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Use and limitations of modular metabolic control analysis in medicine and biotechnology.

By Metabolic Control Analysis (MCA), it has been shown that control on flux is in most cases shared by several enzymes rather than concentrated on one "rate-limiting step." This analysis also allows the quantification of the control exerted by groups (modules) of enzymes. The modules may correspond to spatial compartments or to functional units. A brief outline of the modular approach to MCA is given. The criteria by which the system can be modularized and the concept of monofunctional unit are explained. Various studies in which control analysis was applied to biotechnological and medical issues are reviewed. In particular, MCA has turned out to be helpful in the assessment of the severity of enzyme deficiencies. Another application is the search for target enzymes or enzyme groups where pharmaceuticals can suppress the metabolism of pathogenic microorganisms most. In biotechnology, modular and "traditional" control analyses are valuable tools for choosing the most promising targets for genetic manipulation so as to increase a biosynthetic flux. As control coefficients are linear approximations, the effect of enhancing the activities of enzymes to a larger extent is often overestimated. Further limitations such as the restriction to stationary states, uncertainties due to spatial heterogeneities and the impact of experimental error are discussed.