Back to Home
Home >> Metabolic Engineering for Over production of Metabolites >> Limitations in Metabolic Engineering Due to Network Rigidity
Back to Home

Limitations in Metabolic Engineering Due to Network Rigidity - During metabolic engineering involving primary metabolism (e.g. glycolysis, TCA cycle and pentose phosphate pathway, etc.), the carbon flux distributions at key branch points (called 'nodes') is often radically redirected from the flux distributions that are normally associated with balanced growth.

Such flux alterations are often directly opposed by mechanisms that have evolved to maintain original flux distributions for optimal growth. This opposition to flux alterations at key branch points or nodes is often described as 'metabolic rigidity' or 'nodal rigidity'. There are relatively few examples where this nodal rigidity has been overcome through genetic manipulations leading to successful flux alterations.

The concept of metabolic or network rigidity can be illustrated using the example of overproduction of lysine by Corynebacterium glutamicim. The metabolic flux distributions (using glucose as a substrate) for balanced growth, for 30-40% molar yield and for maximum 'yield (75% molar yield), where glucose uptake was used as a standard indicated by 100 units.

It will be seen that flux distribution for maximum overproduction represents a significant deviation from that for balanced growth or from that for 30-40% overproduction. If pathways leading to production of byproducts (e.g. pyruvate dehydrogenase complex or PDC leading to TCA cycle) are blocked, one would expect a shift in metabolic pathway leading to maximum over production of lysine.

But the metabolic network does not respond to such alterations in metabolic network due to metabolic rigidity at key branch points or nodes. Such metabolic rigidity must be identified and overcome before results of metabolic engineering can be exploited.