Mycophenolic acid (MPA) 具有抗牛皮癬、抗真菌、抗細菌及抗病毒的能力，且已被證實為Inositol MonoPhosphate DeHydrogenase (IMPDH) 之非競爭型免疫抑制劑，針對淋巴細胞之合成路徑進行抑制而達到降低免疫反應的發生，因此在臨床上被用來預防器官移植所產生的排斥現象。實驗上利用微生物Penicillium brevicompactum進行深層液態發酵 (submerged fermentation) 來生產MPA。
本研究探討添加有機酸對P. brevicompactum生長及生產MPA的影響，其中發現於三羧酸循環中所代謝之有機酸如檸檬酸及琥珀酸能影響P. brevicompactum生長及產物代謝。在添加檸檬酸的情況下能促進菌體生長及加速碳源的消耗，提升菌體比生長速率 (μ) ，可達0.0189，為控制組的1.56倍，且能縮短發酵所需時間約25 hr，產率 (productivity) 提升為控制組的1.3倍；而添加琥珀酸則能提高MPA的產量及提升單位菌體對產物的轉化率 (Yp/x) ，以添加1 g/L達最高MPA產量0.536 g/L，約提升為控制組的1.27倍，單位菌體對產物的轉化率為60.06 mg/g，約為控制組1.33倍。

Mycophenolic acid (MPA) has been to be antipsoriasis, antifungal, antibacterial and antiviral. It was demonstrated that MPA is a non-competitive immunosuppressive agent for Inositol MonoPhosphate DeHydrogenase (IMPDH) by inhibiting de novo purine biosynthesis of lymphocytes. Therefore, MPA is used clinically to prevent rejection of transplanted organs. In this study, Penicillium brevicompactum was used to product MPA in submerged fermentation.
Effects of various organic acids on cell growth and production of a useful bioactive metabolite, MPA, by submerged cultivation of Penicillium brevicompactum were investigated. The organic acid such as citric acid and succinic acid, which present in the tricarboxylic acid cycle, were found to affect the cell growth and its metabolism.
Addition of citric acid stimulated cell growth, increased consumption rate of carbon source and reduced fermentation time about 25 hr.The specific growth rate and productivity were 1.56 and 1.3 times than that of control-level, respectively. In addition, addition of succinic acid under 1 g/L concentration increased MPA production to 0.536 g/L, which was 1.27 times than that of control-level. Meanwhile the Yp/x increased 1.33 times than that of control-level.

吳尚訓，2006，“限氮條件添加有機酸鹽對Ralstonia eutropha生合成PHBV之影響”，大葉大學生物產業科技學系，碩士論文。
陳怡倩，2001，“利用批次液態培養來探討檸檬酸對裂褶菌生長及其多醣體生成影響之研究”，國立中央大學化學工程與材料工程研究所，碩士論文。
黃賜源，1996，“靈芝液體培養及氣舉式生化反應器應用之研究”，東海大學化學工程研究所，碩士論文。
游英欽，1996，“以搖瓶震盪及小型發酵槽培養，探討培養基組成及物理化學因子，對於靈芝多醣生成及生長形態變化的影響”，國立交通大學生物科技研究所，碩士論文。
羅心怡，2008，“探討添加界面活性劑Tween 80對Penicillium brevicompactum在液態發酵中生產Mycophenolic acid之影響”，國立中央大學化學工程與材料工程研究所，碩士論文。
辜正弘，1995，“添加正十六烷對青黴菌生長型態及盤尼西林產量之影響”，國立成功大學，碩士論文。
陳奕廷，2005，“探討pH值通氣量對Penicillium brevicompactum生產Mycophenolic acid之影響”，國立中央大學化學工程與材料工程研究所，碩士論文。
張筱琳，(2005)，“建立肝臟移植病患之藥事照護模式”，國立成功大學醫學院，碩士論文。
Mary K. Campbell, Shawn O. Farrell，2007，生物化學(Biochemistry, 5th edition)，偉明圖書有限公司。
王三郎，2002，應用微生物學，高立圖書有限公司。
褚佩瑜，1997，微生物免疫學速攻，藝軒圖書出版社。
嚴群、堵國成、陳堅，2002，真氧產鹼桿菌利用短鏈有機酸合成聚羥基烷酸酯，過程工程學報，2(5)：454-458。
葉勤，2002，現代生物技術原理及其應用，九州圖書文物有限公司。
林昇慧，2007，微生物發酵產業，
網址：http://web1.nsc.gov.tw/ct.aspx?xItem=8522&ctNode=40&mp=1
Akshay G., Jinwon L., Domach M. M., Ataai M. M. (1995) Suppressed acid formation by cofeeding of glucose and citrate in Bacillus cultures: emergence of pyruvate kinase as a potential metabolic engineering site. Biotechnology Progress, 11(4), 380-5.
Allison A. C., Eugui E. M. (1996) Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clinic of transplant, 10, 77-84.
Bentley R. (2000) Mycophenolic Acid：A One Hundred Year Odyssey
from Antibiotic to Immunosuppressant. Chemical Review, 100,
3801-3825.
Besouw N. M., Mast B. J., Gregoor P. J. H. S., Hesse C. J., Ijzermans J.
N. M., Gelder T., W eimar W. (1999) Effect of mycophenolate
mofetil on erythropoiesis in stable renal transplant patients is correlated
with mycophenolic acid trough levels. Nephrol Dial Transplant, 14,
2710-2713
Bo W., Wei W., Jianlong W. (2008) Inhibitory effect of ethanol, acetic acid, propionic acid and butyric acid on fermentative hydrogen production. International Journal of Hydrogen Energy, 33(23), 7013-7019.
Carlo G. Z., Antonella A., Francesco P. (2004) Determination of the immunosuppressant mycophenolic acid in human serum by solid-state microextraction coupled to liquid chromatography. Journal of Chromatography B, 806, 89-93.
Chen C. K., Blaschek H. P. (1999) Acetate enhances solvent production and prevents degeneration in Clostridium beijerinckii BA101. Applied Microbiology and Biotechnology, 52(2), 170-173.
Eiteman M. A., Miller J. H. (1995) Effect of succinic acid on 2, 3- butanediol production by Klebsiella oxytoca. Biotechnology Letters, 17(10), 1057-62.
Esgalhado M. E., Teresa C. A., Roseiro J. C., Emery A. N. (2002) Sublethal acid stress and uncoupling effects on cell growth and product formation in Xanthomonas campestris cultures. Biochemical Engineering Journal, 12(3), 181-192.
Formica R. N., Lorber K. M., Friedman A. L., Bia M. J., Lakkis F., Smith J. D., Lorber M. I. (2003) Sirolimus-Based Immunosuppression With Reduce Dose Cyclosporine or Tacrolimus After Renal Transplantation. Transplantation Proceedings, 35, 95-98.
Goel A., Lee J., Domach M. M., Ataai M. M. (1995) Suppressed acid formation by cofeeding of glucose and citrate in Bacillus cultures : Emergence of pyruvate kinase as a potential metabolic engineering site. Biotechnology Progress, 11, 380-385.
Graham A. F., Lund B. M. (1986) The effect of citric acid on growth of
proteolytic strains of Clostridium botulinum. Journal of Applied Bacteriology, 61, 39–49.
Hachiro O., Koji K., Hiroshi T. (1987) Effects of various adsorbents on mycelium formation and mycophenolic acid production by Penicillium brevicompactum. Agricultural and Biological Chemistry , 51(9), 2503-8.
Hachiro O., Masaru I., Takao K., Shigeru Y., Hiroshiro S. (1987) Mycophenolic acid production by drug-resistant and methionine or glutamic- acid requiring mutants of Penicillium brevicompactum. Agricultural and Biological Chemistry, 51(9), 2509-14.
Henriette D. L., Maarten N., Kristin V., Yves V., Kuypers D. R. (2008) Stability of mycophenolic acid and glucuronide metabolites in human plasma and the impact of deproteinization methodology. Clinica Chimica Acta, 389(1-2), 87-92.
Hiroyuki H., Hiroyasu S., Ikuo S., Takeshi K. (1998) High cell density culture of Rhodococcus rhodochrous by pH – stat feeding and dibenzothiophene degradation. Journal of Fermentation and Bioengineering, 85(3), 334-338.
Husek A. (1997) High-performance Liquid Chromatographic Analysis of
Cyclosporin A and Its Oral Solutions. Journal of Chromatography A, 759, 217-224.
Jana A. K., Purnendu G. (1995) Xanthan biosynthesis in continuous culture : citric acid as an energy source. Journal of
Fermentation and Bioengineering, 80(5), 485-91.
Jana A. K., Purnendu G. (1999) Effect of citric acid on the biosynthesis and composition of xanthan. Journal of General and Applied Microbiology, 45(3), 115-120.
Jekkel A., Barta I., Konya A., Suto J., Boros S., Horvath G., Ambrus G. (2001) Microbiological transformation of mycophenolic acid. Journal of Molecular Catalysis B: Enzymatic, 11(4-6), 423-426.
Karelina N. M., Nils A. (2007) The effect of citric acid and pH on growth and metabolism of anaerobic Saccharomyces cerevisiae and Zygosaccharomyces bailii cultures. Food microbiology, 24(1), 101-5.
Kitchin J. E., Pomeranz M. K., Pak G., Washenik K., Shupack J. L. (1997) Rediscovering mycophenolic acid : a review of its mechanism, side effects, and potential uses. Journal of the American Academy of Dermatology, 37(3 Pt 1), 445-9.
Lu F., He P. J., Shao L. M., Lee D. J. (2008) Stress of pH and acetate on product formation of fermenting polysaccharide-rich organic waste. Biochemical Engineering Journal, 39(1), 97-104.
Narendranath N. V., Thomas K. C., Ingledew W. M. (2001) Effects of acetic acid and lactic acid on the growth of Saccharomyces cerevisiae in a minimal medium. Journal of Industrial Microbiology & Biotechnology, 26(3), 171-177.
Neerman M. F., Boothe D. M. (2003) A possible mechanism of gastrointestinal toxicity posed by mycophenolic acid. Pharmacological
Reserch, 47, 523-526.
Pampulha M. E., Loureiro-Dias M. C. (1989) Combined effect of acetic acid, pH and ethanol on intracellular pH of fermenting yeast. Applied Microbiology and Biotechnology, 31(5-6), 547-50.
Panattoni A., D''Anna F., Triolo E. (2007) Antiviral activity of tiazofurin and mycophenolic acid against Grapevine Leafroll-associated Virus 3 in Vitis vinifera explants. Antiviral Research, 73(3), 206-211.
Ping Z. A., Hanno B., Dieter D. W. (1990) Effect of pH and acetic acid on growth and 2,3-butanediol production of Enterobacter aerogenes in continuous culture. Applied Microbiology and Biotechnology, 33(5), 485-9.
Preez J. C. D., Immelman M., Kock J. L. F., Kilian S. G. (1997) The effect of acetic acid concentration on the growth and production of gamma-linolenic acid by Mucor circinelloides CBS 203.28 in fed-batch culture. World Journal of Microbiology & Biotechnology, 13(1), 81-87.
Preez J. C. D., Immelman M., Kilian S. G. (1996) The utilization of short-chain monocarboxylic acids as carbon sources for the production of gamma-linolenic acid by Mucor strains in fed-batch culture. World Journal of Microbiology & Biotechnology, 12(1), 68-72.
Preez J. C. D., Immelman M., Kock J. L. F., Kilian S. G. (1995) Production of gamma-linolenic acid by Mucor circinelloides and Mucor rouxii with acetic acid as carbon substrate. Biotechnology Letters, 17(9), 933-8.
Qun Y., Guocheng D., Jian C. (2003) Biosynthesis of polyhydroxyalkanoates (PHAs) with continuous feeding of mixed organic acids as carbon sources by Ralstonia eutropha. Process Biochemistry (Oxford, United Kingdom), 39(3), 387-391.
Renner U. D., Thiede C., Bornhauser M., Ehninger G., Thiede H. M. (2001) Determination of Mycophenolic Acid and Mycophenolate Mofetil by High-Performance Liquid Chromatography Using Postcolumn Derivatization. Analytical Chemistry, 73(1), 41-46.
Roe A. J., McLaggan D., Davidson I., O''Byrne C., Booth I. R. (1998) Perturbation of anion balance during inhibition of growth of Escherichia coli by weak acids. Journal of bacteriology, 180(4), 767-72.
Salmond C. V., Kroll R. G., Booth I. R. (1984) The effect of food preservatives on pH homeostasis in Escherichia coli. Journal of general microbiology, 130(11), 2845-50.
Sestakova M. (1979) Growth of Candida utilis on a mixture of monosaccharides, acetic acid and ethanol as a model of waste sulfite liquor. Folia Microbiologica (Prague, Czech Republic), 24(4), 318-27.
Shu C. H., Lung M. Y., Xu C. J. (2005) Effects of supplementation of succinic acid on the production and molecular weight distribution of exopolysaccharides by Antrodia camphorata in batch cultures. Journal of Chemical Technology and Biotechnology, 80(2), 216-222.
Skrinjar M., Danev M., Dimic G. (1995) Interactive effects of propionic acid and temperature on growth and ochratoxin A production by Penicillium aurantiogriseum. Folia Microbiologica (Prague), 40(3), 253-6.
Souw, P., Demain A. L. (1980) Role of citrate in Xanthan production by Xanthomonas campestris. Journal of Fermentation Technology, 58, 411-416.
Venter T., Kock J. L. F., Botes P. J., Smit M. S., Hugo A., Joseph M. (2004) Acetate enhances citric acid production by Yarrowia lipolytica when grown on sunflower oil. Systematic and Applied Microbiology, 27(2), 135-138.
Wenquan R., Jian C., Shiyi L. (2003) Production of biodegradable polymer by A. eutrophus using volatile fatty acids from acidified wastewater. Process Biochemistry (Oxford, United Kingdom), 39(3), 295-299.