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References

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    Pubmed CrossRef
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    Pubmed CrossRef
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    Pubmed CrossRef
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    CrossRef
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Article

Minireview

J. Microbiol. Biotechnol. 2016; 26(3): 441-451

Published online March 28, 2016 https://doi.org/10.4014/jmb.1510.10039

Copyright © The Korean Society for Microbiology and Biotechnology.

Advances in Biochemistry and Microbial Production of Squalene and Its Derivatives

Gopal Prasad Ghimire 1, Nguyen Huy Thuan 2, Niranjan Koirala 1 and Jae Kyung Sohng 1*

1Department of BT-Convergent Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, Asan 31460, Republic of Korea, 2Center for Molecular Biology, Institute of Research and Development, Duy Tan University, Danang City, Vietnam

Received: October 13, 2015; Accepted: December 3, 2015

Abstract

Squalene is a linear triterpene formed via the MVA or MEP biosynthetic pathway and is
widely distributed in bacteria, fungi, algae, plants, and animals. Metabolically, squalene is
used not only as a precursor in the synthesis of complex secondary metabolites such as sterols,
hormones, and vitamins, but also as a carbon source in aerobic and anaerobic fermentation in
microorganisms. Owing to the increasing roles of squalene as an antioxidant, anticancer, and
anti-inflammatory agent, the demand for this chemical is highly urgent. As a result, with the
exception of traditional methods of the isolation of squalene from animals (shark liver oil) and
plants, biotechnological methods using microorganisms as producers have afforded increased
yield and productivity, but a reduction in progress. In this paper, we first review the
biosynthetic routes of squalene and its typical derivatives, particularly the squalene synthase
route. Second, typical biotechnological methods for the enhanced production of squalene
using microbial cell factories are summarized and classified. Finally, the outline and
discussion of the novel trend in the production of squalene with several updated events to
2015 are presented.

Keywords: squalene, biosynthesis, microbial cell factory, terpenes, squalene production

References

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    Pubmed CrossRef
  2. Berger A, Gremaud G, Baumgartner M, Rein D, Monnard I, Kratky E, et al. 2003. Cholesterol-lowering properties of Amaranth grain and oil in hamsters. Int. J. Vitam. Nutr. Res. 73: 39-47.
    Pubmed CrossRef
  3. Bhargava P, Kumar K, Chaudhaery SS, Saxena AK, Roy U. 2010. Cloning, overexpression and characterization of Leishmania donovani squalene synthase. FEMS Microbiol. Lett. 311: 82-92.
    Pubmed CrossRef
  4. Bhat WW, Lattoo SK, Razdan S, Dhar N, Rana S, Dhar RS, et al. 2012. Molecular cloning, bacterial expression and promoter analysis of squalene synthase from Withania somnifera (L.) Dunal. Gene 499: 25-36.
    Pubmed CrossRef
  5. Bhattacharjee P, Shukla VB, Singhal RS, Kulkarni PR. 2001. Studies on fermentative production of squalene. World J. Microbiol. Biotechnol. 17: 811-816.
    CrossRef
  6. Cantwell SG, Lau EP, Watt DS, Fall RR. 1978. Biodegradation of acyclic isoprenoids by Pseudomonas species. J. Bacteriol. 135: 324-333.
    Pubmed KoreaMed
  7. Chang MH, Kim HJ, Jahng KY, Hong SC. 2008. The isolation and characterization of Pseudozyma sp. JCC 207, a novel producer of squalene. Appl. Microbiol. Biotechnol. 78:963-972.
    Pubmed CrossRef
  8. Chan P, Tomlinson B, Lee CB, Lee YS. 1996. Effectiveness and safety of low-dose pravastatin and squalene, alone and in combination, in elderly patients with hypercholesterolemia. J. Clin. Pharmacol. 36: 422-427.
    Pubmed CrossRef
  9. Chen G, Fan KW, Lu FP, Li Q, Aki T, Chen F, Jiang Y. 2010. Optimization of nitrogen source for enhanced production of squalene from thraustochytrid Aurantiochytrium sp. Nat. Biotechnol. 27: 382-389.
    CrossRef
  10. Cho C, Choi SY, Luo ZW, Lee SY. 2014. Recent advances in microbial production of fuels and chemicals using tools and strategies of systems metabolic engineering. Biotechnol. Adv. 33: 1455-1466.
    Pubmed CrossRef
  11. Dellas N, Thomas ST, Manning G, Noel JP. 2013. Discovery of a metabolic alternative to the classical mevalonate pathway. Elife 2: e00672.
    Pubmed KoreaMed CrossRef
  12. Drozdíková E, Garaiová M, Csáky Z, Obernauerov M, Hapala I. 2015. Production of squalene by lactose-fermenting yeast Kluyveromyces lactis with reduced squalene epoxidase activity. Lett. Appl. Microbiol. 61: 77-84.
    Pubmed CrossRef
  13. Fan KW, Aki T, Chen F, Jiang Y. 2010. Enhanced production of squalene in the thraustochytrid Aurantiochytrium mangrovei by medium optimization and treatment with terbinafine. World J. Microbiol. Biotechnol. 26: 1303-1309.
    Pubmed CrossRef
  14. Fang HS. 2014. Frontier and future development of information technology in medicine and education. Lect. Notes Electr. Eng. 269: 1699-1705.
    CrossRef
  15. Furubayashi M, Li L, Katabami A, Saito K, Umeno D. 2014. Directed evolution of squalene synthase for dehydrosqualene biosynthesis. FEBS Lett. 588: 3375-3381.
    Pubmed CrossRef
  16. Garaiová M, Zambojová V, Šimová Z, Gria P, Hapala I. 2014. Squalene epoxidase as a target for manipulation of squalene levels in the yeast Saccharomyces cerevisiae. FEMS Yeast Res. 14: 310-323.
    Pubmed CrossRef
  17. Gershbein LL, Singh EJ. 1969. Hydrocarbons of dogfish and cod livers and herring oil. J. Am. Oil Chem. Soc. 46: 554-557.
    Pubmed CrossRef
  18. Ghimire GP, Oh TJ, Lee HC, Sohng JK. 2009. Squalenehopene cyclase (Spterp25) from Streptomyces peucetius: sequence analysis, expression and functional characterization. Biotechnol. Lett. 31: 565-569.
    Pubmed CrossRef
  19. Ghimire GP, Lee HC, Sohng JK. 2009. Improved squalene production via modulation of the methylerythritol 4-phosphate pathway and heterologous expression of genes from Streptomyces peucetius ATCC 27952 in Escherichia coli. Appl. Environ. Microbiol. 75: 7291-7293.
    Pubmed KoreaMed CrossRef
  20. Glazyrina J, Materne E-M, Dreher T, Storm D, Junne S, Adams T, et al. 2010. High cell density cultivation and recombinant protein production with Escherichia coli in a rocking-motion-type bioreactor. Microb. Cell Fact. 9: 42.
    Pubmed KoreaMed CrossRef
  21. Goldstein JL, Brown MS. 1990. Regulation of the mevalonate pathway. Nature 343: 425-430.
    Pubmed CrossRef
  22. Gupta N, Sharma P, Santosh Kumar RJ, Vishwakarma RK, Khan BM. 2012. Functional characterization and differential expression studies of squalene synthase from Withania somnifera. Mol. Biol. Rep. 39: 8803-8812.
    Pubmed CrossRef
  23. Heller JH, Pasternak VZ, Ransom JP, Heller MS. 1963. A new reticuloendothelial system stimulating agent (restim) from shark livers. Nature 199: 904-905.
    Pubmed CrossRef
  24. Hong WK, Heo SY, Park HM, Kim CH, Sohn JH, Kondo A, Seo JW. 2013. Characterization of a squalene synthase from the thraustochytrid microalga Aurantiochytrium sp. KRS101. J. Microbiol. Biotechnol. 23: 759-765.
    Pubmed CrossRef
  25. Huang ZR, Lin YK, Fang JY. 2009. Biological and pharmacological activities of squalene and related compounds: potential uses in cosmetic dermatology. Molecules 14: 540-554.
    Pubmed CrossRef
  26. Jiang Y, Fan KW, Wong RTY, Chen F. 2004. Fatty acid composition and squalene content of the marine microalga Schizochytrium mangrovei. J. Agric. Food Chem. 52: 1196-1200.
    Pubmed CrossRef
  27. Kajikawa M, Kinohira S, Ando A, Shimoyama M, Kato M, Fukuzawa H. 2015. Accumulation of squalene in a microalga Chlamydomonas reinhardtii by genetic modification of squalene synthase and squalene epoxidase genes. PLoS One 10:e0120446.
    Pubmed KoreaMed CrossRef
  28. Kalra S, Kumar S, Lakhanpal N, Kaur J, Singh K. 2013. Characterization of squalene synthase gene from Chlorophytum borivilianum (Sant. and Fernand.). Mol. Biotechnol. 54: 944953.
    Pubmed CrossRef
  29. Kamimura N, Hidaka M, Masaki H, Uozumi T. 1994. Construction of squalene-accumulating Saccharomyces cerevisiae mutants by gene disruption through homologous recombination. Appl. Microbiol. Biotechnol. 42: 353-357.
    CrossRef
  30. Kasai H, Katsuta A, Sekiguchi H, Matsuda S, Adachi K, Shindo K, et al. 2007. Rubritalea squalenifaciens sp. nov., a squaleneproducing marine bacterium belonging to subdivision 1 of the phylum “Verrucomicrobia.” Int. J. Syst. Evol. Microbiol. 57: 1630-1634.
    Pubmed CrossRef
  31. Katabami A, Li L, Iwasaki M, Furubayashi M, Saito K, Umeno D. 2015. Production of squalene by squalene synthases and their truncated mutants in Escherichia coli. J. Biosci. Bioeng. 119: 165-171.
    Pubmed CrossRef
  32. Katsuki K, Bloch K. 1967. Studies on the biosynthesis of ergosterol in yeast. J. Biol. Chem. 242: 222-227.
    Pubmed
  33. Kelly GS. 1999. Squalene and its potential clinical uses. Altern. Med. Rev. 4: 29-36.
    Pubmed
  34. Kopicová Z, Vavreinová S. 2007. Occurrence of squalene and cholesterol in various species of Czech freshwater fish. Czech J. Food Sci. 25: 195-201.
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