KSBB Journal

The Korean Society for Biotechnology and Bioengineering (한국생물공학회)
권호 표지

Effect of Dissolved Oxygen on the Production of Epothilone in Bioreactor Cultures Sorangium cellulosum

Sorangium cellulosum의 생물반응기 배양에서 용존산소가 epothilone의 생산에 미치는 영향

  • Park, Su-Jeong (Department of Chemical Engineering, Sungkyunkwan University) ;
  • Han, Se-Jong (Department of Chemical Engineering, Sungkyunkwan University) ;
  • Kim, Byung-Woo (Department of Chemical Engineering, Sungkyunkwan University) ;
  • Sim, Sang-Jun (Department of Chemical Engineering, Sungkyunkwan University)
  • 박수정 (성균관대학교 화학공학과) ;
  • 한세종 (성균관대학교 화학공학과) ;
  • 김병우 (성균관대학교 화학공학과) ;
  • 심상준 (성균관대학교 화학공학과)
  • Published : 2009.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

The biological production of a potent anticancer agent, epothilone, by Sorangium cellulosum was carried out using flask and fermentor cultures. Soluble starch was selected as the main carbon source and the concentrations of lactose and yeast extract were optimized at 4 and 0 g/L, respectively, when using the flask cultures. In the fermentor cultures, the cells were cultivated at a high DO level of more than 80% of air saturation in the growth stage and then the DO level was controlled at about 50, 20 or 1-2% when the carbon source was exhausted. The epothilone production increased with decreasing DO level after the exhaustion of the carbon source, and the maximum concentration of epothilone was 5.4 mg/L. It was found that the DO level had significant regulation effects on the epothilone production.

본 연구에서 탄소원이 고갈된 후 용존산소농도로 epothilone의 합성을 조절할 수 있음을 증명하였다. 선행연구로써, soluble starch를 탄소원으로 결정하였고, lactose와 yeast extract의 최적농도가 각각 4 g/L, 0 g/L임을 알 수 있었다. 탄소원이 고갈된 환경에서 산소농도가 낮을 경우 균체가 epothilone을 다량으로 합성하였다. 산소 공급을 조절할 수 없는 flask의 경우 배양이 진행되면서 균제농도가 증가하고 자연적으로 산소 농도도 감소하므로 epothilone이 합성되지만, 생물반응기의 경우 탄소원의 고갈 후 산소 농도를 최대한 낮게 유지시키는 것이 epothilone의 생산을 증가시켰다.

Keywords

References

  1. Gerth, K., N, Bedorf, G. Htlc, H. Irschik, and H. Reichεnbach (1996), Epothilones A and B: Antifungal and cytotoxic compounds from Sorangium cellulosum (myxobacteria) Production, physico-chemical, and biological propertics, J. Antibiot. 49, 560-563 https://doi.org/10.7164/antibiotics.49.560
  2. Julien, B., S. Shah, R. Ziermann, R. Goldman, and L. Katz, and C. Khosla(2000), Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum, Gene 249, 153-160 https://doi.org/10.1016/S0378-1119(00)00149-9
  3. Rosenberg, E., K. H. Keller, and M. Dworkin (1977), Cell density-dependent growth of Myxococcus xanthμs on casein, J. Bacteriol. 129, 770-777
  4. Bollag, D. M., P. A. McQueney, J. Zhu, O. Hensens, L. Koupal, J. Líesch, M. Goetz, E. Lazarides, and C. M. Woods (1995), Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action, Cancer Res, 55, 2325-2333
  5. Rowinsky, E. K., E. A. Eisenhauer, V. Chaudhry, S. G. Arbuck, and R. C. Donehower (1993), Clinical toxicities encountered with paclitaxel (Taxol), Semin. Oncol. 20, 1-15
  6. Han, S. J., S. W. Park, B. W. Kim, and S. J. Sim (2008), Selective production of epothilone B by heterologous expression of propionyl-CoA synthetase in Sorangium cellulosum, J. Microbiol. Biotechnol. 18, 135-137
  7. Molnal, I., T. Schupp, M. Ono, R. Zirkle, M. Milnamow, B. Nowak-Thomapson, N. Engel, C. Toupet, A. Stratmann, D. D. Cyr, J. Gorlach, J. M. Mayo, A. Hu, S. Goff, J. Schmid, and J. M. Ligon (2000), THe Biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90, Chem. Biol. 7. 97-109 https://doi.org/10.1016/S1074-5521(00)00075-2
  8. Su, D.-S., A. Balog, D. Meng, P. Bertinato, S. J. Danishfsky, Y.-H. Zheng, T.-C. Chou. L. He, and S. B. Horwitz (1997), Structure-activity relationships of the epothilones and the first in vívo comparison with paclitaxel, Angew. Chem. Int. ED. Engl. 36, 2093-2096 https://doi.org/10.1002/anie.199720931
  9. Park, S. w., S. H. Choi, Y. J. Yoon, D. H. Lee, D. J. Kim, J.-H. Kim, Y. K. Lee, G. J. Choi, I.-T. Yeom, and S. J. Sim (2006), Enhanced production of epothilones by carbon sources in Sorangium cellulosum, J. Microbiol. Biotechnol. 16, 519-523
  10. Park, S. W., S. J. Han, D.-S. Kim, and S. J. Sim (2007), Improvement of epothilone B production by in situ removal of ammonium using cation exchange resin in Sorangium cellulosum culture, Biochem. Eng. J. 37, 328-331 https://doi.org/10.1016/j.bej.2007.05.013
  11. Park, S. W., S. J. Park, S. J. Han, J. Lee, D.-S. Kim, J.-H. Kim, B. W. Kim, J. Lee, and S. J. Sim (2007), Repeated batch production of epothilone B by immobilized Sorangium cellulosum, J. Microbiol. Biotechnol. 17, 1208-1212
  12. Pfeifer, B. A. and C. Khosla (2001), Biosynthesis of polyketides in heterologous hosts, Microbiol. Mol. Biol. Rev. 65, 106-118 https://doi.org/10.1128/MMBR.65.1.106-118.2001
  13. Reichenbach, H. and M. Dworkin (1992), The myxobacteria, In The Procaryotes, A. Balow, H. G. Truper, M. Dworkin, W. Harder, and K. H. Schleifer, Eds., p3416, Springer-Verlag, New York
  14. Tang, L., S. Shah, L. Chung, J. Camey, L. Katz, C. Khosla, and B. Julien (2000), Cloning and heterologous expression of the epothilone gene cluster, Science 287, 640-642 https://doi.org/10.1126/science.287.5453.640