Optimization of nonlinear biotechnological processes with linear programming: Application to citric acid production by Aspergillus niger.

The metabolic pathway and the properties of many of the enzymes involved in the citric acid biosynthesis in the mold Aspergillus niger are well known. This fact, together with the availability of new theoretical frameworks aimed at quantitative analyses of control and dynamics in metabolic systems, has allowed us to construct a mathematical model of the carbohydrate metabolism in Aspergillus niger under conditions of citric acid accumulation. The model makes use of the S-system representation of biochemical systems, which renders it possible to use linear programming to optimize the process. It was found that maintaining the metabolite pools within narrow physiological limits (20% around the basal steady-state level) and allowing the enzyme concentrations to vary within a range of 0.1 to 50 times their basal values it is possible to triple the glycolytic flux while maintaining 100% yield of substrate transformation. To achieve these improvements it is necessary to modulate seven or more enzymes simultaneously. Although this seems difficult to implement at present, the results are useful because they indicate what the theoretical limits are and because they suggest several alternative strategies. (c) 1996 John Wiley & Sons, Inc.