Why is the metabolic cost of synthesising an amino acid important? This is a good question to ask myself since I am writing a paper on this subject, and I likely to be asked again in the future. One answer is that the atoms that form the structure of the amino acid, and the energy expended during synthesis must come from a competitive environment. So, if I am budding yeast and I can reproduce myself for 1% less the cost than my neighbours, then I am more competitive.
This is an over simple explanation and where the selection pressures involved in protein evolution are numerous, however several researchers have shown, that the the cost of producing a protein is a significant factor. Whether through examining the correlation of protein cost with predicted expression, or the correlation of amino acid cost with usage.
But what does the word cost mean? The quantity of cell resources spent during synthesis is a good place to start, but defining an all-inclusive number is difficult. Here is a list of five different types that I’m looking at in my research.
Biosynthetic complexity
This cost is based on the total number of enzymes required in the synthesis of the amino acid, where more expensive and complex amino acids require more steps to create. This method may take into account metabolic factors such as the expense of maintaining the expression of the enzymes to enable the reactions, as well as maintaining sufficient concentrations of the intermediate metabolites to allow the synthetic reactions to proceed in the required direction.
Papers: Craig and Weber 1998
Biosynthetic energy
This cost is derived from the manual curation of the metabolic network to count how many high energy molecules are required in the synthesis of each amino acid molecule. ATP is the predominant energetic currency in the synthesis of most compounds, and molecules such NADH and NADPH are converted to ATP in various stoichiometries to yield single cost measure for each amino acid. This is the most common cost measure in the literature and variations have been calculated for a range of organisms and environments.
Papers: Craig and Weber 1998, Akashi and Gojobori 2002, Wagner 2005, Heizer et al 2006
Molecular weight
This is simply the weight of the amino acid in Daltons. The reasoning behind this, is that the previous manual curation methods may not take into account all the investment the cell makes when producing each molecule. A large, heavy amino acid is inherently more complex and will require more resources to create. The advantage of using molecular weight, is that this is fixed across species, and so makes comparative analysis much easier.
Papers: Seligmann 2003
Atomic investment
This is not specifically a cost measure, but some researchers have looked at how environmental limitation for a specific atom affects the expression of proteins rich in that atom. For example, the proteins in pathways that scavenge atoms under use this atom. The likely explanation is that this allows quicker expression in response to environmental limitation.
Papers: Baudoin-Cornu et al 2001, Bragg et al 2006, Bragg et al 2007
Metabolic control analysis (MCA)
This is my own work into deriving a whole-cell based approach to estimating metabolic cost, which includes aspects of the previously published cost measures. Using large scale (700+ reactions) metabolic models of organisms such as E.coli and S.cerevisiae, I’m looking at how changing requirements of amino acids affects the speed at which a cell can grow or reproduce. My reasoning is that this takes into account any limitations of energy or atoms, as well as the complexity of the metabolic network. The drawback to this, is that a organism specific genome scale model is required, but the cost type can be quickly calculated for any molecule.
Papers: Duarte et al 2004, Rossell et al 2005