Abstract
Lovastatin, and its semisynthetic derivative simvastatine, has great medical and economic importance, besides great potential for other uses. In the last years, a deeper and more complex view of secondary metabolism regulation has emerged, with the incorporation of cluster-specific and global transcription factors, and their relation to signaling cascades, as well as the new level of epigenetic regulation. Recently, a new mechanism, which regulates lovastatin biosynthesis, at transcriptional level, has been discovered: reactive oxygen species (ROS) regulation; also new unexpected environmental stimuli have been identified, which induce the synthesis of lovastatin, like quorum sensing-type molecules and support stimuli. The present review describes this new panorama and uses this information, together with the knowledge on lovastatin biosynthesis and genomics, as the foundation to analyze literature on optimization of fermentation parameters and medium composition, and also to fully understand new strategies for strain genetic improvement. This new knowledge has been applied to the development of more effective culture media, with the addition of molecules like butyrolactone I, oxylipins, and spermidine, or with addition of ROS-generating molecules to increase internal ROS levels in the cell. It has also been applied to the development of new strategies to generate overproducing strains of Aspergillus terreus, including engineering of the cluster-specific transcription factor (lovE), global transcription factors like the ones implicated in ROS regulation (or even mitochondrial alternative respiration aox gen), or the global regulator LaeA. Moreover, there is potential to apply some of these findings to the development of novel unconventional production systems.
Key points
• New findings in regulation of lovastatin biosynthesis, like ROS regulation.
• Induction by unexpected stimuli: autoinducer molecules and support stimuli.
• Recent reports on culture medium and process optimization from this stand point.
• Applications to molecular genetic strain improvement methods and production systems.
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References
Alberts AW, 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 (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A 77:3957–3961. https://doi.org/10.1073/pnas.77.7.3957
Askenazi M, Driggers E, Holtzman D, 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 21:150–156. https://doi.org/10.1038/nbt781
Auclair K, Kennedy J, Hutchinson CR, 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. https://doi.org/10.1016/s0960-894x(01)00290-6
Ávila N, Tarragó-Castellanos MR, Barrios-González J (2017) Environmental cues that induce the physiology of solid medium: a study on lovastatin production by Aspergillus terreus. J Appl Microbiol 122:1029–1038. https://doi.org/10.1111/jam.13391
Baños JG, Tomasini A, Szakacs 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 108:105–110. https://doi.org/10.1016/j.jbiosc.2009.03.006
Barrios-González J (2012) Solid-state fermentation: physiology of solid medium, its molecular basis and applications. Process Biochem 47:175–185. https://doi.org/10.1016/j.procbio.2011.11.016
Barrios-González J (2018) Chapter 13-Secondary metabolites production: physiological advantages in solid-state fermentation. In: Pandey A, Larroche C, Soccol CR (eds) Current developments in biotechnology and bioengineering: current advances in solid-state fermentation, 1st edn. Elsevier, Amsterdam, pp 257–283
Barrios-González J, Mejía A (1996) Production of secondary metabolites by solid-state fermentation. In: El-Gewely MR (ed) Biotechnology annual review, 2nd edn. Elsevier, Amsterdam, pp 185–121
Barrios-González J, Mejía A (2008) Production of antibiotics and other commercially valuable secondary metabolites. In: Pandey A, Soccol CR, Larroche C (eds) Current developments in solid-state fermentation, 1st edn. Springer, New York, pp 302–336
Barrios-González J, Miranda RU (2010) Biotechnological production and applications of statins. Appl Microbiol Biotechnol 85:869–883. https://doi.org/10.1007/s00253-009-2239-6
Barrios-González J, Tarragó-Castellanos MR (2017) Solid-state fermentation: special physiology of fungi. In: Mérillon JM, Ramawat KG (eds) Fungal metabolites, 1st edn. Springer, Switzerland, pp 319–347
Barrios-González J, Fernández FJ, Tomasini A (2003) Microbial secondary metabolites production and strain improvement. Indian J Biotechnol 2:322–333
Barrios-Gonzalez J, Baños JG, Covarrubias AA, Garay-Arroyo A (2008) Lovastatin biosynthetic genes of Aspergillus terreus are expressed differentially in solid-state and in liquid submerged fermentation. Appl Microbiol Biotechnol 79:179–186. https://doi.org/10.1007/s00253-008-1409-2
Barriuso J, Nguyen DT, Li JW, Roberts JN, MacNevin G, Chaytor JL, Marcus SL, Vederas JC, Ro DK (2011) Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin J by a single cytochrome P450 monooxygenase, LovA. J Am Chem Soc 133:8078–8808. https://doi.org/10.1021/ja201138v
Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon NJ, Keller NP, Yu JH, Braus GH (2008) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320:1504–1506. https://doi.org/10.1126/science.1155888
Bibb MJ (2005) Regulation of secondary metabolism in Streptomycetes. Curr Opin Microbiol 8:208–215. https://doi.org/10.1016/j.mib.2005.02.016
Bibián ME, Pérez-Sánchez A, Mejía A, Barrios-González J (2020) Penicillin and cephalosporin biosynthesis are also regulated by reactive oxygen species. Appl Microbiol Biotechnol 104:1773–1783. https://doi.org/10.1007/s00253-019-10330-2
Bigelis R, He H, Yang H, Chang LP, Greenstein M (2006) Production of fungal antibiotics using polymeric solid supports in solid-state and liquid fermentation. J Ind Microbiol Biotechnol 33:815–826. https://doi.org/10.1007/s10295-006-0126-z
Bizukojc M, Gonciarz J (2015) Influence of oxygen on lovastatin biosynthesis by Aspergillus terreus ATCC 20542 quantitatively studied on the level of individual pellets. Bioprocess Biosyst Eng 38:1251–1266. https://doi.org/10.1007/s00449-015-1366-y
Bizukojc M, Ledakowicz S (2007a) A macrokinetic modelling of the biosynthesis of lovastatin by Aspergillus terreus. J Biotechnol 130:422–435. https://doi.org/10.1016/j.jbiotec.2007.05.007
Bizukojc M, Ledakowicz S (2007b) Simultaneous biosynthesis of (+)-geodin by a lovastatin producing fungus Aspergillus terreus. J Biotechnol 132:453–460. https://doi.org/10.1016/j.jbiotec.2007.07.493
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 42:198–207. https://doi.org/10.1016/j.bej.2008.06.022
Bizukojc M, Ledakowicz S (2009) Physiological, morphological and kinetic aspects of lovastatin biosynthesis by Aspergillus terreus. Biotechnol J 4:647–664. https://doi.org/10.1002/biot.200800289
Bizukojc M, Ledakowicz S (2010) The morphological and physiological evolution of Aspergillus terreus mycelium in the submerged culture and its relation to the formation of secondary metabolites. World J Microbiol Biotechnol 26:41–54. https://doi.org/10.1007/s11274-009-0140-1
Bizukojc M, Pecyna M (2011) Lovastatin and (+)-geodin formation by Aspergillus terreus ATCC 20542 in a batch culture with the simultaneous use of lactose and glycerol as carbon sources. Eng Life Sci 3:272–282. https://doi.org/10.1002/elsc.201000179
Bizukojc M, Pawlak M, Boruta T, Gonciarz J (2012) Effect of pH on biosynthesis of lovastatin and other secondary metabolites by Aspergillus terreus ATCC 20542. J Biotecnol 162:253–261. https://doi.org/10.1016/j.jbiotec.2012.09.007
Bok JW, Keller NP (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot 3:527–535. https://doi.org/10.1128/ec.3.2.527-535.2004
Bok JW, Noordermeer D, Kale SP, Keller NP (2006) Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol Microbiol 61:1636–1645. https://doi.org/10.1111/j.1365-2958.2006.05330.x
Brown SH, Scott JB, Bhaheetharan J, Sharpee WC, Milde L, Wilson RA, Keller NP (2009) Oxygenase coordination is required for morphological transition and the host–fungus interaction of Aspergillus flavus. Mol Plant-Microbe Interact 22:882–894. https://doi.org/10.1094/MPMI-22-7-0882
Caddick MX, Brownlee AG, Arst HN (1986) Regulation of gene expression by pH of the growth medium in Aspergillus nidulans. Mol Gen Genet 203:346–353. https://doi.org/10.1007/BF00333978
Campbell CD, Vederas JC (2010) Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes. Biopolymers 93:755–763. https://doi.org/10.1002/bip.21428
Casas-Lopéz 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. Enzym Microb Technol 33:270–277. https://doi.org/10.1016/S0141-0229(03)00130-3
Casas-López JL, Rodríguez Porcel EM, Vilches Ferrón MA, Sánchez Pérez JA, Fernández Sevilla JM, Chisti Y (2004) Lovastatin inhibits its own synthesis in Aspergillus terreus. J Ind Microbiol Biotechnol 31:48–50. https://doi.org/10.1007/s10295-004-0108-y
Casas-Lopéz 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 116:61–77. https://doi.org/10.1016/j.jbiotec.2004.10.005
Couch RD, Gaucher GM (2004) Rational elimination of Aspergillus terreus sulochrin production. J Biotechnol 108:171–177. https://doi.org/10.1007/s00253-009-2239-6
Endo A (2010) A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 86:484–493. https://doi.org/10.2183/pjab.86.484
Fuqua C, Parsek MR, Greenberg EP (2001) Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing. Annu Rev Genet 3:439–468. https://doi.org/10.1146/annurev.genet.35.102401.090913
Hajjaj H, Niederberger P, Duboc P (2001) Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Environ Microbiol 67:2596–2602. https://doi.org/10.1128/AEM.67.6.2596-2602.2001
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 a multifunctional polyketide synthase gene. Chem Biol 6:429–439. https://doi.org/10.1016/S1074-5521(99)80061-1
Hong SY, Roze LV, Wee J, Linz JE (2013) Evidence that a transcription factor regulatory network coordinates oxidative stress response and secondary metabolism in Aspergilli. Microbiologyopen 2:144–160. https://doi.org/10.1002/mbo3.63
Horowitz-Brown S, Zarnowski R, Sharpee WC, Keller NP (2008) Morphological transitions governed by density dependence and lipoxygenase activity in Aspergillus flavus. Appl Environ Microbiol 74:5674–5685. https://doi.org/10.1128/AEM.00565-08
Huang X, Li H (2009) Cloning and bioinformatic analysis of lovastatin biosynthesis regulatory gene lovE. Chin Med J 122:1800–1805. https://doi.org/10.3760/cma.j.issn.0366-6999.2009.15.016
Huang X, Tang S, Zheng L, Teng Y, Yang Y, Zhu J, Lu X (2019) Construction of an efficient and robust Aspergillus terreus cell factory for monacolin J production. ACS Synth Biol 8:818–825. https://doi.org/10.1021/acssynbio.8b00489
Istvan E (2003) Statin inhibition of HMG-CoA reductase: a 3-dimensional view. Atheroscler Suppl 4:3–8. https://doi.org/10.1016/s1567-5688(03)00003-5
Itoh H, Miura A, Matsui M, Arazoe T, Nishida K, Kumagai T, Arita M, Tamano K, Machida M, Shibata T (2018) Knockout of the SREBP system increases production of the polyketide FR901512 in filamentous fungal sp. No. 14919 and lovastatin in Aspergillus terreus ATCC20542. Appl Microbiol Biotechnol 102:1393–1405. https://doi.org/10.1007/s00253-017-8685-7
Jahromi MF, Liang JB, Mohamad R, Goh YM, Shokryazdan P, Ho YW (2013) Lovastatin-enriched rice straw enhances biomass quality and suppresses ruminal methanogenesis. Biomed Res Int 2013:1–13. https://doi.org/10.1155/2013/604721
Jia Z, Zhang X, Zhao Y, Cao X (2009) Effects of carbon sources on fungal morphology and lovastatin biosynthesis by submerged cultivation of Aspergillus terreus. Asia Pac J Chem Eng 4:672–677. https://doi.org/10.1002/apj.316
Jia Z, Zhang X, Zhao Y, Cao X (2010) Enhancement of lovastatin production by supplementing polyketide antibiotics to the submerged culture of Aspergillus terreus. Appl Biochem Biotechnol 160:2014–2025. https://doi.org/10.1007/s12010-009-8762-1
Keller NP (2015) Translating biosynthetic gene clusters into fungal armor and weaponry. Nat Chem Biol 11:671–677. https://doi.org/10.1038/nchembio.1897
Kenne GJ, Gummadidala PM, Omebeyinje MH, Mondal AM, Bett DK, McFadden S, Bromfield S, Banaszek N, Velez-Martinez M, Mitra C, Mikell I, Chatterjee S, Wee J, Chanda A (2018) Activation of aflatoxin biosynthesis alleviates total ROS in Aspergillus parasiticus. Toxins 10:57. https://doi.org/10.3390/toxins10020057
Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR (1999) Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284:1368–1372. https://doi.org/10.1126/science.284.5418.1368
Lai L-ST, Kuo C-M, Tsai S-Y (2001) Influence of increased dissolved oxygen tensions by agitation on secondary metabolite production by a mutant of Aspergillus terreus in a 5 L fermentor. J Chin Inst Chem Eng 32:135–142
Lai L-ST, Tsai T-H, Wang TC (2002) Application of oxygen vectors to Aspergillus terreus cultivation. J Biosci Bioeng 94:453–459. https://doi.org/10.1016/S1389-1723(02)80224-9
Lai L-ST, 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 38:1317–1326. https://doi.org/10.1016/S0032-9592(02)00330-8
Lai L-ST, Tsai T-H, Wang TC, Cheng TY (2005) The influence of culturing environments on lovastatin production by Aspergillus terreus in submerged cultures. Enzym Microb Technol 36:737–748. https://doi.org/10.1016/j.enzmictec.2004.12.021
Lai L-ST, Hung CS, Lo CC (2007) Effects of lactose and glucose on production of itaconic acid and lovastatin by Aspergillus terreus ATCC 20542. J Biosci Bioeng 104:9–13
Li SW, Li M, Song HP, Feng JL, Tai XS (2011) Induction of a high-yield lovastatin mutant of Aspergillus terreus by (1)(2)C(6)(+) heavy-ion beam irradiation and the influence of culture conditions on lovastatin production under submerged fermentation. Appl Biochem Biotechnol 165:913–925
Ma SM, Li JW, Choi JW, Zhou H, Lee KK, Moorthie VA, Xie X, Kealey JT, Da Silva NA, Vederas JC, Tang Y (2009) Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326:589–592. https://doi.org/10.1126/science.1175602
Mäkelä MR, Aguilar-Pontes MV, van Rossen-Uffink D, Peng N, de Vries RP (2018) The fungus Aspergillus niger consumes sugars in a sequential manner that is not mediated by the carbon catabolite repressor CreA. Sci Rep 8:6655. https://doi.org/10.1038/s41598-018-25152-x
Maron DJ, Fazio S, Linton MF (2000) Current perspectives on statins. Circulation 101:207–213. https://doi.org/10.1161/01.cir.101.2.207
Martín JF, Casqueiro J, Kosalková K, Marcos AT, Gutiérrez S (1999) Penicillin and cephalosporin biosynthesis: mechanism of carbon catabolite regulation of penicillin production. Anton Leeuw Int J G 75:21–31. https://doi.org/10.1023/A:1001820109140
Martín J, García-Estrada C, Rumbero A, Recio E, Albillos SM, Ullán RV, Martín JF (2011) Characterization of an autoinducer of penicillin biosynthesis in Penicillium chrysogenum. Appl Environ Microbiol 77:5688–5696. https://doi.org/10.1128/AEM.00059-11
Martín J, García-Estrada C, Kosalková K, Ullán RV, Albillos SM, Martín JF (2012) The inducers 1,3 diaminopropane and spermidine produce a drastic increase in the expression of the penicillin biosynthetic genes for prolonged time, mediated by the LaeA regulator. Fungal Genet Biol 49:1004–1013. https://doi.org/10.1016/j.fgb.2012.10.001
Miranda RU, Gómez-Quiroz LE, Mejía A, Barrios-González J (2013) Oxidative sate in idiophase links reactive oxygen species (ROS) and lovastatin biosynthesis: differences and similarities in submerged-and solid-sate fermentations. Fungal Biol 117:85–93. https://doi.org/10.1016/j.funbio.2012.12.001
Miranda RU, Gómez-Quiroz LE, Mendoza M, Pérez-Sánchez A, Fierro F, Barrios-González J (2014) Reactive oxygen species regulate lovastatin biosynthesis in Aspergillus terreus during submerged and solid-state fermentation. Fungal Biol 118:879–989. https://doi.org/10.1016/j.funbio.2014.09.002
Moore RN, Bigam G, Chan JK, Hogg AM, Nakashima TT, Vederas JC (1985) Biosynthesis of the hypocholesterolemic agent mevinolin by Aspergillus terreus. Determination of the origin of carbon, hydrogen, and oxygen atoms by carbon-13 NMR and mass spectrometry. J Am Chem Soc 107:3694–3701. https://doi.org/10.1021/ja00298a046
Mulder KC, Mulinari F, Franco OL, Soares MS, Magalhães BS, Parachin NS (2015) Lovastatin production: from molecular basis to industrial process optimization. Biotechnol Adv 33:648–665. https://doi.org/10.1016/j.biotechadv.2015.04.001
Ohnishi Y, Yamazaki H, Kato JY, Tomono A, Horinouchi S (2005) AdpA, a central transcriptional regulator in the A-factor regulatory cascade that leads to morphological development and secondary metabolism in Streptomyces griseus. Biosci Biotechnol Biochem 69:431–439. https://doi.org/10.1271/bbb.69.431
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 18:356–360. https://doi.org/10.1016/S0167-7799(00)01466-9
Osman ME, Khattab OH, Zaghlol GM, Abd El-Hameed RM (2011) Optimization of some physical and chemical factors for lovastatin productivity by local strain of Aspergillus terreus. AJBAS 5:718–732 https://pdfs.semanticscholar.org/072a/138e428f0d08d5a0bc7ff00fd6619f2cc908.pdf
Palmer JM, Keller NP (2010) Secondary metabolism in fungi: does chromosomal location matter? Curr Opin Microbiol 13:431–436. https://doi.org/10.1016/j.mib.2010.04.008
Palonen EK, Neffling MR, Raina S, Brandt A, Keshavarz T, Meriluoto J, Soini J (2014) Butyrolactone I quantification from lovastatin producing Aspergillus terreus using tandem mass spectrometry-evidence of signalling functions. Microorganisms 2:111–127. https://doi.org/10.3390/microorganisms2020111
Patil RH, Krishnan P, Maheshwari VL (2011) Production of lovastatin by wild strains of Aspergillus terreus. Nat Prod Commun 6:183–186. https://doi.org/10.1177/1934578X1100600207
Peberdy JF (1985) Biology of Penicillium. In: Demain AL, Solomon NA (eds) Biology of industrial microorganisms. The Benjamin/Cummings Pub Co Inc London, Amsterdam, Don Mills, Ontario, Sydney, Tokyo, pp 407–431
Pecyna M, Bizukojc M (2011) Lovastatin biosynthesis by Aspergillus terreus with the simultaneous use of lactose and glycerol in a discontinuous fed-batch culture. J Biotechnol 151:77–86. https://doi.org/10.1016/j.jbiotec.2010.10.079
Pérez T, Mejía A, Barrios-González J (2015) Amplification of laeA gene in Aspergillus terreus: a strategy to generate lovastatin-overproducing strains for solid-state fermentation. Int J Curr Microbiol App Sci 4:537–555
Pérez-Sánchez A, Uribe-Carvajal S, Cabrera-Orefice A, Barrios-González J (2017) Key role of alternative oxidase in lovastatin solid-state fermentation. Appl Microbiol Biotechnol 101:7347–7356. https://doi.org/10.1007/s00253-017-8452-9
Porcel EMR, Lopéz JLC, Perez JAS, Sevilla JMF, Chisti Y (2005) Effects of pellet morphology on broth rheology in fermentations of Aspergillus terreus. Biochem Eng J 26:139–144
Porcel ER, López JLC, Ferrón MAV, Pérez JA, Sánchez JL, Chisti Y (2006) Effects of the sporulation conditions on the lovastatin production by Aspergillus terreus. Bioprocess Biosyst Eng 29:1–5. https://doi.org/10.1007/s00449-006-0048-1
Porcel EMR, Lopéz JLC, Perez JAS, Chisti Y (2007) Enhanced production of lovastatin in a bubble column by Aspergillus terreus using a two-stage feeding strategy. J Chem Technol Biotechnol 82:58–64
Porcel EMR, Lopez JLC, Pérez JAS, Chisti Y (2008) Lovastatin production by Aspergillus terreus in a two-staged feeding operation. J Chem Technol Biotechnol 83:1236–1243. https://doi.org/10.1002/jctb.1932
Raina S, De Vizio D, Palonen EK, Odell M, Brandt AM, Soini JT, Keshavarz T (2012) Is quorum sensing involved in lovastatin production in the filamentous fungus Aspergillus terreus? Process Biochem 47:843–852. https://doi.org/10.1016/j.procbio.2012.02.021
Recio E, Colinas A, Rumbero A, Aparicio JF, Martín JF (2004) PI factor, a novel type quorum-sensing inducer elicits pimaricin production in Streptomyces natalensis. J Biol Chem 279:41586–41593. https://doi.org/10.1074/jbc.M402340200
Reverberi M, Punelli F, Scarpari M, Camera E, Zjalic S, Ricelli A, Fanelli C, Fabbri AA (2010) Lipoperoxidation affects ochratoxin A biosynthesisin Aspergillus ochraceus and its interaction with wheat seeds. Appl Microbiol Biotechnol 85:1935–1946. https://doi.org/10.1007/s00253-009-2220-4
Riad A, Bien S, Westermann D, Becher PM, Loya K, Landmesser U, Kroemer HK, Schultheiss HP, Tschöpe C (2009) Pretreatment with statin attenuates the cardiotoxicity of doxorubicin in mice. Cancer Res 69:695–699. https://doi.org/10.1158/0008-5472.CAN-08-3076
Sanchez S, Demain AL (2002) Metabolic regulation of fermentation processes. Enzym Microb Technol 31:895–906. https://doi.org/10.1016/S0141-0229(02)00172-2
Schimmel TG, Coffman AD, Parsons SJ (1998) Effect of butyrolactone I on the producing fungus, Aspergillus terreus. Appl Environ Microbiol 64:3707–3712. https://doi.org/10.1128/AEM.64.10.3707-3712.1998
Schmitt EK, Kempken R, Kück U (2001) Functional analysis of promoter sequences of cephalosporin C biosynthesis genes from Acremonium chrysogenum: specific DNA-protein interactions and characterization of the transcription factor PACC. Mol Gen Genomics 265:508–518. https://doi.org/10.1007/s004380000439
Seenivasan A, Subhagar S, Aravindan R, Viruthagiri T (2008) Microbial production and biomedical applications of lovastatin. Indian J Pharm Sci 70:701–709. https://doi.org/10.4103/0250-474X.49087
Segreth MP, Bonnefoy A, Bronstrup M, Kanuf M, Schummer D, Toti L, Vértesy L, Wetzel-Raynal MC, Wink J, Seibert G (2003) Conisetin a novel tetramic from Coniochaeta ellipsoidea DSM 13856. J Antibiot 56:114–122. https://doi.org/10.7164/973antibiotics.56.114
Shi DK, Zhu J, Sun ZH, Zhang G, Liu R, Zhang TJ, Wang SL, Ren A, Zhao MW (2017) Alternative oxidase impacts ganoderic acid biosynthesis by regulating intracellular ROS levels in Ganoderma lucidum. Microbiology 163:1466–1476. https://doi.org/10.1099/mic.0.000527
Singh SK, Pandey A (2013) Emerging approaches in fermentative production of statins. Appl Biochem Biotechnol 171:927–938. https://doi.org/10.1007/s12010-013-0400-2
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. https://doi.org/10.1007/s00253-010-2722-0
Strauss J, Reyes-Dominguez Y (2011) Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet Biol 48:62–69. https://doi.org/10.1016/j.fgb.2010.07.009
Suárez T, Peñalva MA (1996) Characterization of a Penicillium chrysogenum gene encoding a PacC transcription factor and its binding sites in the divergent pcbAB-pcbC promoter of the penicillin biosynthetic cluster. Mol Microbiol 20:529–540. https://doi.org/10.1046/j.1365-2958.1996.5421065
Subazini TK, Kumar GR (2011) Characterization of lovastatin biosynthetic cluster proteins in Aspergillus terreus strain ATCC 20542. Bioinformation 6:250–254. https://doi.org/10.6026/97320630006250
Subhan M, Faryal R, Macreadie I (2016) Exploitation of Aspergillus terreus for the production of natural statins. J Fungi 2:13. https://doi.org/10.3390/jof2020013
Suryanarayan S (2003) Current industrial practice in solid state fermentations for secondary metabolite production: the Biocon India experience. Biochem Eng J 13:189–195. https://doi.org/10.1016/S1369-703X(02)00131-6
Tilburn J, Sarkar S, Widdick DA, Espeso EA, Orejas M, Mungroo J, Peñalva MA, Herbert NA (1995) The Aspergillus PacC zinc-finger transcription factor mediates regulation of both acid- and alkaline-expressed genes by ambient pH. EMBO J 14:779–790. https://doi.org/10.1002/j.1460-2075.1995.tb07056
Tsitsigiannis DI, Keller NP (2006) Oxylipins act as determinants of natural product biosynthesis and seed colonization in Aspergillus nidulans. Mol Microbiol 59:882–892. https://doi.org/10.1111/j.1365-2958.2005.05000.x
Tudzynski B (2014) Nitrogen regulation of fungal secondary metabolism in fungi. Front Microbiol 5:656. https://doi.org/10.3389/fmicb.2014.00656
Van den Berg MA, Hans M (2011) Improved statin production. US 20110223640 A1
Veillard N, Mach F (2002) Statins: the new aspirin? Cell Mol Life Sci 59:1771–1786. https://doi.org/10.1007/PL00012505
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 Microbiol 8:113–120. https://doi.org/10.1007/BF01578762
Wagschal K, Yoshizawa Y, Witter DJ, Liu Y, Vederas JC (1996) Biosynthesis of ML-236C and the hypocholesterolemic agents compactin by Penicillum aurantiogriseum and lovastatin by Aspergillus terreus: determination of the origin of carbon, hydrogen and oxygen atoms by 13C NMR spectrometry and observation of unusual labeling of acetatederived oxygen by 18O2. J Chem Soc Perkin Trans 1:2357–2363. https://doi.org/10.1039/P19960002357
Wakisaka Y, Segawa T, Imamura K, Sakiyama T, Nakanishi K (1998) Development of a cylindrical apparatus for membrane-surface liquid culture and production of kojic acid using Aspergillus oryzae NRRL484. J Ferment Bioeng 85:488–494. https://doi.org/10.1016/S0922-338X(98)80067-6
Waters CM, Bassler BL (2005) Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol 21:319–346. https://doi.org/10.1146/annurev.cellbio.21.012704.131001
Wen Q, Cao X, Chen Z, Zheng Z, Long C, Zheng B, Huang Z (2020) An overview of Monascus fermentation processes for monacolin K production. Open Chem 18:10–21. https://doi.org/10.1515/chem-2020-0006
Xie X, Watanabe K, Wojcicki WA, Wang CCC, Tang Y (2006) Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem Biol 13:1161–1169. https://doi.org/10.1016/j.chembiol.2006.09.008
Xu W, Chooi YH, Choi JW, Li S, Vederas JC, Da Silva NA, Tang Y (2013) LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis. Angew Chem Int Ed Eng 52:6472–6475. https://doi.org/10.1002/anie.201302406
Yasuhara A, Ogawa A, Tanaka T, Sakiyama T, Nakanishi K (1994) Production of neutral protease from Aspergillus oryzae by a novel cultivation method on a microporous membrane. Biotechnol Tech 8:249–254. https://doi.org/10.1007/bf00155416
Zhgun AA, Kalinin SG, Novak MI, Domracheva AG, Petukhov DV, Dzhavakhiya VV, Eldarov MA, Bartoshevich IE (2015) The influence of polyamines on cephalosporine c biosynthesis in Acremonium chrysogenum strains. Izv Vuzov Prikl Khim Biotekhn 14:47–54
Zhgun AA, Nuraeva GK, Dumina MV, Voinova TM, Dzhavakhiya VV, Eldarov MA (2019) 1,3-diaminopropane and spermidine upregulate lovastatin production and expression of lovastatin biosynthetic genes in Aspergillus terreus via LaeA regulation. Appl Biochem Microbiol 55:243–254. https://doi.org/10.1134/S0003683819020170
Funding
This study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico, project CB-2013-01 222028. ME Bibián and A. Pérez-Sánchez received scholarships from CONACyT, Mexico, Nos. 300611 and 283909 respectively.
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JBG analyzed data and wrote the manuscript, APS gathered and selected information and figure design, and MEB gathered and selected information, and wrote tables and references.
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Barrios-González, J., Pérez-Sánchez, A. & Bibián, M.E. New knowledge about the biosynthesis of lovastatin and its production by fermentation of Aspergillus terreus. Appl Microbiol Biotechnol 104, 8979–8998 (2020). https://doi.org/10.1007/s00253-020-10871-x
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DOI: https://doi.org/10.1007/s00253-020-10871-x