1SNAPSHOTS OF SYSTEMS- METABOLIC CONTROL ANALYSIS AND BIOTECHNOLOGY IN THE POST-GENOMIC ERA by

We provide a critical survey of some of the major limitations of the principles and applications of metabolic control analysis, with special reference to the enhancement of fluxes of biotechnological interest. Experimental methods of single-cell analysis such as flow cytometry show that the implicit assumption that we study and model ensembles of identical cells is often completely untenable, and that cellular heterogeneity is much greater than we normally assume. A feature of the post-genomic era is the recognition that many more genes exist, and are expressed, than we had ever recognised, and that methods are being developed for the quantitative assessment of this. Even if the individual flux-control coefficients of these gene products were each very small their enormous number means that over-simplified analyses that ignore them are very likely to lead to erroneous analyses of the true structure and organisation of a metabolic system or subsystem of interest. Even the assumption that the components of moiety-conserved cycles do not change their total concentrations during an experiment ignores what may be a large impact of this on the control structure. In the absence of compartmentation or channelling, such cycles also serve to connect segments of metabolism usually considered rather distant from each other. Simplified (‘top-down’) methods in which the system structure is assumed a priori often will not work to give unequivocal answers for complex systems where the combinatorial explosion of possible interactions requires much more sophisticated methods for syste