Multiple feedback loop design in the tryptophan regulatory network of Escherichia coli suggests a paradigm for robust regulation of processes in series

Abstract

Biological networks have evolved through adaptation in uncertain environments. Of the different possible design paradigms, some may offer functional advantages over others. These designs can be quantified by the structure of the network resulting from molecular interactions and the parameter values. One may, therefore, like to identify the design motif present in the evolved network that makes it preferable over other alternatives. In this work, we focus on the regulatory networks characterized by serially arranged processes, which are regulated by multiple feedback loops. Specifically, we consider the tryptophan system present in Escherichia coli, which may be conceptualized as three processes in series, namely transcription, translation and tryptophan synthesis. The multiple feedback loop motif results from three distinct negative feedback loops, namely genetic repression, mRNA attenuation and enzyme inhibition. A framework is introduced to identify the key design components of this network responsible for its physiological performance. We demonstrate that the multiple feedback loop motif, as seen in the tryptophan system, enables robust performance to variations in system parameters while maintaining a rapid response to achieve homeostasis. Superior performance, if arising from a design principle, is intrinsic and, therefore, inherent to any similarly designed system, either natural or engineered. An experimental engineering implementation of the multiple feedback loop design on a two-tank system supports the generality of the robust attributes offered by the design.

Influence of the feedback loops in the trp operon of B. subtilis on the system dynamic response and noise amplitude

“…In conclusion, transcription-attenuation makes the trp operon more sensitive to environmental changes under conditions of tryptophan starvation given that it allows the synthesis of large polypeptide amounts. These results are in agreement with those of Bhartiya et al (2006), who suggest that a similar overshoot gives E. coli an evolutionary advantage because it reaches the tryptophan concentration necessary to grow and reproduce more rapidly.…”

“…This means that transcription attenuation speeds up the trp operon response to reactivation experiments. Our results agree with those of Bhartiya et al (2006).…”

“…For instance, Bhartiya et al (2006) demonstrated that the multiple feedback loops enable the system with a rapid response to achieve homeostasis; Santillá n and Zeron (2004) studied the dynamical influence of feedback loops and found that transcription attenuation speeds up its response to nutritional shifts, while feedback enzyme inhibition increases the operon stability; and Herná ndez-Valdé z et al (2010) took into account more molecular details in the trp operon and found that the E. coli inhibition-free mutant strain expresses cyclically. Furthermore, it is known that negative feedback is the most common noise-attenuation regulatory mechanism.…”

Diverse metabolic model parameters generate similar methionine cycle dynamics

“…A series of recent modeling studies have made major strides towards identifying topological features of bionetworks that give rise to emergent properties such as the ability to sense and respond to environmental signals, maintain metabolic homeostasis, and form complex developmental patterns, all in a manner that is robust to environmental and genetic noise (Barkai and Leibler, 1997;Bhartiya et al, 2006;Brandman et al, 2005;Kollmann et al, 2005;Meir et al, 2002;Stelling et al, 2002;von Dassow et al, 2000;Wagner, 2005). A complement to understanding the topological features of bionetworks that lead to their qualitative properties is finding the precise parameter values which lead to specific quantitative phenotypes.…”

Development of l-tryptophan production strains by defined genetic modification in Escherichia coli

“…Although the L-Trp production of FB-04/pSV03 (13.3 g/l) was lower than that of the strains constructed by Azuma et al (54.6 g/l) and Dodge et al (42 g/l) [2,9] and the conversion ratio from glucose to L-Trp of FB-04/ pSV03 (10%) was also lower than that of the strain constructed by Dodge et al (18%) [2,9], FB-04/pSV03 has completely defined genome traits. A lot of new explorations on biosynthetic mechanism of L-Trp [4,19,23] and various large-scale analytical techniques such as transcriptome and proteome analysis [20,24], which are difficult to be applied on the random mutagenesis strains because of unknown mutations in their genomes, can provide new information for the further improvement of the strain FB-04/pSV03.…”