Misconceptions in Metabolism II

October 2, 2012 8:58 am

A week ago I wrote about some misconceptions about metabolism that arose from a trip to a systems biology workshop in Holland. This week I discovered that Nature is perpetrating similar misconceptions in their News and Views section.

I came across the News and Views article: "Cancer Metabolism: When more is less" by Lei Jiang & Ralph J. DeBerardinis. They review a recent paper in Nature Chemical Biology by Anastasiou et al. which showed that increases in Pyruvate Kinase levels may depress metabolites concentrations upstream of the enzyme step. Not a surprising conclusion if one understands basic enzyme kinetics. The original paper was ok though it seemed to overemphasize the structural aspects of the story compared to the system implications which were perhaps more interesting.

The News and Views article however went rogue on us and perpetrated in fine form the misleading notion of bottlenecks in metabolic pathways, something I thought had been laid to rest 40 years ago with the publication of the seminal works by Kacser and Burns and Heinrich and Rapoport. The term bottleneck is a very imprecise word to use for something which is actually far more subtle. What really annoyed me was Nature's use of the figure shown below. The figure is nicely drawn but it overly simplifies a much more complex situation. More dangerous however is it gives the impression that metabolism can be regulated at single steps which in general is quite wrong. Nature has done a great disservice to the scientific community with this article. Molecular Biologists have enough difficulties most of the time understanding complex systems without giving them tempting simplistic stories and pretty pictures. Being published Nature, unfortunately, gives the story an unwarranted air of authority that it does not deserve.

From "Cancer metabolism: When more is less", Nature 489, 511–512 (27 September 2012) doi:10.1038/489511a by Lei Jiang & Ralph J. DeBerardinis

Ludicrous as it may sound

August 23, 2012 2:13 pm

I was reminded the other day of an interesting quote from a 2000 FEBS paper which starts with:

"How highly would one rate an economic analysis of a factory that ignored the consumer demand for its products? Ludicrous as it may sound, this is precisely what most metabolic studies of the past century have been doing."

FEBS Lett. 2000 Jun 30;476(1-2):47-51.Regulating the cellular economy of supply and demand. Hofmeyr JS, Cornish-Bowden A.

The Delphi Color Palette

September 19, 2012 7:30 pm

This is the Delphi color palette, both 'normal' and 'web' colors. The 'normal' colors start with red and end with black. The 'web' colors start at Moccasin. 

See http://docwiki.embarcadero.com/RADStudio/en/Colors_in_VCL) for more information.

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.