Cybernetic modeling for citric acid fermentation by Aspergillus niger

doi:10.11949/j.issn.0438-1157.20141879

Abstract

Abstract:

Aspergillus niger fermentation is the main way for the industrial production of citric acid. Modeling of Aspergillus niger from the perspective of cybernetics is significant for better understanding the metabolic behavior of this industrial microorganism. The metabolic pathways in Aspergillus niger during citric acid fermentation are investigated. Based on the simplified metabolic network, a cybernetic model describing the balance of intracellular metabolites and enzyme levels is constructed. Meanwhile, a first-order closed-loop regulator model is used to describe the transient enzyme pool establishment shortly after the inoculation. Combining with the bioreactor model, it is found that model simulations of intracellular enzyme concentrations are in coincidence with the measurements qualitatively, while the macroscopic state variables (biomass concentration, substrate concentrate and product concentrations) agree well with the offline assays.

Key words: Aspergillus niger, citric acid, cybernetic, kinetic model, intracellular enzyme concentration, metabolism simulation

摘要：

黑曲霉发酵是工业生产柠檬酸的主要途径,研究该过程的动力学模型对更好地理解这一工业微生物的代谢机理有重要意义。基于黑曲霉(Aspergillus niger)柠檬酸发酵过程主要代谢途径的分析,构建了简化的碳代谢网络,建立了胞内物质和酶浓度的平衡模型。引入一阶闭环调节器模型描述发酵初期微生物酶系的建立过程。结合生物反应器模型,给出了重要宏观状态变量(如细胞物质浓度、基质浓度、产物浓度)和胞内酶浓度的动态仿真结果与实验值的对比。

关键词: 黑曲霉, 柠檬酸, 控制论, 动力学模型, 胞内酶浓度, 代谢仿真

CLC Number:

TP273

HAN Lingyu, CHENG Baokun, ZHENG Xiaomei, SUN Jibin, YUAN Jingqi. Cybernetic modeling for citric acid fermentation by Aspergillus niger[J]. CIESC Journal, 2015, 66(11): 4534-4539.

韩玲玉, 成宝琨, 郑小梅, 孙际宾, 袁景淇. 黑曲霉生产柠檬酸的控制论模型[J]. 化工学报, 2015, 66(11): 4534-4539.

References 31

[1]	Angumeenal A, Venkappayya D. An overview of citric acid production [J]. LWT Food Sci. Technol., 2013, 50 (2): 367-370.
[2]	Guo Yanmei (郭艳梅), Zheng Ping (郑平), Sun Jibin (孙际宾). Aspergillus niger as a potential cellular factory: prior knowledge and key technology [J].Chin. J. Biotech., 2010, 26 (10): 1410-1418.
[3]	Papagianni M. Advances in citric acid fermentation by Aspergillus niger: biochemical aspects. Membrane transport and modeling [J]. Biotechnol. Adv., 2007, 25 (3): 244-263.
[4]	Nie Guoxing (聂国兴), Song Dongying (宋东蓥), Ming Hong (明红), Hu Xiaolong (胡晓龙), Gao Hang (高航). Construction of kinetic model for C71 batch fermentation by Aspergillus niger [J]. Henan Normal University: Natural Science (河南师范大学学报:自然科学版), 2010, 38 (2): 148-155.
[5]	Zhang Xiaohao (张小昊), Tong Qunyi (童群义). The kinetics model of producing sodium gluconate for batch fermentation by Aspergillus niger [J]. Food Industry (食品工业科技), 2010, 31 (12): 221-223.
[6]	Liu Jianzhong (刘建中), Weng Liping (翁丽萍), Zhang Qianling (张黔玲), Ji Liangnian (计亮年). A mathematical model of catalase fermentation process by A. niger [J]. Industrial Microbiology (工业微生物), 2002, 32 (3): 6-9.
[7]	García J, Torres N. Mathematical modeling and assessment of the pH homeostasis mechanisms in Aspergillus niger while in citric acid producing conditions [J]. Journal of Theoretical Biology, 2011, 282: 23-35.
[8]	Straight J V, Ramkrishna D. Cybernetic modeling and regulation of metabolic pathways, growth on complementary nutrients [J]. Biotechnology Progress, 1994, 10 (6): 574-587.
[9]	Kompala D S, Ramkrishna D, Tsao G T. Cybernetic modeling of microbial growth on multiple substrates [J]. Biotechnol. Bioeng., 1984, 26: 1272-1281.
[10]	Mandli A R, Modak J M. Cybernetic modeling of adaptive prediction of environmental changes by microorganisms [J]. Math. Biosci., 2014, 248: 40-45.
[11]	Varner J, Ramkrishna D. Metabolic engineering from a cybernetic perspective (Ⅰ): Theoretical preliminaries [J]. Biotechnol. Progr., 1999, 15: 407-425.
[12]	Gadkar K G, Doyle III F J, Crowley T J, Varner J D. Cybernetic model predictive control of a continuous bioreactor with cell recycle [J]. Biotechnol. Progr., 2003, 19: 1487-1497.
[13]	Li Yin (李寅),Cao Zhu'an (曹竹安). Microbial metabolic engineering: gateway to develop blueprints for cell factories [J]. Journal of Chemical Industry and Engineering (China) (化工学报), 2004, 55 (10): 1573-158.
[14]	Gao Zhen (高振), Xiong Qiang (熊强), Xu Qing (徐晴), Song Ping (宋萍), Li Shuang (李霜). Application of metabolic flux analysis in the progress of enzyme synthesis [J]. Chemical Industry and Engineering Progress (化工进展), 2013, 32 (7): 1625-1628.
[15]	Sun J B, Lu X, Rinas U, Zeng A P. Metabolic peculiarities of Aspergillus niger disclosed by comparative metabolic genomics [J]. Genome Biology, 2007, 8 (9): R182.
[16]	Andersen M R, Nielsen M L, Nielsen J. Metabolic model integration of the bibliome, genome, metabolome and reactome of Aspergillus niger [J]. Molecular Systems Biology, 2008, 4: 178.
[17]	Torres N V. Modeling approach to control of carbohydrate metabolism during citric acid accumulation by Aspergillus niger (I): Model definition and stability of the steady state [J]. Biotechnol. Bioeng., 1994, 44: 104-111.
[18]	Karaffa L, Kubicek C P. Aspergillus niger citric acid accumulation: do we understand this well working black box [J]. Applied Microbiology and Biotechnology, 2003, 61: 189-196.
[19]	Sweetlove L J, Beard K, Nunes-Nesi A, Fernie A R, Ratcliffe R G. Not just a circle: flux modes in the plant TCA cycle [J]. Trends in Plant Science, 2010, 15 (8): 462-470.
[20]	Straight J, Ramkrishna D. Cybernetic modeling and regulation of metabolic pathways. Growth on complimentary nutrients [J]. Biotechnol. Progr., 1994, 10: 574-587.
[21]	Varner J, Ramkrishna D. The non-linear analysis of cybernetic models. Guidelines for model formulation [J]. Journal of Biotechnology, 1999, 71 (1): 67-103.
[22]	Kim J, Varner J, Ramkrishna D. A hybrid model of anaerobic E. coli GJT001: combination of elementary flux modes and cybernetic variables [J]. Biotechnol. Progr., 2008, 24: 993-1006.
[23]	Namjoshi A A, Ramkrishina. A cybernetic modeling framework for analysis of metabolic systems [J]. Computers and Chemical Engineering, 2004, 29: 487-498.
[24]	Bellgardt K H, Kuhlmann W, Meyer H D, et al. Application of an extended Kalman filter for state estimation of a yeast fermentation [J]. IEE Proceedings D:Control Theory and Applications, 1986, 133 (5): 226-234.
[25]	Ren H T, Yuan J Q, Bellgardt K H. Macrokinetic model for methylotrophic Pichia pastoris based on stoichiometric balance [J]. Journal of Biotechnology, 2003, 106 (1): 53-68.
[26]	Kubicek C P, Zehentgruber O, Röhr M. An indirect method for studying fine control of citric acid accumulation by Aspergillus niger [J]. Biotechnology Letters, 1979, 1: 47-52.
[27]	Habison A, Kubicek C P, Röhr M. Partial purification and regulatory properties of phosphofructokinase from Aspergillus niger [J]. Biochem. J., 1983, 209: 669-676.
[28]	Steinbock F A, Chojun S, Held I, Röhr M, Kubicek C P. Characterization and regulatory properties of a single hexokinase from the citric acid accumulating fungus Aspergillus niger [J]. Biochim. Biophys. Acta, 1994, 1200: 215-223.
[29]	Cleland W W, Johnson M J. Tracer experiments on the mechanism of citric acid formation by Aspergillus niger [J]. J. Biol. Chem.,1954, 208:679-692.
[30]	Mattey M. The production of organic acids [J]. Crit. Rev. Biotechnol., 1992, 12: 87-132.
[31]	Meixner-Monori B, Kubicek C P, Röhr M. Pyruvate kinase from Aspergillus niger: a regulatory enzyme in glycolysis [J]. Can. J. Microbiol., 1983, 30: 16-22.