Misconceptions in Metabolism I

 September 26, 2012 10:27 pm

I'm currently at the ISGSB meeting (International Study group for Systems Biology - formally BTK) in Holland. This is a group that values both theoretical analysis and experimentation in biochemical network analysis. It's an interesting group of people that I have literally followed for a couple of decades. A new researcher in the field of metabolism gave an interesting but false statement in their talk that requires some clarification.

The statement was this, (using their terminology).If a particular step in a metabolic pathway is rate-limiting then the substrate to that reaction step is also rate-limiting. True or false? First of all, what did they mean by the terms rate-limiting? If a biochemical step is rate-limiting it means that increasing the enzyme activity will increase the steady-state flux through the pathway, in MCA (metabolic control analysis) this is measured using the flux control coefficient.  A rate-limiting substrate is similarly defined where if the substrate concentration is increased the reaction rate of the step increases (note, not the flux but the reaction rate associated with the substrate). We measure the rate limitingness of a substrate using its elasticity coefficient.

One of the well-known results from MCA is the connectivity theorem, which states that the magnitude of a flux control coefficient is inversely proportional to the substrate elasticity of the same step. This is easy to understand. If we were to increase the activity of a biochemical step that has a high flux control coefficient, the flux through the pathway will increase. If we look at this more closely, when we increase the enzyme activity this must result in a higher consumption of substrate which in turn will trend to decrease the substrate concentration. If the substrate happened to have a high elasticity, this drop in substrate would tend to cancel out any increase in reaction rate brought about by increasing the enzyme activity. That is, a biochemical step that has a high flux control coefficient must necessarily have a low elasticity.

We, therefore, conclude that the original premise was false. For a biochemical step that is rate-limiting, the substrate for that reaction step will NOT be rate-limiting.