Effects of Carbon and Nitrogen Sources on Immunosuppressant Mycophenolic Acid Fermentation by Penicillium brevi-compactum

Penicillium brevi-compactum을 이용한 면역억제제 Mycophenolic Acid 발효에서 탄소원 및 질소원의 영향

  • Rho, Yong-Taek (Department of Biomedical Science, College of Health and Industry, Youngdong University)
  • 노용택 (영동대학교 보건산업대학 의생명과학과)
  • Received : 2011.09.14
  • Accepted : 2011.09.27
  • Published : 2011.09.30

Abstract

Mycophenolic acid blocking the synthesis of xanthosine monophosphate is a nonnucleoside inhibitor of inosine monophosphate dehydrogenase. Therefore mycopholoic acid is a drug currently used as immunosuppressive agent in transplantation of heart, kidney and liver. Mycophenolic acid has been industrially produced through fermentation process by fungus Penicillium brevi-compactum. In this study, the profile of mycophenolic acid fermentation was observed in 5L-jar fermentor to investigate the utilization of carbon and nitrogen sources and the production of mycophenolic acid. It was investigated that what kind of carbon sources was better to cell growth and mycophenolic acid production. Fructose was the best carbon source for mycophenolic acid fermentation, but it is the most expensive one. Thereafter molasses containing sucrose as the supply source of fructose was confirmed to be the best carbon source for the industrial production. Use of molasses increased the fermentation yield of mycophenolic acid more than two times higher than glucose. It was confirmed that urea was the best inorganic nitrogen source, which did not give rise to sudden drop of culture pH. Addition of urea increased the fermentation yield of mycophenolic acid about 3.6 times higher than addition of ammonium nitrate as control. Casein, peptone and casamino acid originated from milk protein increased the fermentation yield of mycophenolic acid about 3.4 times higher than control. Peptone and casamino acid, which are casein hydrolysates, increased cell growth considerably as well.

Keywords

Penicillium brevi-compactum;fermentation;immunosuppressant;mycophenolic acid

References

  1. Allison, A.C. and E.M. Eugui. 1999. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47, 85-118.
  2. Diamond, M.S., M. Zachariah, and E. Harris. 2002. Mycophenolic acid inhibits Dengue virus infection by preventing replication of viral RNA. Virology 304, 211-221. https://doi.org/10.1006/viro.2002.1685
  3. DIFCO manual.1995. Dehydrated culture media and reagents for microbiology 11th ed., Difco Laboratories, Detroit, USA.
  4. Dipchand, A.I., B. Pietra, B.W. McCrindle, H.L. Rosebrook- Bicknell, and M.M. Boucek. 2001. Mycopheolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. J. Heart Lung Transplant. 20, 1035-1043. https://doi.org/10.1016/S1053-2498(01)00305-9
  5. Doerfler, D.L., C.D. Bartman, and I.M. Campbell. 1979. Mycophenolic acid production by Penicillium brevicompactum in two media. Microbiology 25, 940-943.
  6. Fulton, B. and A. Markham. 1996. Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 51, 278-298. https://doi.org/10.2165/00003495-199651020-00007
  7. Jonsson, C.A. and H. Carlsten. 2002. Mycophenolic acid inhibits inosine 5′-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages. Cell. Immunol. 216, 93-101. https://doi.org/10.1016/S0008-8749(02)00502-6
  8. Kida, T., T. Ishikawa, and H. Shibai. 1981. Method for production of mycophenolic acid by fermentation. U.S. Patent. 4,452,891.
  9. Lafont, P., J.P. Debeaupuis, E.M. Gaillaardin, and J. Payen. 1979. Production of mycophenolic acid by Penicillium roqueforti strains. Appl. Environ. Microbiol. 37, 365-368.
  10. Lee, B.K., J.K. Kim, H.I. Kang, and J.W. Lee. 2001. Enhanced production of avermectin B1a with Streptomyces avermitilis by optimization of medium and glucose feeding. Kor. J. Microbiol. 37(2), 158-163.
  11. Mele, T.S. and P.F. Halloran. 1999. The use of mycophenolate mofetil in transplant recipients. Immunopharmacology 47, 215-245.
  12. Na-Bangchang K., O. Supasyndh, T. Supaporn, V. Banmairuroi, and J. Karbwang. 1999. Simple and sensitive high-performance liquid chromatographic method for the determination of mycophenolic acid in plasma. J. Chromatogr. B 738, 169-173.
  13. Peter J.H., S. Gregoor, T.V. Gelder, and W. Weimar. 2000. Mycophenolate mofetil, Cellcept, a new immunosuppressive drug with great potential in internal medicine. Nether. J. Med. 57, 233-246. https://doi.org/10.1016/S0300-2977(00)00069-3
  14. Pirsch, J.D. and H.W. Sollinger. 1996. Mycophnolate mofetilclinical and experimental experience. Ther. Drug Monit. 18, 357-361. https://doi.org/10.1097/00007691-199608000-00007
  15. Queener S.W. and C.H. Nash II. 1978. Procedure for obtaining Penicillium species mutants with improved ability to synthesize mycophenolic acid. U.S. Patent 4,115,197.
  16. Ransom, J.T. 1995. Mechanism of action of mycophenolate mofetil. Ther. Drug Monit. 17, 681-684. https://doi.org/10.1097/00007691-199512000-00023
  17. Sadhukhan, A.K., M.V.R. Murthy, R.A. Kumar, E.V.S. Mohan, G. Vandana, C. Bhar, and K.V. Rao. 1999. Optimization of mycophenolic acid production in solid state fermentation using response surface methodology. J. Ind. Microbiol. Biotechnol. 22, 33-38. https://doi.org/10.1038/sj.jim.2900597
  18. Stanbury, P.F., A. Whitaker, and S.J. Hall. 1999. Principles of fermentation technology, 2nd ed., p. 175-177. Butterworth- Heinemann, Oxford, UK.
  19. Yalowitz, J.A., K. Pankiewicz, S.E. Patterson, and H.N. Jayaram. 2002. Cytotoxicity and cellular differentiation activity of methylenebis (phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell line. Cancer Lett. 181, 31-38. https://doi.org/10.1016/S0304-3835(02)00045-9