Modeling the effect of the XylSh loop in TOL system. (a) Signal transmission/conversion in the TOL system. The diagram sketches interactions between the active forms of the regulators and the metabolic intermediate 3-methylbenzoate (3 MBz). To the left, inactive XylR (XylRi) becomes activated by m-xylene to produce the transcriptionally competent form XylRa. This in turn, results in activation of the upper pathway and overproduction of XylS (XylSh), which can by itself activate meta pathway. Such a XylSh loop (marked in blue), which does not involve 3 MBz, links the meta pathway directly to m-xylene presence. To the right, XylS produced at low levels, insufficient for activating meta (XylSi) turns into an active form (XylSa) to the same end upon binding the 3 MBz produced by the action of upper on m-xylene. Finally, production of meta converts 3 MBz into Krebs' cycle intermediates. (b) Simulation conditions. Wild type considers the complete model where meta is concomitantly expressed through both XylSa-mediated and XylSh-mediated paths. In No XylS hyper-expressed conditions the effect of XylSh has been removed and meta is activated only by XylSa. In No XylS activation condition, the effect of XylSa has been deleted and meta is under the sole control of XylSh. (c) Temporal sequence of qualitative states for each of the three conditions. Each scenario was simulated until the system reached a steady state.