title: Allosteric interactions and bifunctionality make the response of glutamine synthetase cascade system of Escherichia coli robust and ultrasensitive.
abstract: Glutamine synthetase (GS) regulation in Escherichia coli by reversible covalent modification cycles is a prototype of signal transduction by enzyme cascades. Such enzyme cascades are known to exhibit ultrasensitive response to primary stimuli and act as signal integration systems. Here, we have quantified GS bicyclic cascade based on steady state analysis by evaluating Hill coefficient. We demonstrate that adenylylation of GS with glutamine as input is insensitive to total enzyme concentrations of GS, uridylyltransferase/uridylyl-removing enzyme, regulatory protein PII, and adenylyltransferase/adenylyl-removing enzyme. This robust response of GS adenylylation is also observed for change in system parameters. From numerical analyses, we show that the robust ultrasensitive response of bicyclic cascade is because of allosteric interactions of glutamine and 2-ketoglutarate, bifunctionality of converter enzymes, and closed loop bicyclic cascade structure. By system level quantification of the GS bicyclic cascade, we conclude that such a robust response may help the cell in adapting to different carbon and nitrogen status.
authors.affiliation: Department of Chemical Engineering and School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Powai, Mumbai 400 076, India.
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Mutalik
authors.forename: Parag
authors.initials: P
authors.lastname: Shah
authors.forename: K V
authors.initials: KV
authors.lastname: Venkatesh
mesh_terms: D000494:Allosteric Regulation; D004926:Escherichia coli / Q000201:enzymology*; D005974:Glutamate-Ammonia Ligase / Q000737:chemistry / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000378:metabolism; D051922:PII Nitrogen Regulatory Proteins; D015398:Signal Transduction
chemical_list: D007656:Ketoglutaric Acids; D051922:PII Nitrogen Regulatory Proteins; D005973:Glutamine; D009713:Nucleotidyltransferases; C020658:glutamine-synthetase adenylyltransferase; C022515:regulatory protein uridylyltransferase; D005974:Glutamate-Ammonia Ligase