An indirect optimization method for biochemical systems: description of method and application to the maximization of the rate of ethanol, glycerol, and carbohydrate production in Saccharomyces cerevisiae.

Three metabolic models for the production of ethanol, glycerol, and carbohydrates in yeast are optimized with respect to different production rates. While originally nonlinear, all three optimization problems are reduced in such a way that methods of linear programming can be used. The optimizations lead to profiles of enzyme activities that are compatible with the physiology of the cells, which guarantees their viability and fitness, and yield higher rates of the desired final end products than the original systems. In order to increase ethanol rate production at least three times, six enzymes must be modulated. By contrast, when the production of glycerol or carbohydrates is optimized, modulation of just one enzyme (in the case of glycerol) or two enzymes (in the case of carbohydrates) is necessary to yield significant increases in product flux rate. Comparisons of our results with those obtained from other methods show great similarities and demonstrate that both are valid methods. The choice of one or the other method depends on the question of interest. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 758-772, 1997.