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

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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 different 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