A model for the proteolytic regulation of LpxC in the lipopolysaccharide pathway of Escherichia coli

Article


Emiola, A., Falcarin, Paolo, Tocher, Joanne and George, John 2013. A model for the proteolytic regulation of LpxC in the lipopolysaccharide pathway of Escherichia coli. Computational Biology and Chemistry.
AuthorsEmiola, A., Falcarin, Paolo, Tocher, Joanne and George, John
Abstract

Lipopolysaccharide (LPS) is an essential structural component found in Gram-negative bacteria. The molecule is comprised of a highly conserved lipid A and a variable outer core consisting of various sugars. LPS plays important roles in membrane stability in the bacterial cell and is also a potent activator of the human immune system. Despite its obvious importance, little is understood regarding the regulation of the individual enzymes involved or the pathway as a whole. LpxA and LpxC catalyze the first two steps in the LPS pathway. The reaction catalyzed by LpxA possesses a highly unfavourable equilibrium constant with no evidence of coupling to an energetically favourable reaction. In our model the presence of the second enzyme LpxC was sufficient to abate this unfavourable reaction and confirming previous studies suggesting that this reaction is the first committed step in LPS synthesis. It is believed that the protease FtsH regulates LpxC activity via cleavage. It is also suspected that the activity of FtsH is regulated by a metabolite produced by the LPS pathway; however, it is not known which one. In order to investigate these mechanisms, we obtained kinetic parameters from literature and developed estimates for other simulation parameters. Our simulations suggest that under modest increases in LpxC activity, FtsH is able to regulate the rate of product formation. However, under extreme increases in LpxC activities such as over-expression or asymmetrical cell division then FtsH activation may not be sufficient to regulate this first stage of synthesis.

KeywordsMetabolic pathway; Lipid A; FtsH cleavage
JournalComputational Biology and Chemistry
ISSN1476-9271
Year2013
PublisherElsevier
Accepted author manuscript
License
CC BY-ND
Supplemental file
License
CC BY-ND
Supplemental file
License
CC BY-ND
Web address (URL)http://dx.doi.org/10.1016/j.compbiolchem.2013.06.001
Publication dates
Print14 Jun 2013
Publication process dates
Deposited04 Jul 2013
Copyright informationNOTICE: this is the author’s version of a work that was accepted for publication in Computational Biology and Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication.
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