Multiple feedback loops are key to a robust dynamic performance of tryptophan regulation in Escherichia coli

Abstract

Living systems must adapt quickly and stably to uncertain environments. A common theme in cellular regulation is the presence of multiple feedback loops in the network. An example of such a feedback structure is regulation of tryptophan concentration in Escherichia coli. Here, three distinct feedback mechanisms, namely genetic regulation, mRNA attenuation and enzyme inhibition, regulate tryptophan synthesis. A pertinent question is whether such multiple feedback loops are ''a case of regulatory overkill, or do these di¡erent feedback regulators have distinct functions?'' [Freeman (2000) Nature 295, 313^319]. Another moot question is how robustness to uncertainties can be achieved structurally through biological interactions. Correlation between the feedback structure and robustness can be systematically studied by tools commonly employed in feedback theory. An analysis of feedback strategies in the tryptophan system in E. coli reveals that the network complexity arising due to the distributed feedback structure is responsible for the rapid and stable response observed even in the presence of system uncertainties. ß

Inhibition of Steroid Receptor Coactivator-1 Blocks Estrogen and Androgen Action on Male Sex Behavior and Associated Brain Plasticity

“…As a result of antisense administration, untranslated SRC-1 mRNA may have accumulated [antisense oligonucleotides are supposed to increase RNase H activity that would counteract this effect, but this enzyme is apparently not expressed at detectable levels and unlikely to play a major role in the brain (Sawai et al, 1977;Landgraf et al, 1997)], and, with the cessation of the treatment, this accumulated message was translated and resulted in the detected increase in the protein. Feedback loops of this sort between message expression and the protein are common in many vertebrate and invertebrate systems (Han et al, 1999;Allada et al, 2001;Venkatesh et al, 2004).…”

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

“…The tryptophan system has been quantified through various mathematical models (Koh et al 1998;Santillan & Zeron 2004;Venkatesh et al 2004), which have been verified with experimental data. Among these, Venkatesh et al (2004) delineated the role of regulation by explicitly modelling the multiple feedback loops resulting from repression, attenuation and inhibition. The authors showed that the multiple feedback loops enable rapid synthesis of tryptophan in a stable manner.…”

“…Knowledge of the structure and the parameter values defines a dynamic model of the network. Biological models, however, do not distinguish 'process' components from 'regulatory' components (El-Samad et al 2002Venkatesh et al 2004). Such a non-discriminative approach fails to explicitly identify the role of the structure in the system-wide performance.…”

“…The authors showed that the multiple feedback loops enable rapid synthesis of tryptophan in a stable manner. In this work, we use the model of Venkatesh et al (2004) to assess the role of multiple feedback loops in providing robustness to perturbations in parameter or structure, relative to a single feedback loop design.…”

System and Control Theory Furthers the Understanding of Biological Signal Transduction

“…The last three can be achieved by appropriate network structures. Best known are feedback loops for robustness, combined with feedforward loops to increase performance [12], as for example in the heat shock response system [17,45] or the Tryptophan regulation in E. coli [71].…”