Agathos S N, Lee J
Department of Chemical and Biochemical Engineering, State University of New Jersey, Piscataway 08855-0909.
Biotechnol Prog. 1993 Jan-Feb;9(1):54-63. doi: 10.1021/bp00019a008.
A mathematical model was developed to describe the kinetics of submerged fungal growth, consumption of nutrients, and production of the immunosuppressant drug, cyclosporin A (CyA). Special emphasis was placed on the experimentally observed stimulatory effect of L-valine on CyA production. The proposed model was based on kinetic information and emerging mechanistic data on CyA biosynthesis. It was assumed that L-valine acts as both precursor and inducer of the CyA-synthesizing multienzyme (CyA synthetase), and an unmethylated intermediate of CyA was postulated in the biosynthetic process. The model consisted of two parts: one describing cell growth and substrate consumption and the other addressing the kinetics of internal properties such as endogenous valine, biosynthetic enzyme, CyA intermediate, and CyA. The success of this extensive model was confirmed by its ability to simulate adequately the kinetic profiles of both external and internal variables. For instance, the model correctly predicted the time course of intracellular L-valine accumulation. In addition, both the optimal level and timing of exogenous L-valine addition could be predicted for maximum drug production. This study suggests rational new ways of improving the fungal production process of this important immunosuppressant.
建立了一个数学模型来描述深层真菌生长动力学、营养物质消耗以及免疫抑制剂环孢菌素A（CyA）的产生。特别强调了实验观察到的L-缬氨酸对CyA产生的刺激作用。所提出的模型基于关于CyA生物合成的动力学信息和新出现的机制数据。假定L-缬氨酸既是CyA合成多酶（CyA合成酶）的前体又是诱导剂，并且在生物合成过程中假定存在一种未甲基化的CyA中间体。该模型由两部分组成：一部分描述细胞生长和底物消耗，另一部分涉及内源性缬氨酸、生物合成酶、CyA中间体和CyA等内部特性的动力学。这个广泛模型的成功通过其充分模拟外部和内部变量动力学曲线的能力得到了证实。例如，该模型正确地预测了细胞内L-缬氨酸积累的时间进程。此外，还可以预测外源L-缬氨酸添加的最佳水平和时间，以实现最大药物产量。这项研究提出了改进这种重要免疫抑制剂真菌生产过程的合理新方法。
