Evidence of selection for low cognate amino acid bias in amino acid biosynthetic enzymes

Abstract

If the enzymes responsible for biosynthesis of a given amino acid are repressed and the cognate amino acid pool suddenly depleted, then derepression of these enzymes and replenishment of the pool would be problematic, if the enzymes were largely composed of the cognate amino acid. In the proverbial "Catch 22", cells would lack the necessary enzymes to make the amino acid, and they would lack the necessary amino acid to make the needed enzymes. Based on this scenario, we hypothesize that evolution would lead to the selection of amino acid biosynthetic enzymes that have a relatively low content of their cognate amino acid. We call this the "cognate bias hypothesis". Here we test several implications of this hypothesis directly using data from the proteome of Escherichia coli. Several lines of evidence show that low cognate bias is evident in 15 of the 20 amino acid biosynthetic pathways. Comparison with closely related Salmonella typhimurium shows similar results. Comparison with more distantly related Bacillus subtilis shows general similarities as well as significant differences in the detailed profiles of cognate bias. Thus, selection for low cognate bias plays a significant role in shaping the amino acid composition for a large class of cellular proteins.

Fig. 1

Schematic model of a specific amino acid biosynthetic path-way in its cellular context. X₁- mRNA coding for the enzymes of the pathway that synthesizes the kth amino acid; X₂- enzymes of the pathway that synthesizes the kth amino acid; X₃- cognate amino acid (kth) of the biosynthetic pathway. See text for further discussion.

Fig. 2

Time-course of derepression and amino acid recovery for the computer model of the tryptophan biosynthetic pathway from E. coli. Cells growing in a medium with excess Trp (k₁₁ = 1) are switched to media containing various lower amounts of Trp (k₁₁ < 1): A and B (k₁₁ = 0.5), C and D (k₁₁ = 0.41), E and F (k₁₁ = 0, which corresponds to no Trp). Expression of the trp operon undergoes derepression and is allowed to reach a new steady state. The upper curve in each panel corresponds to the case in which the rate of enzyme synthesis is independent of Trp concentration (k_M = 0), and the curves then decrease in the order of increasing dependence on Trp concentration (k_M = 0, 0.1, 1, 10, 20, 50, 100, 500). The steady state concentrations of Trp and of the Trp-biosynthetic enzymes in a Trp-reduced media decrease with increasing k_M. A, C and E. Dimensionless time-course for protein levels, which are normalized with respect to the maximum derepressed steady-state value in (E). B, D and F. Dimensionless time-course for intracellular amino acid levels, which are normalized with respect to the same initial value. Note that the y-axes changes scale progressively from panel to panel in order to show differences while accommodating the increasing degrees of derepression. See text for further discussion.

Fig. 3

Schematic representation of amino acid biosynthetic pathways. Names for each enzyme, represented here by their EC number, and the corresponding gene are given in Table 2.

Fig. 4

The compositional bias of biosynthetic pathways with respect to their cognate amino acid.

Fig. 5

Enzyme with the lowest value for cognate bias in the biosynthetic pathway of each amino acid. The order of the pathways is the same as that in Fig. 4. The x-axis shows the name of the gene coding for the enzyme. The numbers indicate the probability that this lowest bias occurs in a set of proteins, containing the same number of proteins as the pathway, and drawn randomly from the proteome of each organism.