi.org/10.1007/s10924-018-1278-4] 
[159] 
Upendra, R.; Pratima, K.; Amiri, Z.; Shwetha, L.; Ausim, M. Screening and molecular characterization of natural fungal isolates producing lovastatin. J. Microb. Biochem. Technol.,  2013, 5(2), 25-30.
[160] 
Korani, S.; Korani, M.; Butler, A.E.; Sahebkar, A. Genetics and rheumatoid arthritis susceptibility in Iran. J. Cell. Physiol.,  2019, 234(5), 5578-5587.
[http://dx.doi.org/10.1002/jcp.27379] [PMID:  30238988] 
[161] 
Wang, G.; Zhang, L.; Zhang, J. A review of electrode materials for electrochemical supercapacitors. Chem. Soc. Rev.,  2012, 41(2), 797-828.
[http://dx.doi.org/10.1039/C1CS15060J] [PMID:  21779609] 
[162] 
Padhye, S.G.; Nagarsenker, M.S. Simvastatin solid lipid nanoparticles for oral delivery: Formulation development and in vivo evaluation. Indian J. Pharm. Sci.,  2013, 75(5), 591-598.
[PMID:  24403661] 
[163] 
Shah, M.; Pathak, K. Development and statistical optimization of solid lipid nanoparticles of simvastatin by using 2(3) full-factorial design. AAPS PharmSciTech,  2010, 11(2), 489-496.
[http://dx.doi.org/10.1208/s12249-010-9414-z] [PMID:  20309652] 
[164] 
Safwat, S.; Hathout, R.M.; Ishak, R.A.; Mortada, N.D. Augmented simvastatin cytotoxicity using optimized lipid nanocapsules: A potential for breast cancer treatment. J. Liposome Res.,  2017, 27(1), 1-10.
[http://dx.doi.org/10.3109/08982104.2015.1137313] [PMID:  26872624] 
[165] 
Anitha, A.; Sowmya, S.; Kumar, P.S.; Deepthi, S.; Chennazhi, K.; Ehrlich, H.; Tsurkan, M.; Jayakumar, R. Chitin and chitosan in selected biomedical applications. Prog. Polym. Sci.,  2014, 39(9), 1644-1667.
[http://dx.doi.org/10.1016/j.progpolymsci.2014.02.008] 
[166] 
Prabaharan, M. Chitosan-based nanoparticles for tumor-targeted drug delivery. Int. J. Biol. Macromol.,  2015, 72, 1313-1322.
[http://dx.doi.org/10.1016/j.ijbiomac.2014.10.052] [PMID:  25450550] 
[167] 
Zhang, B.B.; Xing, H.B.; Jiang, B.J.; Chen, L.; Xu, G.R.; Jiang, Y.; Zhang, D.Y. Using millet as substrate for efficient production of monacolin K by solid-state fermentation of Monascus ruber. J. Biosci. Bioeng.,  2018, 125(3), 333-338.
[http://dx.doi.org/10.1016/j.jbiosc.2017.10.011] [PMID:  29157871] 
[168] 
Lee, S.S.; Lee, J.H.; Lee, I. Strain improvement by overexpression of the laeA gene in Monascus pilosus for the production of monascus-fermented rice. J. Microbiol. Biotechnol.,  2013, 23(7), 959-965.
[http://dx.doi.org/10.4014/jmb.1303.03026] [PMID:  23727802] 
[169] 
Dikshit, R.; Tallapragada, P. Statistical optimization of lovastatin and confirmation of nonexistence of citrinin under solid-state fermentation by Monascus sanguineus. Yao Wu Shi Pin Fen Xi,  2016, 24(2), 433-440.
[http://dx.doi.org/10.1016/j.jfda.2015.11.008] [PMID:  28911599] 
[170] 
Manzoni, M.; Bergomi, S.; Rollini, M.; Cavazzoni, V. Production of statins by filamentous fungi. Biotechnol. Lett.,  1999, 21(3), 253-257.
[http://dx.doi.org/10.1023/A:1005495714248] 
[171] 
Brown, A.G.; Smale, T.C.; King, T.J.; Hasenkamp, R.; Thompson, R.H. Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum. J. Chem. Soc. Perkin 1,  1976, 11, 1165-1170.
[172] 
Shaligram, N.S.; Singh, S.K.; Singhal, R.S.; Pandey, A.; Szakacs, G. Compactin production studies using Penicillium brevicompactum under solid-state fermentation conditions. Appl. Biochem. Biotechnol.,  2009, 159(2), 505-520.
[http://dx.doi.org/10.1007/s12010-008-8461-3] [PMID:  19099208] 
[173] 
Bazaraa, W.A.; Hamdy, M.K.; Toledo, R. Bioreactor for continuous synthesis of compactin by Penicillium cyclopium. J. Ind. Microbiol. Biotechnol.,  1998, 21(4), 192-202.
[http://dx.doi.org/10.1038/sj.jim.2900565] 
[174] 
Doss, S.L.; Chu, C.K.; Mesbah, M.K.; Cutler, H.G.; Cole, P.D.; Arrendale, R.F.; Springer, J.P. Isolation of compactin (a hypocholestrolemic metabolite) from a new source: Penicillium cyclopium. J. Nat. Prod.,  1986, 49(2), 357-358.
[http://dx.doi.org/10.1021/np50044a036] [PMID:  3734817] 
[175] 
Primrose, S.; King, D.; Yaworski, E.; Radhakrishnan, J.; He, D.; Xiao, X.U.S. U.S. Patent US 5,691,173.. 
[176] 
Chung, K.J.; Lee, J.K.; Lee, S.C.; Park, J.W.; Seo, D.J. Method for
producing pravastatin precursor, ML-236B. U.S. Patent US
6,204,032 B1, March 28. 2001.
[177] 
Dikshit, R.; Tallapragada, P. Bio-synthesis and screening of nutrients for lovastatin by Monascus sp. under solid-state fermentation. J. Food Sci. Technol.,  2015, 52(10), 6679-6686.
[http://dx.doi.org/10.1007/s13197-014-1678-y] [PMID:  26396416] 
Cite As
Current Pharmaceutical Biotechnology

Biotechnological Production of Statins: Metabolic Aspects and Genetic Approaches

Abstract

Graphical Abstract
