Abstract
Distinguishing feature of the outer membrane (OM) of Gram-negative bacteria is its asymmetry due to the presence of lipopolysaccharide (LPS) in the outer leaflet of the OM and phospholipids in the inner leaflet. Recent studies have revealed the existence of regulatory controls that ensure a balanced biosynthesis of LPS and phospholipids, both of which are essential for bacterial viability. LPS provides the essential permeability barrier function and act as a major virulence determinant. In Escherichia coli, more than 100 genes are required for LPS synthesis, its assembly at inner leaflet of the inner membrane (IM), extraction from the IM, translocation to the OM, and in its structural alterations in response to various environmental and stress signals. Although LPS are highly heterogeneous, they share common structural elements defining their most conserved hydrophobic lipid A part to which a core polysaccharide is attached, which is further extended in smooth bacteria by O-antigen. Defects or any imbalance in LPS biosynthesis cause major cellular defects, which elicit envelope responsive signal transduction controlled by RpoE sigma factor and two-component systems (TCS). RpoE regulon members and specific TCSs, including their non-coding arm, regulate incorporation of non-stoichiometric modifications of LPS, contributing to LPS heterogeneity and impacting antibiotic resistance.
Highlights
The cell envelope of Gram-negative bacteria, including Escherichia coli, contains two distinct membranes, an inner (IM) and an outer (OM) membrane separated by the periplasm, a hydrophilic compartment that includes a layer of peptidoglycan
LapB recruits LpxC, FtsH, glycosyltransferases, myristoyltrasferase LpxM and other proteins that are required for LPS synthesis at the inner membrane (IM), presumably acting as a scaffold to deliver completely synthesized LPS to its other interacting partners in the Lpt transport system
These LPS alterations are regulated by the RpoE sigma factor, two-component systems (TCS) like BasS/R, PhoP/Q, PhoB/R and Rcs system with an overwhelming role played by noncoding small regulatory RNAs (sRNAs)
Summary
The cell envelope of Gram-negative bacteria, including Escherichia coli, contains two distinct membranes, an inner (IM) and an outer (OM) membrane separated by the periplasm, a hydrophilic compartment that includes a layer of peptidoglycan. A second R-3-hydroxymyristate chain is added by LpxD leading to the synthesis of UDP-2,3-diacyl-GlcN This serves as a substrate for LpxH to generate 2,3-diacyl-GlcN-1-phosphate, called lipid X [3]. The steps involve a condensation reaction generating the β,1 -6-linked disaccharide by LpxB, followed by its phosphorylation at 4 position by LpxH This generates the lipid IVA precursor, which serves as an acceptor for the WaaA-mediated incorporation of two 3-deoxy-α-d-manno-oct-2-ulsonic acid (Kdo) residues. Kdo2-lipid IVA comprises a key intermediate in LPS biosynthesis that acts 2-fold as a specific substrate: (i) for acyltransferases that generate Kdo2-lipid A moiety by the transfer of two additional fatty acids to the (R)-3-hydroxyl groups of both acyl chains, which are directly bound to position 2 and 3 of the non-reducing GlcN residue and (ii) for glycosyltransferases catalyzing further steps of the core oligosaccharide biosynthesis. After the completion of LPS synthesis on the inner leaflet of the IM, LPS is flipped by the essential IM-located MsbA transporter to the periplasmic side of the IM, where it is a substrate for the LptB2FG ABC transporter for translocation, using ATP as the energy, potentially in complex with LapA/B proteins
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