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Overexpression of global regulator LaeA increases secondary metabolite production in Monascus purpureus


Monascus is a filamentous fungus that produces several secondary metabolites. Here, we investigated the effects of the global regulator LaeA on the synthesis of pigments and monacolin K in Monascus purpureus with spectrophotometer and HPLC methods. The LaeA gene was isolated from M. purpureus M1 to create an overexpression construct. An LaeA-overexpressing strain L3 was with 48.6% higher monacolin K production than the M1 strain. The L3 strain also produced higher Monascus pigments than the M1 strain. SEM showed that LaeA overexpression resulted in altered mycelial morphology. Compared with the M1 strain, the L3 strain expressed higher levels of monacolin K synthesis-related genes mokA, mokB, mokE, and mokH. Overall, these results suggest that LaeA plays a role in regulating the production of secondary metabolites and mycelial growth in Monascus. This study provides important insights into the mechanisms underlying the effects of the LaeA gene on the secondary metabolites of M. purpureus.

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  1. Abe Y, Suzuki T, Mizuno T, Ono C, Iwamoto K, Hosobuchi M, Yoshikawa H (2002) Effect of increased dosage of the ML-236B (compactin) biosynthetic gene cluster on ML-236B production in Penicillium citrinum. Mol Gen Genomics 268(1):130–137.

  2. Blanc PJ, Laussac JP, Bars JL, Bars PL, Loret MO, Pareilleux A, Prome D, Prome JC, Santerre AL, Goma G (1995) Characterization of monascidin A from Monascus as citrinin. Int J Food Microbiol 27(2–3):201.

  3. Bok J, Balajee S, Marr K, Andes D, Nielsen K, Frisvad J, Keller N (2005) LaeA, a regulator of morphogenetic fungal virulence factors. Eukaryot Cell 4(9):1574–1582.

  4. Chen FC, Manchand PS, Whalley WB (1971) The chemistry of fungi. LXIV. The structure of monascin: the relative stereochemistry of the azaphilones. J Chem Soc Perkin 21(21):3577–3579.

  5. Chen W, Chen R, Liu Q, He Y, He K, Ding X, Kang L, Guo X, Xie N, Zhou Y (2017) Orange, red, yellow: biosynthesis of azaphilone pigments in Monascus fungi. Chem Sci 8(7):4917–4925.

  6. Chun-Lin L, Tsung-Yu T, Jyh-Jye W, Tzu-Ming P (2006) In vivo hypolipidemic effects and safety of low dosage Monascus powder in a hamster model of hyperlipidemia. Appl Microbiol Biotechnol 70(5):533–540.

  7. Crespo-Sempere A, Marín S, Sanchis V, Ramos AJ (2013) VeA and LaeA transcriptional factors regulate ochratoxin A biosynthesis in Aspergillus carbonarius. Int J Food Microbiol 166(3):479–486.

  8. Dhale MA, Divakar S, Umesh K S, Vijayalakshmi G (2007) Isolation and characterization of dihydromonacolin-MV from Monascus purpureus for antioxidant properties. Appl Microbiol Biotechnol 73(5):1197–1202.

  9. Endo A (1979) Monacolin K, a new hypocholesterolemic sgent produced by a Monascus species. J Antibiot 32(8):852–854.

  10. Feng Y, Shao Y, Zhou Y, Chen F (2015) Effects of glycerol on pigments and monacolin K production by the high-monacolin K-producing but citrinin-free strain, Monascus pilosus MS-1. Eur Food Res Technol 240(3):635–643.

  11. Feng Y, Chen W, Chen F (2016) A Monascus pilosus MS-1 strain with high-yield monacolin K but no citrinin. Food Sci Biotechnol 25(4):1115–1122.

  12. Heinz T, Schuchardt JP, Möller K, Hadji P, Hahn A (2016) Low daily dose of 3 mg monacolin K from RYR reduces the concentration of LDL-C in a randomized, placebo-controlled intervention. Nutr Res 36(10):1162–1170.

  13. Jeun J, Jung H, Kim JH, Yong OK, Youn SH, Shin CS (2008) Effect of the monascus pigment threonine derivative on regulation of the cholesterol level in mice. Food Chem 107(3):1078–1085.

  14. Jin WB, Keller NP (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot Cell 3(2):527–535.

  15. Jůzlová P, Martínková L, Křen V (1996) Secondary metabolites of the fungus Monascus: a review. J Ind Microbiol 16(3):163–170.

  16. Kale SP, Milde L, Trapp MK, Frisvad JC, Keller NP, Jin WB (2008) Requirement of LaeA for secondary metabolism and sclerotial production in Aspergillus flavus. Fungal Genet Biol 45(10):1422–1429.

  17. Karimiaghcheh R, Jin WB, Phatale PA, Smith KM, Baker SE, Lichius A, Omann M, Zeilinger S, Seiboth B, Rhee C (2013) Functional analyses of Trichoderma reesei LAE1 reveal conserved and contrasting roles of this regulator. G3:Genes Genomes Genet 3(2):369–378.

  18. Keats S E, Keller NP (2008) Regulation of secondary metabolite production in filamentous ascomycetes. Mycol Res 112(2):225–230.

  19. Keller NP, Turner G, Bennett JW (2005) Fungal secondary metabolism-from biochemistry to genomics. Nat Rev Microbiol 3(12):937–947.

  20. Ko CY, Lin HTV, Tsai GJ (2013) Gamma-aminobutyric acid production in black soybean milk by Lactobacillus brevis FPA 3709 and the antidepressant effect of the fermented product on a forced swimming rat model. Process Biochem 48(4):559–568.

  21. Koli SH, Mohite BV, Suryawanshi RK, Borase HP, Patil SV (2018) Extracellular red Monascus pigment-mediated rapid one-step synthesis of silver nanoparticles and its application in biomedical and environment. Bioprocess Biosyst Eng 41(5):1–13.

  22. Lee CL, Kung YH, Wu CL (2010) Monascin and Ankaflavin act as novel hypolipidemic and high-density lipoprotein cholesterol-raising agents in Red Mold Dioscorea. J Agric Food Chem 58(16):9013–9019.

  23. Li W, Zhang Z, Lin L, Terenius O (2017) Antheraea pernyi (Lepidoptera: Saturniidae) and its importance in sericulture, food consumption, and traditional Chinese medicine. J Econ Entomol 110(4):1404–1411.

  24. Lian X, Wang C, Guo K (2007) Identification of new red pigments produced by Monascus ruber. Dyes Pigments 73(1):121–125.

  25. López JLC, Pérez JAS, Sevilla JMF, Fernández FGA, Grima EM, 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(2):270–277.

  26. Lv J, Zhang BB, Liu XD, Zhang C, Chen L, Xu GR, Cheung PCK (2017) Enhanced production of natural yellow pigments from Monascus purpureus by liquid culture: the relationship between fermentation conditions and mycelial morphology. J Biosci Bioeng 124(4):452–458.

  27. Maron DJ, Fazio S, Linton MF (2000) Current perspectives on statins. Circ 101(2):207–213.

  28. Md Pravej A, Alka P, Ali M, Bibhu Prasad P (2013) Five new secondary metabolites from Monascus purpureus-fermented Hordeum vulgare and Sorghum bicolor. Nat Prod Res 27(20):1848–1855.

  29. Ming-Jen C, Ming-Der W, Ih-Sheng C, Chung-Yi C, Wen-Li L, Gwo-Fang Y (2010) Secondary metabolites from the red mold rice of Monascus purpureus BCRC 38113. Nat Prod Res 24(18):1719–1725.

  30. Ozlem SB, Ozgür B, Oliver V, Hee Soo P, Stefan I, Jennifer G, Kap-Hoon H, Jae-Hyuk Y, Braus GH (2010) LaeA control of velvet family regulatory proteins for light-dependent development and fungal cell-type specificity. PLoS Genet 6(12):e1001226.

  31. Patakova P (2013) Monascus secondary metabolites: production and biological activity. J Ind Microbiol Biotechnol 40(2):169–181.

  32. Perrin RM, Fedorova ND, Woo BJ, Cramer RA, Wortman JR, Stanley K H, Nierman WC, Keller NP (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog 3(4):e50.

  33. Sakai K, Kinoshita H, Nihira T (2012) Heterologous expression system in Aspergillus oryzae for fungal biosynthetic gene clusters of secondary metabolites. Appl Microbiol Biotechnol 93(5):2011–2022.

  34. Seiboth B, Karimi RA, Phatale PA, Linke R, Hartl L, Sauer DG, Smith KM, Baker SE, Freitag M, Kubicek CP (2012) The putative protein methyltransferase LAE1 controls cellulase gene expression in Trichoderma reesei. Mol Microbiol 84(6):1150–1164.

  35. Sung-Yun H, Jee-Hwan O, Inhyung L (2011) Simultaneous enrichment of deglycosylated ginsenosides and monacolin K in red ginseng by fermentation with Monascus pilosus. Biosci Biotechnol Biochem 75(8):1490–1495.

  36. Venil CK, Zakaria ZA, Wan AA (2013) Bacterial pigments and their applications. Process Biochem 48(7):1065–1079.

  37. Wang C, Chen D, Chen M, Wang Y, Li Z, Li F (2015) Stimulatory effects of blue light on the growth, monascin and ankaflavin production in Monascus. Biotechnol Lett 37(5):1043–1048.

  38. Wang R, Leng Y, Shrestha S, Zhong S (2016) Coordinated and independent functions of velvet -complex genes in fungal development and virulence of the fungal cereal pathogen Cochliobolus sativus. Fungal Biol 120(8):948–960.

  39. Xing W, Deng C, Hu CH (2010) Molecular cloning and characterization of the global regulator LaeA in Penicillium citrinum. Biotechnol Lett 32(11):1733–1737.

  40. Yi-Pei C, Ching-Ping T, Li-Ling L, Chun-Lin W, I-Ching C, Wen-Jung W, Ming-Der W, Gwo-Fang Y (2008) Cloning and characterization of monacolin K biosynthetic gene cluster from Monascus pilosus. J Agric Food Chem 56(14):5639–5646.

  41. Yi-Pei C, Gwo-Fang Y, Sung-Yuan H, Yu-Shan L, Wei-Yi W, Li-Ling L, Ching-Ping T (2013) Identification of the mokH gene encoding transcription factor for the upregulation of monacolin K biosynthesis in Monascus pilosus. J Agric Food Chem 58(1):287–293.

  42. Zhang C, Liang J, Yang L, Sun B, Wang C (2017) De Novo RNA sequencing and transcriptome analysis of Monascus purpureus and analysis of key genes involved in Monacolin K biosynthesis. PLoS One 12(1):e0170149.

  43. Zhang C, Liang J, Zhang A, Hao S, Zhang H, Zhu Q, Sun B, Wang C (2019) Overexpression of Monacolin K biosynthesis genes in the Monascus purpureus azaphilone polyketide pathway. J Agric Food Chem 67(9):2563–2569.

  44. Zheng Y, Cao S, Huang Y, Liao G, Hu C (2014) Overexpression of LaeA enhances mevastatin production and reduces sporulation of Penicillium citrinum. Acta Microbiol Sin 54(12):1438–1445

  45. Zheng G, Zhan Y, Tang Q, Chen T, Zhang X (2018) Monascin inhibits IL-1β induced catabolism in mouse chondrocytes and ameliorates murine osteoarthritis. Food Funct 9(3):1454–1464.

  46. Zhiyuan LU, Zhang Y, Xuejuan LI, Feng X, Xue H, Guo S, Liu J, Xian SA (2017) Determination of β-Phenylethanol in rice wine by solid phase extraction-gas chromatography. Food Sci 38(24):212–217.

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This work was supported by Beijing Nova Program (Grant No. Z181100006218021), Beijing Natural Science Foundation (Grant No. KZ201810011015), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five--year Plan (Grant No. CIT&TCD201804023), National Natural Science Foundation of China (Grant No. 31301411, 31571801, and 31401669), National Key Research and Development Program (Grant No. 2016YFD0400802, 2016YFD0400502-02), The construct of innovation service ability--Science and technology achievement transformation--Upgrade project (Grant No. PXM 2016-014213-000034), Beijing Municipal Science and Technology Project (Grant No. Z171100002217019), and Beijing Excellent Talents Training Project (Grant No. 2016000020124G025).

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Correspondence to Chan Zhang or Chengtao Wang.

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Zhang, C., Zhang, H., Zhu, Q. et al. Overexpression of global regulator LaeA increases secondary metabolite production in Monascus purpureus. Appl Microbiol Biotechnol (2020).

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  • Monascus purpureus
  • Monacolin K
  • Gene overexpression
  • LaeA gene