A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli

Article


Emiola, A., George, John and Andrews, Steven S. 2015. A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli. PLOS ONE. 10 (4), p. e0121216.
AuthorsEmiola, A., George, John and Andrews, Steven S.
Abstract

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component
of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and
elicits a strong immune response from humans and other animals. We developed a quantitative
model of the nine enzyme-catalyzed steps ofEscherichia colilipid A biosynthesis,
drawing parameters from the experimental literature. This model accounts for biosynthesis
regulation, which occurs through regulated degradation of the LpxC and WaaA (also called
KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide
concentration, which we deduced from prior results, model results, and new LpxK overexpression
results. The model agrees reasonably well with many experimental findings, including
the lipid A production rate, the behaviors of mutants with defective LpxA enzymes,
correlations between LpxC half-lives and cell generation times, and the effects of LpxK
overexpression on LpxC concentrations. Its predictions also differ from some experimental
results, which suggest modifications to the current understanding of the lipid A pathway,
such as the possibility that LpxD can replace LpxA and that there may be metabolic
channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to
regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO)
concentration is low and/or to control the number of KDO residues that get attached to lipid
A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if
pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation
is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate
concentrations are not in excess. Based on these results, we suggest that LpxK may
be a much better drug target than LpxC, which has been pursued most often.

JournalPLOS ONE
Journal citation10 (4), p. e0121216
ISSN1932-6203
Year2015
PublisherPublic Library of Science
Publisher's version
License
CC BY
Web address (URL)http://dx.doi.org/10.1371/journal.pone.0121216
Publication dates
Print28 Apr 2015
Publication process dates
Deposited23 Jun 2015
Accepted12 Feb 2015
FunderNational Institute of General Medical Sciences
Copyright information© 2015 Emiola et. al.
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