Is Transcriptional Regulation of Metabolic Pathways an Optimal Strategy for Fitness?

Abstract

BackgroundTranscriptional regulation of the genes in metabolic pathways is a highly successful strategy, which is virtually universal in microorganisms. The lac operon of E. coli is but one example of how enzyme and transporter production can be made conditional on the presence of a nutrient to catabolize.MethodologyWith a minimalist model of metabolism, cell growth and transcriptional regulation in a microorganism, we explore how the interaction between environmental conditions and gene regulation set the growth rate of cells in the phase of exponential growth. This in silico model, which is based on biochemical rate equations, does not describe a specific organism, but the magnitudes of its parameters are chosen to match realistic values. Optimizing the parameters of the regulatory system allows us to quantify the fitness benefit of regulation. When a second nutrient and its metabolic pathway are introduced, the system must further decide whether and how to activate both pathways.ConclusionsEven the crudest transcriptional network is shown to substantially increase the fitness of the organism, and this effect persists even when the range of nutrient levels is kept very narrow. We show that maximal growth is achieved when pathway activation is a more or less steeply graded function of the nutrient concentration. Furthermore, we predict that bistability of the system is a rare phenomenon in this context, but outline a situation where it may be selected for.

Comparative transcriptomic profile analysis of fed-batch cultures expressing different recombinant proteins in Escherichia coli

“…Thus the metabolic activity which is linked to substrate uptake rate fell only after 4 hours post-induction. The down-regulation of energy generating pathways also leads to a drop in growth rate ( Kasimoglu et al 1996 ; Troein et al 2007 ) which was also observed in the present case. It has been previously reported that in complex medium, several genes of energy generating pathways such as hycB, cyoA, cydA, and ndh , were down-regulated, along with the ATP synthase gene ( Oh and Liao 2000 ), which is similar to our observations.…”

Construction of a tunable promoter library to optimize gene expression in Methylomonas sp. DH-1, a methanotroph, and its application to cadaverine production

“…In addition, the non-optimized expression of enzyme genes may facilitate the accumulation of toxic intermediate metabolites, which decreases the production yield. To resolve this problem, promoters with different strengths are widely employed to fine-tune the expression levels of enzyme genes [ 8 , 9 ].…”

Adaptive Benefits of Storage Strategy and Dual AMPK/TOR Signaling in Metabolic Stress Response

“…Although these two main modeling frameworks are well-adapted to determine optimal flux balance in detailed metabolic reaction networks, they remain dependent on steady-state or quasi-steady-state assumptions or on small perturbation approximations. A third approach consists in using simplified models depicting generic motifs (unbranched or cyclic pathways) or a prototypical metabolism, which allows studying regulation in simple resource allocation problem such as the switch from one to another substrate [ 29 , 30 ], the switch between respiratory and fermentation metabolism [ 31 ], or the evolution of regulatory complexity [ 32 ]. The total number of kinetic parameters in these models is usually low enough to allow for extensive parameter space exploration or for parameter optimization through evolutionary computation techniques, without necessarily requiring additional assumptions of steady state or of small enough environmental fluctuations.…”