Skip to main content
Log in

Improvement of Lipid and Terpenoid Yield in Thraustochytrids Using Chemical Regulators: A Review

  • Review Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

For the increasing demand for lipids and terpenoids in humans, biological fermentation has become an attractive choice due to the safety and sustainability. Thraustochytrids have been identified as promising producers of polyunsaturated fatty acids because of their high lipid content and simple fatty acid composition. In addition, thraustochytrids are also potential producers of terpenoids for their completed mevalonate pathway. Chemical regulators can be used to stimulate or inhibit metabolic pathways, which are equivalent to effects of overexpression and suppression approaches. The application of chemical regulators is potentially an easy and practical approach to improve the lipid and terpenoid yield in thraustochytrids, which has become a research focus. In this review, the mechanisms of chemical regulators promoting lipid and terpenoid biosynthesis in thraustochytrids are elucidated. Various chemical regulators which can directly enhance the biosynthesis of lipids and terpenoids are summarized depending on the type of chemicals. In addition, some chemical regulators are demonstrated to indirectly improve lipid and terpenoid yield by reducing the conversion of metabolites and reducing oxidative stress. Therefore, the addition of chemical regulators can be a useful alternative strategy for improving lipid and terpenoid accumulation in large-scale cultivation of thraustochytrids.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  1. Fossier Marchan, L., K. J. Lee Chang, P. D. Nichols, W. J. Mitchell, J. L. Polglase, and T. Gutierrez (2018) Taxonomy, ecology and biotechnological applications of thraustochytrids: a review. Biotechnol. Adv. 36: 26–46.

    Article  CAS  PubMed  Google Scholar 

  2. Patel, A. K., A. S. Chauhan, P. Kumar, P. Michaud, V. K. Gupta, J.-S. Chang, C.-W. Chen, C.-D. Dong, and R. R. Singhania (2022) Emerging prospects of microbial production of omega fatty acids: recent updates. Bioresour. Technol. 360: 127534.

    Article  CAS  PubMed  Google Scholar 

  3. Leyland, B., S. Leu, and S. Boussiba (2017) Are Thraustochytrids algae? Fungal Biol. 121: 835–840.

    Article  PubMed  Google Scholar 

  4. Du, F., Y.-Z. Wang, Y.-S. Xu, T.-Q. Shi, W.-Z. Liu, X.-M. Sun, and H. Huang (2021) Biotechnological production of lipid and terpenoid from thraustochytrids. Biotechnol. Adv. 48: 107725.

    Article  CAS  PubMed  Google Scholar 

  5. Anthony, S., E. Caderby, S. Bouhouda, F. Rébeillé, H. Griffiths, and S. Da Rocha Gomes (2022) How do algae oils change the omega-3 polyunsaturated fatty acids market? OCL. 29: 20.

    Article  Google Scholar 

  6. Gupta, A., C. J. Barrow, and M. Puri (2022) Multiproduct biorefinery from marine thraustochytrids towards a circular bioeconomy. Trends Biotechnol. 40: 448–462.

    Article  CAS  PubMed  Google Scholar 

  7. Kikukawa, H., K. Watanabe, S. Kishino, M. Takeuchi, A. Ando, Y. Izumi, and E. Sakuradani (2022) Recent trends in the field of lipid engineering. J. Biosci. Bioeng. 133: 405–413.

    Article  CAS  PubMed  Google Scholar 

  8. Wang, Q., W. Han, W. Jin, S. Gao, and X. Zhou (2021) Docosahexaenoic acid production by Schizochytrium sp.: review and prospect. Food Biotechnol. 35: 111–135.

    Article  CAS  Google Scholar 

  9. Zhang, X.-Y., B. Li, B.-C. Huang, F.-B. Wang, Y.-Q. Zhang, S.-G. Zhao, M. Li, H.-Y. Wang, X.-J. Yu, X.-Y. Liu, J. Jiang, and Z.-P. Wang (2022) Production, biosynthesis, and commercial applications of fatty acids from oleaginous fungi. Front. Nutr. 9: 873657.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ali, M. K., B. Sen, Y. He, M. Bai, and G. Wang (2022) Media supplementation with mannitol and biotin enhances squalene production of Thraustochytrium ATCC 26185 through increased glucose uptake and antioxidative mechanisms. Molecules 27: 2449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu, X., C. Huang, Z. Xu, H. Xu, Z. Wang, and X. Yu (2020) The strategies to reduce cost and improve productivity in DHA production by Aurantiochytrium sp.: from biochemical to genetic respects. Appl. Microbiol. Biotechnol. 104: 9433–9447.

    Article  CAS  PubMed  Google Scholar 

  12. Lyu, L., Q. Wang, and G. Wang (2020) Cultivation and diversity analysis of novel marine thraustochytrids. Mar. Life Sci. Technol. 3: 263–275.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Saini, R. K., P. Prasad, R. V. Sreedhar, K. Akhilender Naidu, X. Shang, and Y.-S. Keum (2021) Omega-3 polyunsaturated fatty acids (PUFAs): emerging plant and microbial sources, oxidative stability, bioavailability, and health benefits-a review. Antioxidants (Basel) 10: 1627.

    Article  CAS  PubMed  Google Scholar 

  14. Yan, Q. and B. F. Pfleger (2020) Revisiting metabolic engineering strategies for microbial synthesis of oleochemicals. Metab. Eng. 58: 35–46.

    Article  CAS  PubMed  Google Scholar 

  15. Bellou, S., I. E. Triantaphyllidou, D. Aggeli, A. M. Elazzazy, M. N. Baeshen, and G. Aggelis (2016) Microbial oils as food additives: recent approaches for improving microbial oil production and its polyunsaturated fatty acid content. Curr. Opin. Biotechnol. 37: 24–35.

    Article  CAS  PubMed  Google Scholar 

  16. Chi, G., Y. Xu, X. Cao, Z. Li, M. Cao, Y. Chisti, and N. He (2022) Production of polyunsaturated fatty acids by Schizochytrium (Aurantiochytrium) spp. Biotechnol. Adv. 55: 107897.

    Article  CAS  PubMed  Google Scholar 

  17. Liu, Y., X. Ren, C. Fan, W. Wu, W. Zhang, and Y. Wang (2022) Health benefits, food applications, and sustainability of microalgae-derived N-3 PUFA. Foods 11: 1883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Echeverría, F., R. Valenzuela, M. Catalina Hernandez-Rodas, and A. Valenzuela (2017) Docosahexaenoic acid (DHA), a fundamental fatty acid for the brain: new dietary sources. Prostaglandins Leukot. Essent. Fatty Acids 124: 1–10.

    Article  Google Scholar 

  19. Power, R., A. Prado-Cabrero, R. Mulcahy, A. Howard, and J. M. Nolan (2019) The role of nutrition for the aging population: implications for cognition and Alzheimer’s disease. Annu. Rev. Food Sci. Technol. 10: 619–639.

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz-Roso, M. B., V. Echeverry-Alzate, B. Ruiz-Roso, J. C. Quintela, S. Ballesteros, V. Lahera, N. de Las Heras, J. A. López-Moreno, and B. Martín-Fernández (2018) Low phytanic acid-concentrated DHA prevents cognitive deficit and regulates Alzheimer disease mediators in an ApoE(-/-) mice experimental model. Nutrients 11: 11.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cardoso, C., C. Afonso, and N. M. Bandarra (2016) Dietary DHA and health: cognitive function ageing. Nutr. Res. Rev. 29: 281–294.

    Article  CAS  PubMed  Google Scholar 

  22. Khozin-Goldberg, I., U. Iskandarov, and Z. Cohen (2011) LC-PUFA from photosynthetic microalgae: occurrence, biosynthesis, and prospects in biotechnology. Appl. Microbiol. Biotechnol. 91: 905–915.

    Article  CAS  PubMed  Google Scholar 

  23. Ren, X., Y. Liu, C. Fan, H. Hong, W. Wu, W. Zhang, and Y. Wang (2022) Production, processing, and protection of microalgal n-3 PUFA-rich oil. Foods 11: 1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yarkent, Ç. and S. S. Oncel (2022) Recent progress in microalgal squalene production and its cosmetic application. Biotechnol. Bioprocess Eng. 27: 295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reboleira, J., R. Felix, T. F. L. Vicente, A. P. Januário, C. Félix, M. M. R. de Melo, C. M. Silva, A. C. Ribeiro, J. A. Saraiva, N. M. Bandarra, M. Sapatinha, M. C. Paulo, J. Coutinho, and M. F. L. Lemos (2022) Uncovering the bioactivity of Aurantiochytrium sp.: a comparison of extraction methodologies. Mar. Biotechnol (NY). 24: 40–54.

    Article  CAS  PubMed  Google Scholar 

  26. Cheng, P., S. Okada, C. Zhou, P. Chen, S. Huo, K. Li, M. Addy, X. Yan, and R. R. Ruan (2019) High-value chemicals from Botryococcus braunii and their current applications - A review. Bioresour. Technol. 291: 121911.

    Article  CAS  PubMed  Google Scholar 

  27. Rau, E.-M., Z. Bartosova, K. A. Kristiansen, I. M. Aasen, P. Bruheim, and H. Ertesvåg (2022) Overexpression of two new Acyl-CoA:diacylglycerol acyltransferase 2-like Acyl-CoA:sterol acyltransferases enhanced squalene accumulation in Aurantiochytrium limacinum. Front. Microbiol. 13: 822254.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Aasen, I. M., H. Ertesvåg, T. M. Heggeset, B. Liu, T. Brautaset, O. Vadstein, and T. E. Ellingsen (2016) Thraustochytrids as production organisms for docosahexaenoic acid (DHA), squalene, and carotenoids. Appl. Microbiol. Biotechnol. 100: 4309–4321.

    Article  CAS  PubMed  Google Scholar 

  29. Xie, Y., B. Sen, and G. Wang (2017) Mining terpenoids production and biosynthetic pathway in thraustochytrids. Bioresour. Technol. 244: 1269–1280.

    Article  CAS  PubMed  Google Scholar 

  30. Orozco Colonia, B. S., G. Vinícius de Melo Pereira, and C. R. Soccol (2020) Omega-3 microbial oils from marine thraustochytrids as a sustainable and technological solution: a review and patent landscape. Trends Food Sci. Technol. 99: 244–256.

    Article  CAS  Google Scholar 

  31. Chen, X., B. Sen, S. Zhang, M. Bai, Y. He, and G. Wang (2021) Chemical and physical culture conditions significantly influence the cell mass and docosahexaenoic acid content of Aurantiochytrium limacinum strain PKU#SW8. Mar. Drugs 19: 671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pawar, P. R., A. M. Lali, and G. Prakash (2021) Integration of continuous-high cell density-fed-batch fermentation for Aurantiochytrium limacinum for simultaneous high biomass, lipids and docosahexaenoic acid production. Bioresour. Technol. 325: 124636.

    Article  CAS  PubMed  Google Scholar 

  33. Qiu, X., X. Xie, and D. Meesapyodsuk (2020) Molecular mechanisms for biosynthesis and assembly of nutritionally important very long chain polyunsaturated fatty acids in microorganisms. Prog. Lipid Res. 79: 101047.

    Article  CAS  PubMed  Google Scholar 

  34. Huang, P.-W., Y.-S. Xu, X.-M. Sun, T.-Q. Shi, Y. Gu, C. Ye, and H. Huang (2021) Development of an efficient gene editing tool in Schizochytrium sp. and improving its lipid and terpenoid biosynthesis. Front. Nutr. 8: 795651.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Larroude, M., T. Rossignol, J.-M. Nicaud, and R. Ledesma-Amaro (2018) Synthetic biology tools for engineering Yarrowia lipolytica. Biotechnol. Adv. 36: 2150–2164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sun, X.-M., Y.-S. Xu, and H. Huang (2021) Thraustochytrid cell factories for producing lipid compounds. Trends Biotechnol. 39: 648–650.

    Article  CAS  PubMed  Google Scholar 

  37. Hasan, M., M. S. Ahmad-Hamdani, A. M. Rosli, and H. Hamdan (2021) Bioherbicides: an eco-friendly tool for sustainable weed management. Plants (Basel) 10: 1212.

    Article  CAS  PubMed  Google Scholar 

  38. Choi, I., H. Son, and J.-H. Baek (2021) Tricarboxylic acid (TCA) cycle intermediates: regulators of immune responses. Life (Basel) 11: 69.

    CAS  PubMed  Google Scholar 

  39. Nagappan, S., S. Devendran, P.-C. Tsai, H. Jayaraman, V. Alagarsamy, A. Pugazhendhi, and V. K. Ponnusamy (2020) Metabolomics integrated with transcriptomics and proteomics: evaluation of systems reaction to nitrogen deficiency stress in microalgae. Process Biochem. 91: 1–14.

    Article  CAS  Google Scholar 

  40. Tan, K. W. and Y. K. Lee (2016) The dilemma for lipid productivity in green microalgae: importance of substrate provision in improving oil yield without sacrificing growth. Biotechnol. Biofuels 9: 255.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wu, X., D. B. Tovilla-Coutiño, and M. A. Eiteman (2020) Engineered citrate synthase improves citramalic acid generation in Escherichia coli. Biotechnol. Bioeng. 117: 2781–2790.

    Article  CAS  PubMed  Google Scholar 

  42. Icard, P., L. Poulain, and H. Lincet (2012) Understanding the central role of citrate in the metabolism of cancer cells. Biochim. Biophys. Acta 1825: 111–116.

    CAS  PubMed  Google Scholar 

  43. Zhang, A., Y. He, B. Sen, W. Wang, X. Wang, and G. Wang (2022) Optimal NaCl medium enhances squalene accumulation in Thraustochytrium sp. ATCC 26185 and influences the expression levels of key metabolic genes. Front. Microbiol. 13: 900252.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Cui, G. Z., Z. Wang, W. Hong, Y.-J. Liu, Z. Chen, Q. Cui, and X. Song (2019) Enhancing tricarboxylate transportation-related NADPH generation to improve biodiesel production by Aurantiochytrium. Algal Res. 40: 101505.

    Article  Google Scholar 

  45. Ren, L. J., H. Huang, A.-H. Xiao, M. Lian, L.-J. Jin, and X.-J. Ji (2009) Enhanced docosahexaenoic acid production by reinforcing acetyl-CoA and NADPH supply in Schizochytrium sp. HX-308. Bioprocess Biosyst. Eng. 32: 837–843.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, M., Y. Gao, C. Yu, J. Wang, K. Weng, Q. Li, Y. He, Z. Guo, H. Zhang, J. Huang, and L. Li (2022) Transcriptome analysis of malate-induced Schizochytrium sp. FJU-512 reveals a novel pathway for biosynthesis of docosahexaenoic acid with enhanced expression of genes responsible for acetyl-CoA and NADPH accumulation. Front. Microbiol. 13: 1006138.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Chen, W., P.-p. Zhou, M. Zhang, Y.-m. Zhu, X.-p. Wang, X.-a. Luo, Z.-d. Bao, and L.-j. Yu (2016) Transcriptome analysis reveals that up-regulation of the fatty acid synthase gene promotes the accumulation of docosahexaenoic acid in Schizochytrium sp. S056 when glycerol is used. Algal Res. 15: 83–92.

    Article  Google Scholar 

  48. Li, Y., L. Chen, W. Chen, J. Zhu, Y. Chen, and D. Li (2023) Transcriptomic analysis of the metabolic regulatory mechanism of Schizochytrium limacinum B4D1 using sodium acetate to produce DHA. Biochem. Eng. J. 197: 108963.

    Article  CAS  Google Scholar 

  49. Liu, L., M. Bai, S. Zhang, J. Li, X. Liu, B. Sen, and G. Wang (2021) ARTP mutagenesis of Schizochytrium sp. PKU#Mn4 and clethodim-based mutant screening for enhanced docosahexaenoic acid accumulation. Mar. Drugs 19: 564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Parsons, J. B. and C. O. Rock (2013) Bacterial lipids: metabolism and membrane homeostasis. Prog. Lipid Res. 52: 249–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nagano, N., K. Sakaguchi, Y. Taoka, Y. Okita, D. Honda, M. Ito, and M. Hayashi (2011) Detection of genes involved in fatty acid elongation and desaturation in thraustochytrid marine eukaryotes. J. Oleo Sci. 60: 475–481.

    Article  CAS  PubMed  Google Scholar 

  52. Hoang, M. H., C. Nguyen, H. Q. Pham, L. Van Nguyen, L. Hoang Duc, L. Van Son, T. N. Hai, C. H. Ha, L. D. Nhan, H. T. Anh, leT. Thom, H. T. Quynh, N. C. Ha, P. Van Nhat, and D. D. Hong (2016) Transcriptome sequencing and comparative analysis of Schizochytrium mangrovei PQ6 at different cultivation times. Biotechnol. Lett. 38: 1781–1789.

    Article  CAS  PubMed  Google Scholar 

  53. Hu, F., A. L. Clevenger, P. Zheng, Q. Huang, and Z. Wang (2020) Low-temperature effects on docosahexaenoic acid biosynthesis in Schizochytrium sp. TIO01 and its proposed underlying mechanism. Biotechnol. Biofuels 13: 172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Meesapyodsuk, D. and X. Qiu (2016) Biosynthetic mechanism of very long chain polyunsaturated fatty acids in Thraustochytrium sp. 26185. J. Lipid Res. 57: 1854–1864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang, A., K. Mernitz, C. Wu, W. Xiong, Y. He, G. Wang, and X. Wang (2021) ATP drives efficient terpene biosynthesis in marine thraustochytrids. mBio 12: e0088121.

    Article  PubMed  Google Scholar 

  56. Lombard, J. and D. Moreira (2011) Origins and early evolution of the mevalonate pathway of isoprenoid biosynthesis in the three domains of life. Mol. Biol. Evol. 28: 87–99.

    Article  CAS  PubMed  Google Scholar 

  57. Varete, J. C., H. Pereira, M. Vila, and R. León (2015) Production of carotenoids by microalgae: achievements and challenges. Photosynth. Res. 125: 423–436.

    Article  Google Scholar 

  58. Han, X., Z. Zhao, Y. Wen, and Z. Chen (2020) Enhancement of docosahexaenoic acid production by overexpression of ATP-citrate lyase and acetyl-CoA carboxylase in Schizochytrium sp. Biotechnol. Biofuels 13: 131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang, Q., Z. Xie, X. Zheng, K. Li, T. Lu, Y. Lu, C. Chen, and X. Ling (2022) Genetic regulation and fermentation strategy for squalene production in Schizochytrium sp. Appl. Microbiol. Biotechnol. 106: 2415–2431.

    Article  CAS  PubMed  Google Scholar 

  60. Yoshimi, T., S. Hashimoto, Y. Kubo, M. Takeuchi, D. Morimoto, S. Nakagawa, and S. Sawayama (2023) Improvement of astaxanthin production in Aurantiochytrium limacinum by overexpression of the beta-carotene hydroxylase gene. Appl. Biochem. Biotechnol. 195: 1255–1267.

    Article  CAS  PubMed  Google Scholar 

  61. Heggeset, T. M. B., H. Ertesvåg, B. Liu, T. E. Ellingsen, O. Vadstein, and I. M. Aasen (2019) Lipid and DHA-production in Aurantiochytrium sp. - Responses to nitrogen starvation and oxygen limitation revealed by analyses of production kinetics and global transcriptomes. Sci. Rep. 9: 19470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ratledge, C. (2014) The role of malic enzyme as the provider of NADPH in oleaginous microorganisms: a reappraisal and unsolved problems. Biotechnol. Lett. 36: 1557–1568.

    Article  CAS  PubMed  Google Scholar 

  63. Raghukumar, S. (2008) Thraustochytrid marine protists: production of PUFAs and other emerging technologies. Mar. Biotechnol. (NY). 10: 631–640.

    Article  CAS  PubMed  Google Scholar 

  64. Li, Z., X. Ling, H. Zhou, T. Meng, J. Zeng, W. Hang, Y. Shi, and N. He (2019) Screening chemical modulators of benzoic acid derivatives to improve lipid accumulation in Schizochytrium limacinum SR21 with metabolomics analysis. Biotechnol. Biofuels 12: 209.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bao, Z., Y. Zhu, Y. Feng, K. Zhang, M. Zhang, Z. Wang, and L. Yu (2022) Enhancement of lipid accumulation and docosahexaenoic acid synthesis in Schizochytrium sp. H016 by exogenous supplementation of sesamol. Bioresour. Technol. 345: 126527.

    Article  CAS  PubMed  Google Scholar 

  66. Bi, Z.-Q., L.-J. Ren, X.-C. Hu, X.-M. Sun, S.-Y. Zhu, X.-J. Ji, and H. Huang (2018) Transcriptome and gene expression analysis of docosahexaenoic acid producer Schizochytrium sp. under different oxygen supply conditions. Biotechnol. Biofuels 11: 249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dong, L., F. Wang, L. Chen, and W. Zhang (2023) Metabolomic analysis reveals the responses of docosahexaenoic-acid-producing Schizochytrium under hyposalinity conditions. Algal Res. 70: 102987.

    Article  Google Scholar 

  68. Feng, Y., Y. Zhu, Z. Bao, B. Wang, T. Liu, H. Wang, T. Yu, Y. Yang, and L. Yu (2022) Construction of glucose-6-phosphate dehydrogenase overexpression strain of Schizochytrium sp. H016 to improve docosahexaenoic acid production. Mar. Drugs 21: 17.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wang, F., Y. Bi, J. Diao, M. Lv, J. Cui, L. Chen, and W. Zhang (2019) Metabolic engineering to enhance biosynthesis of both docosahexaenoic acid and odd-chain fatty acids in Schizochytrium sp. S31. Biotechnol. Biofuels 12: 141.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ling, X., H. Zhou, Q. Yang, S. Yu, J. Li, Z. Li, N. He, C. Chen, and Y. Lu (2020) Functions of enyolreductase (ER) domains of PKS cluster in lipid synthesis and enhancement of PUFAs accumulation in Schizochytrium limacinum SR21 Using triclosan as a regulator of ER. Microorganisms 8: 300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Duan, R., X. Pan, K. Li, Q. Yang, X. Cui, Y. Zheng, Y. Lu, C. Yao, and X. Ling (2023) Metabolism balance regulation for squalene production by disturbing triglyceride (TAG) synthesis in Schizochytrium sp. Algal Res. 69: 102946.

    Article  Google Scholar 

  72. Voß, U., A. Bishopp, E. Farcot, and M. J. Bennett (2014) Modelling hormonal response and development. Trends Plant Sci. 19: 311–319.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zhao, Y., H.-P. Wang, B. Han, and X. Yu (2019) Coupling of abiotic stresses and phytohormones for the production of lipids and high-value by-products by microalgae: a review. Bioresour. Technol. 274: 549–556.

    Article  CAS  PubMed  Google Scholar 

  74. Lu, Y. and J. Xu (2015) Phytohormones in microalgae: a new opportunity for microalgal biotechnology? Trends Plant Sci. 20: 273–282.

    Article  CAS  PubMed  Google Scholar 

  75. Yu, X.-J., J. Sun, J.-Y. Zheng, Y.-Q. Sun, and Z. Wang (2016) Metabolomics analysis reveals 6-benzylaminopurine as a stimulator for improving lipid and DHA accumulation of Aurantiochytrium sp. J. Chem. Technol. Biotechnol. 91: 1199–1207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yu, X.-J., J.-H. Liu, J. Sun, J.-Y. Zheng, Y.-J. Zhang, and Z. Wang (2016) Docosahexaenoic acid production from the acidic hydrolysate of Jerusalem artichoke by an efficient sugar-utilizing Aurantiochytrium sp. YLH70. Ind. Crops Prod. 83: 372–378.

    Article  CAS  Google Scholar 

  77. Yu, X.-J., J. Sun, Y.-Q. Sun, J.-Y. Zheng, and Z. Wang (2016) Metabolomics analysis of phytohormone gibberellin improving lipid and DHA accumulation in Aurantiochytrium sp. Biochem. Eng. J. 112: 258–268.

    Article  CAS  Google Scholar 

  78. Yu, X. J., H. Chen, C.-Y. Huang, X.-Y. Zhu, Z.-P. Wang, D.-S. Wang, X.-Y. Liu, J. Sun, J.-Y. Zheng, H.-J. Li, and Z. Wang (2019) Transcriptomic mechanism of the phytohormone 6-benzylaminopurine (6-BAP) stimulating lipid and DHA synthesis in Aurantiochytrium sp. J. Agric. Food Chem. 67: 5560–5570.

    Article  CAS  PubMed  Google Scholar 

  79. Wang, K., T. Sun, J. Cui, L. Liu, Y. Bi, G. Pei, L. Chen, and W. Zhang (2018) Screening of chemical modulators for lipid accumulation in Schizochytrium sp. S31. Bioresour. Technol. 260: 124–129.

    Article  PubMed  Google Scholar 

  80. Sun, X.-M., L.-J. Ren, X.-J. Ji, and H. Huang (2018) Enhancing biomass and lipid accumulation in the microalgae Schizochytrium sp. by addition of fulvic acid and EDTA. AMB Express 8: 150.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Oosterink, J. E., E. F. Naninck, A. Korosi, P. J. Lucassen, J. B. van Goudoever, and H. Schierbeek (2015) Accurate measurement of the essential micronutrients methionine, homocysteine, vitamins B6, B12, B9 and their metabolites in plasma, brain and maternal milk of mice using LC/MS ion trap analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 998–999: 106–113.

    Article  PubMed  Google Scholar 

  82. Hayashi, M., T. Yukino, F. Watanabe, E. Miyamoto, and Y. Nakano (2007) Effect of vitamin B12-enriched thraustochytrids on the population growth of rotifers. Biosci. Biotechnol. Biochem. 71: 222–225.

    Article  CAS  PubMed  Google Scholar 

  83. Helliwell, K. E., G. L. Wheeler, K. C. Leptos, R. E. Goldstein, and A. G. Smith (2011) Insights into the evolution of vitamin B12 auxotrophy from sequenced algal genomes. Mol. Biol. Evol. 28: 2921–2933.

    Article  CAS  PubMed  Google Scholar 

  84. Wagner-Döbler, I., B. Ballhausen, M. Berger, T. Brinkhoff, I. Buchholz, B. Bunk, H. Cypionka, R. Daniel, T. Drepper, G. Gerdts, S. Hahnke, C. Han, D. Jahn, D. Kalhoefer, H. Kiss, H.-P. Klenk, N. Kyrpides, W. Liebl, H. Liesegang, L. Meincke, A. Pati, J. Petersen, T. Piekarski, C. Pommerenke, S. Pradella, R. Pukall, R. Rabus, E. Stackebrandt, S. Thole, L. Thompson, P. Tielen, J. Tomasch, M. von Jan, N. Wanphrut, A. Wichels, H. Zech, and M. Simon (2010) The complete genome sequence of the algal symbiont Dinoroseobacter shibae: a hitchhiker’s guide to life in the sea. ISME J. 4: 61–77.

    Article  PubMed  Google Scholar 

  85. Tani, N., K. Yoneda, and I. Suzuki (2018) The effect of thiamine on the growth and fatty acid content of Aurantiochytrium sp. Algal Res. 36: 57–66.

    Article  Google Scholar 

  86. Yu, X.-J., Z.-Q. Yu, Y.-L. Liu, J. Sun, J.-Y. Zheng, and Z. Wang (2015) Utilization of high-fructose corn syrup for biomass production containing high levels of docosahexaenoic acid by a newly isolated Aurantiochytrium sp. YLH70. Appl. Biochem. Biotechnol. 177: 1229–1240.

    Article  CAS  PubMed  Google Scholar 

  87. Quilodrán, B., I. Hinzpeter, E. Hormazabal, A. Quiroz, and C. Shene (2010) Docosahexaenoic acid (C22:6n-3, DHA) and astaxanthin production by Thraustochytriidae sp. AS4-A1 a native strain with high similitude to Ulkenia sp.: evaluation of liquid residues from food industry as nutrient sources. Enzyme Microb. Technol. 47: 24–30.

    Article  Google Scholar 

  88. Liu, Z.-X., S. You, B.-P. Tang, B. Wang, S. Sheng, F.-A. Wu, and J. Wang (2019) Inositol as a new enhancer for improving lipid production and accumulation in Schizochytrium sp. SR21. Environ. Sci. Pollut. Res. Int. 26: 35497–35508.

    Article  CAS  PubMed  Google Scholar 

  89. Yin, F.-W., Y.-T. Zhang, J.-Y. Jiang, D.-S. Guo, S. Gao, and Z. Gao (2019) Efficient docosahexaenoic acid production by Schizochytrium sp. via a two-phase pH control strategy using ammonia and citric acid as pH regulators. Process Biochem. 77: 1–7.

    Article  CAS  Google Scholar 

  90. Shafiq, M., L. Zeb, G. Cui, M. Jawad, and Z. Chi (2020) High-density pH-auxostat fed-batch culture of Schizochytrium limacinum SR21 with acetic acid as a carbon source. Appl. Biochem. Biotechnol. 192: 1163–1175.

    Article  CAS  PubMed  Google Scholar 

  91. Du, H., X. Liao, Z. Gao, Y. Li, Y. Lei, W. Chen, L. Chen, X. Fan, K. Zhang, S. Chen, Y. Ma, C. Meng, and D. Li (2019) Effects of methanol on carotenoids as well as biomass and fatty acid biosynthesis in Schizochytrium limacinum B4D1. Appl. Environ. Microbiol. 85: e01243–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, K., L. Chen, J. Liu, F. Gao, R. He, W. Chen, W. Guo, S. Chen, and D. Li (2017) Effects of butanol on high value product production in Schizochytrium limacinum B4D1. Enzyme Microb. Technol. 102: 9–15.

    Article  CAS  PubMed  Google Scholar 

  93. Saini, R. K. and Y.-S. Keum (2017) Progress in microbial carotenoids production. Indian J. Microbiol. 57: 129–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, C. and K. Hong (2020) Production of terpenoids by synthetic biology approaches. Front. Bioeng. Biotechnol. 8: 347.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang, C., M. Liwei, J.-B. Park, S.-H. Jeong, G. Wei, Y. Wang, and S.-W. Kim (2018) Microbial platform for terpenoid production: Escherichia coli and yeast. Front. Microbiol. 9: 2460.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Shi, T.-Q., H. Huang, E. J. Kerkhoven, and X.-J. Ji (2018) Advancing metabolic engineering of Yarrowia lipolytica using the CRISPR/Cas system. Appl. Microbiol. Biotechnol. 102: 9541–9548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lin, Y.-C., E. M. Leaño, and K.-L. Pang (2010) Effects of Cu(II) and Zn(II) on growth and cell morphology of thraustochytrids isolated from fallen mangrove leaves in Taiwan. Bot Mar. 53: 581–586.

    Article  CAS  Google Scholar 

  98. Nagano, N., Y. Taoka, D. Honda, and M. Hayashi (2013) Effect of trace elements on growth of marine eukaryotes, tharaustochytrids. J. Biosci. Bioeng. 116: 337–339.

    Article  CAS  PubMed  Google Scholar 

  99. Watanabe, K., K. H. V. Arafiles, R. Higashi, Y. Okamura, T. Tajima, Y. Matsumura, Y. Nakashimada, K. Matsuyama, and T. Aki (2018) Isolation of high carotenoid-producing Aurantiochytrium sp. mutants and improvement of astaxanthin productivity using metabolic information. J. Oleo Sci. 67: 571–578.

    Article  CAS  PubMed  Google Scholar 

  100. Xu, Y.-S., W. Ma, J. Li, P.-W. Huang, X.-M. Sun, and H. Huang (2023) Metal cofactor regulation combined with rational genetic engineering of Schizochytrium sp. for high-yield production of squalene. Biotechnol. Bioeng. 120: 1026–1037.

    Article  CAS  PubMed  Google Scholar 

  101. McMurry, L. M., M. Oethinger, and S. B. Levy (1998) Triclosan targets lipid synthesis. Nature 394: 531–532.

    Article  CAS  PubMed  Google Scholar 

  102. Omura, S. (1976) The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev. 40: 681–697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, J., H. Zhou, X. Pan, Z. Li, Y. Lu, N. He, T. Meng, C. Yao, C. Chen, and X. Ling (2019) The role of fluconazole in the regulation of fatty acid and unsaponifiable matter biosynthesis in Schizochytrium sp. MYA 1381. BMC Microbiol. 19: 256.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Sun, X.-M., L.-J. Ren, Q.-Y. Zhao, L.-H. Zhang, and H. Huang (2019) Application of chemicals for enhancing lipid production in microalgae-a short review. Bioresour. Technol. 293: 122135.

    Article  CAS  PubMed  Google Scholar 

  105. Ma, W., Y.-Z. Wang, F.-T. Nong, F. Du, Y.-S. Xu, P.-W. Huang, and X.-M. Sun (2021) An emerging simple and effective approach to increase the productivity of thraustochytrids microbial lipids by regulating glycolysis process and triacylglycerols’ decomposition. Biotechnol. Biofuels 14: 247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hong, J.-H., E.-Y. Hwang, H.-J. Kim, Y.-J. Jeong, and I. S. Lee (2009) Artemisia capillaris inhibits lipid accumulation in 3T3-L1 adipocytes and obesity in C57BL/6J mice fed a high fat diet. J. Med. Food. 12: 736–745.

    Article  PubMed  Google Scholar 

  107. Beopoulos, A., Z. Mrozova, F. Thevenieau, M. T. Le Dall, I. Hapala, S. Papanikolaou, T. Chardot, and J. M. Nicaud (2008) Control of lipid accumulation in the yeast Yarrowia lipolytica. Appl. Environ. Microbiol. 74: 7779–7789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang, S., Y. He, B. Sen, X. Chen, Y. Xie, J. D. Keasling, and G. Wang (2018) Alleviation of reactive oxygen species enhances PUFA accumulation in Schizochytrium sp. through regulating genes involved in lipid metabolism. Metab. Eng. Commun. 6: 39–48.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Spanova, M. and G. Daum (2011) Squalene - biochemistry, molecular biology, process biotechnology, and applications. Eur. J. Lipid Sci. Technol. 113: 1299–1320.

    Article  CAS  Google Scholar 

  110. Spanova, M., T. Czabany, G. Zellnig, E. Leitner, I. Hapala, and G. Daum (2010) Effect of lipid particle biogenesis on the subcellular distribution of squalene in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 285: 6127–6133.

    Article  CAS  PubMed  Google Scholar 

  111. Sun, X.-M., L.-J. Ren, X.-J. Ji, S.-L. Chen, D.-S. Guo, and H. Huang (2016) Adaptive evolution of Schizochytrium sp. by continuous high oxygen stimulations to enhance docosahexaenoic acid synthesis. Bioresour. Technol. 211: 374–381.

    Article  CAS  PubMed  Google Scholar 

  112. Montibus, M., L. Pinson-Gadais, F. Richard-Forget, C. Barreau, and N. Ponts (2015) Coupling of transcriptional response to oxidative stress and secondary metabolism regulation in filamentous fungi. Crit. Rev. Microbiol. 41: 295–308.

    Article  CAS  PubMed  Google Scholar 

  113. Zhang, S., Y. He, B. Sen, and G. Wang (2020) Reactive oxygen species and their applications toward enhanced lipid accumulation in oleaginous microorganisms. Bioresour. Technol. 307: 123234.

    Article  CAS  PubMed  Google Scholar 

  114. Niki, E. (2009) Lipid peroxidation: physiological levels and dual biological effects. Free Radic. Biol. Med. 47: 469–484.

    Article  CAS  PubMed  Google Scholar 

  115. Sun, X.-M., L.-J. Geng, L.-J. Ren, X.-J. Ji, N. Hao, K.-Q. Chen, and H. Huang (2018) Influence of oxygen on the biosynthesis of polyunsaturated fatty acids in microalgae. Bioresour. Technol. 250: 868–876.

    Article  CAS  PubMed  Google Scholar 

  116. Ren, L.-J., X.-M. Sun, X.-J. Ji, S.-L. Chen, D.-S. Guo, and H. Huang (2017) Enhancement of docosahexaenoic acid synthesis by manipulation of antioxidant capacity and prevention of oxidative damage in Schizochytrium sp. Bioresour. Technol. 223: 141–148.

    Article  CAS  PubMed  Google Scholar 

  117. Singh, D., A. S. Mathur, D. K. Tuli, M. Puri, and C. J. Barrow (2015) Propyl gallate and butylated hydroxytoluene influence the accumulation of saturated fatty acids, omega-3 fatty acid and carotenoids in thraustochytrids. J. Funct. Foods. 15: 186–192.

    Article  CAS  Google Scholar 

  118. Bao, Z., Y. Zhu, K. Zhang, Y. Feng, X. Chen, M. Lei, and L. Yu (2021) High-value utilization of the waste hydrolysate of Dioscorea zingiberensis for docosahexaenoic acid production in Schizochytrium sp. Bioresour. Technol. 336: 125305.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 22038007) and the Natural Science Foundation of Jiangsu Province (No. BK20200732).

Author information

Authors and Affiliations

Authors

Contributions

Zi-Lei Chen: Writing - original draft (lead); writing - review and editing (equal); investigation (equal); supervision (equal). Lin-Hui Yang: Writing - review and editing (equal); investigation (equal); supervision (equal). Ling-Ling Tong: Investigation (equal); supervision (equal). Yue Wang: Investigation (equal); supervision (equal). Meng-Zhen Liu: Investigation (equal); supervision (equal). Dong-Sheng Guo: Conceptualization (lead); resources (lead); supervision (lead); writing - review and editing (lead).

Corresponding author

Correspondence to Dong-Sheng Guo.

Ethics declarations

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

Additional information

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, ZL., Yang, LH., Tong, LL. et al. Improvement of Lipid and Terpenoid Yield in Thraustochytrids Using Chemical Regulators: A Review. Biotechnol Bioproc E 28, 720–733 (2023). https://doi.org/10.1007/s12257-023-0086-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-023-0086-4

Keywords

Navigation