Comput Biol Chem - A model for the proteolytic regulation of LpxC in the lipopolysaccharide pathway of Escherichia coli.

Tópicos

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Resumo

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.

Resumo Limpo

lipopolysaccharid lps essenti structur compon found gramneg bacteria molecul compris high conserv lipid variabl outer core consist various sugar lps play import role membran stabil bacteri cell also potent activ human immun system despit obvious import littl understood regard regul individu enzym involv pathway whole lpxa lpxc catalyz first two step lps pathway reaction catalyz lpxa possess high unfavour equilibrium constant evid coupl energet favour reaction model presenc second enzym lpxc suffici abat unfavour reaction confirm previous studi suggest reaction first commit step lps synthesi believ proteas ftsh regul lpxc activ via cleavag also suspect activ ftsh regul metabolit produc lps pathway howev known one order investig mechan obtain kinet paramet literatur develop estim simul paramet simul suggest modest increas lpxc activ ftsh abl regul rate product format howev extrem increas lpxc activ overexpress asymmetr cell divis ftsh activ may suffici regul first stage synthesi

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