On the Universality of the Universal Method

摘要

The universal method (Kacser & Acerenza, 1993) was conceived as a way of increasing the production and yield of molecules excreted by microorganisms. It rests on the knowledge provided by two areas of investigation: establishment of the structure of metabolic pathways represented by the metabolic map; and molecular biology, which alows changes in enzyme concentrations by modifying gene copy number or expression. The combination of the two areas can provide a modified organism with an enzyme profile that improves the production of the molecule of interest. The problem is to decide which genes to modify and in what way. Answering this question requires a model of the genotype-phenotype relationship, as Bailey discusses in Chapter 4 of this book. Several models have been used to describe the effects of changes in enzyme concentrations on metabolic fluxes. One possible strategy is to try to mimic reality. In this case, everything that is known is fed into a formalism intended to behave like the organism. These models aim to be useful for answering any question about the system, but Is suspect that, owing to the complex nature of life, achievement of this goal could be an endless task. I prefer question-oriented strategies designed to answer particular questions, acceptiing at the outset that most of the other possible questions will remain unanswered. With this point of view one must necessarily make major simplifications to avoid most of the complexities of reality. In fact, metabolic control analysis could be regarded as one of these approaches. Perhaps the most dramatic simplification in this formalism is that it considers only infinitesimal changes. Genetic manipulation, however, produces large effects on enzyme concentrations. The universal method was developed to fill this gap. It tells one which steps need to be manipulated, and by how much, to extract a desired increase in the flux towards a molecule of interest, leaving the rest of metabolism and other important functions of the cell unchanged. The occurrence of deleterious pleiotropic effects that may appear as a result of large changes would therefore be prevented.