The Effect of Methionine and Acetate Concentrations on Mycophenolic Acid Production by Penicillium bervicompactum MUCL 19011 in Submerged Culture

Mycophenolic acid “MPA" is a secondary metabolite of Penicillium bervicompactum with antibiotic and immunosuppressive properties. In this study, fermentation process was established for production of mycophenolic acid by Penicillium bervicompactum MUCL 19011 in shake flask. The maximum MPA production, product yield and productivity were 1.379 g/L, 18.6 mg/g glucose and 4.9 mg/L.h respectively. Glucose consumption, biomass and MPA production profiles were investigated during fermentation time. It was found that MPA production starts approximately after 180 hours and reaches to a maximum at 280 h. In the next step, the effects of methionine and acetate concentrations on MPA production were evaluated. Maximum MPA production, product yield and productivity (1.763 g/L, 23.8 mg/g glucose and 6.30 mg/L. h respectively) were obtained with using 2.5 g/L methionine in culture medium. Further addition of methionine had not more positive effect on MPA production. Finally, results showed that the addition of acetate to the culture medium had not any observable effect on MPA production

Authors:

• Fatemeh Ardestani
• Seyed Safa-ali Fatemi
• Bagher Yakhchali
• Seyed Morteza Hosseyni
• Ghasem Najafpour

Keywords:

• Penicillium bervicompactum
• Methionine
• Mycophenolic acid
• Submerged culture.

References:

[1] T.Rainiene, Immunosuppression in the past and today, Acta Medica
Lituanica. 12 No. 3 (2005)10-17.
[2] S. Tian, P. Mele, F. Halloran, The use of mycophenolate mofetil in
transplant recipients, J. Immunopharma. 47 (2000) 215-245.
[3] A.Charlotte, J. Hans Charleston, Mycophenolic acid inhibits inosine 5-
monophosphate dehydrogenase and suppresses immunoglobulin and
cytokine production of B cells, Int. Immunopharma. 3 (2003) 31-37.
[4] C. D. Bartman, et al, Mycophenolic Acid Production by Penicillium
brevicompactum on Solid Media, Appl. Environ. Microbiol. (1981)
729-736.
[5] D. L. Doerfler, C. D. Bartman, L. M. Campbell, Mycophenolic acid
production by Penicillium brevicompactum in two media. Can. J.
Microbiol. 25 (1979) 940-943.
[6] Vinokurova, NG., Ivanushkina, NE., Kochkina, GA., Arinbasarov,
MU., Ozer-skaya, SM., Production of mycophenolic acid by fungi of
the genus Penicillium link, Appl Biochem Microbiol., 41, Pp 83-6
(2005).
[7] N. Vinokurova, N. Ivanushkina, G. Kochkina, M. Arinbasarov, S.
Ozerskaya, Production of mycophenolic acid by fungi of the genus
Penicillium link, Appl. Biochem. Microbiol. 41 (2005) 83-86.
[8] J. L. Adrio, A. L. Demain, Fungal biotechnology, Int. Microbiol. 6
(2003) 191-199.
[9] Z. Xu, S. Yang, Production of mycophenolic acid by Penicillium
brevicompactum immobilized in a rotating fibrous-bed bioreactor,
Enzyme Microb. Technol. 40 (2007) 623-628.
[10] A. Sircar, et al. Manufacture and purification of mycophenolic acid,
United States Patent. PCT No.: PCT/INOO/00017 (2003).
[11] C. T. Bedford, C. Fairlipe, Sequence Studies in Biosynthesis;
Mycophenolic Acid, Chem. Com. (1971) 323-324.
[12] A. Fawzy, A. Elbarbry, Simple high performance liquid
chromatographic assay for mycophenolic acid in renal transplant
patients, J. Pharma. Biomedica. Ana. 43 (2007) 788-792
[13] W. L. Muth, I. Nash, Biosynthesis of mycophenolic acid: purification
and characterization of S-adenosyl-L-methionine:
demethylmycophenolic acid o-methyltransferase, Antimicrob. Chemo. 8
No 3 (1975) 321-327.
[14] S. AK, M. MR, K. RA, M. EVS, et al., Optimization of mycophenolic
acid production in solid state fermentation using response surface
methodology. J Ind Microbiol Biotechnol, 22, Pp 33-38 (1999). M.
[15] H. Ozaki, M. Ishihara, T. Kida, S. Yamanaka, H. Shibai, Mycophenolic
acid production by drug-resistant and methionine or glutamic-acid
requiring mutants of Penicillium brevicopactum, Agric Biol Chem. 51
(1987) 2509-2514.
[16] O. Puel, S. Tadrist, et al, Byssochlamys nivea as a source of
mycophenolic acid, Appl. Environ. Microbiol. 71 No 1 (2005) 550-553.
[17] P. Lafont, J. Debeaupuis, M. Gaillardia, J. Payen, Production of
mycophenolic acid by Penicillium roqueforti strains, Appl. Environ.
Microbiol. 37 (1978) 365-368.