Abstract
Overcoming the stress of starvation is one of an organism’s most challenging phenotypic responses. Those organisms that frequently survive the challenge, by virtue of their fitness, will have evolved genomes that are shaped by their specific environments. Understanding this genotype–environment–phenotype relationship at a deep level will require quantitative predictive models of the complex molecular systems that link these aspects of an organism’s existence. Here, we treat one of the most fundamental molecular systems, protein synthesis, and the amino acid biosynthetic pathways involved in the stringent response to starvation. These systems face an inherent logical dilemma: Building an amino acid biosynthetic pathway to synthesize its product—the cognate amino acid of the pathway—may require that very amino acid when it is no longer available. To study this potential “catch-22,” we have created a generic model of amino acid biosynthesis in response to sudden starvation. Our mathematical analysis and computational results indicate that there are two distinctly different outcomes: Partial recovery to a new steady state, or full system failure. Moreover, the cell’s fate is dictated by the cognate bias, the number of cognate amino acids in the corresponding biosynthetic pathway relative to the average number of that amino acid in the proteome. We test these implications by analyzing the proteomes of over 1,800 sequenced microbes, which reveals statistically significant evidence of low cognate bias, a genetic trait that would avoid the biosynthetic quandary. Furthermore, these results suggest that the pattern of cognate bias, which is readily derived by genome sequencing, may provide evolutionary clues to an organism’s natural environment.
Highlights
Predicting or measuring the natural microenvironment of an organism is a complex and challenging task (Savageau 1983; Ward et al 1998; Xu 2006)
Before describing a larger model of amino acid biosynthesis and regulation, we present a model of translation that accounts for the effect of starvation, or for a decreased supply of the cognate amino acid of interest
They consider the incorporation of an amino acid in isolation—a single instance of those three steps—and use the result to represent the average rate of amino acid consumption in a larger model of global protein synthesis
Summary
Predicting or measuring the natural microenvironment of an organism is a complex and challenging task (Savageau 1983; Ward et al 1998; Xu 2006). The cognate bias hypothesis (Alves and Savageau 2005) suggests that nutritional stress places evolutionary pressure on the composition of the enzymes in the amino acid biosynthetic pathways. It is clear that the stringent response is a general reaction to stress and starvation that is conserved across species (Draper 1996; Harris et al 1998; van der Biezen et al 2000; Chatterji and Ojha 2001), and is characterized by increased levels of guanosine tetraphosphate (ppGpp) (Cashel 1969; Wendrich et al 2002), which has at least 75 known effects in Escherichia coli, including decreased rRNA and tRNA transcription, decreased growth rate, and increased expression of the biosynthetic enzymes for many amino acids (Draper 1996; Magnusson et al 2005; Potrykus and Cashel 2008; Dalebroux and Swanson 2012). The missing amino acid could hold up the construction of the enzymes needed to create more of their cognate amino acid, a stalemate from
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