Abstract
The outer membrane (OM) of Gram-negative bacteria, such as Escherichia coli, is essential for their viability. Lipopolysaccharide (LPS) constitutes the major component of OM, providing the permeability barrier, and a tight balance exists between LPS and phospholipids amounts as both of these essential components use a common metabolic precursor. Hence, checkpoints are in place, right from the regulation of the first committed step in LPS biosynthesis mediated by LpxC through its turnover by FtsH and HslUV proteases in coordination with LPS assembly factors LapB and LapC. After the synthesis of LPS on the inner leaflet of the inner membrane (IM), LPS is flipped by the IM-located essential ATP-dependent transporter to the periplasmic face of IM, where it is picked up by the LPS transport complex spanning all three components of the cell envelope for its delivery to OM. MsbA exerts its intrinsic hydrocarbon ruler function as another checkpoint to transport hexa-acylated LPS as compared to underacylated LPS. Additional checkpoints in LPS assembly are: LapB-assisted coupling of LPS synthesis and translocation; cardiolipin presence when LPS is underacylated; the recruitment of RfaH transcriptional factor ensuring the transcription of LPS core biosynthetic genes; and the regulated incorporation of non-stoichiometric modifications, controlled by the stress-responsive RpoE sigma factor, small RNAs and two-component systems.
Highlights
Gram-negative bacteria, such as Escherichia coli, are endowed with a cell envelope, which is comprised of an outer membrane (OM) and an inner membrane (IM) separated by the periplasm, containing a thin layer of peptidoglycan
Biosynthesis by LpxC as it is a topic of more recent studies with the discovery of the critical role played by the essential IM-anchored LPS assembly protein LapC, the identification of additional proteolytic control mechanisms exerted by HslUV protease at high temperatures and the regulation by the GcvB regulatory RNA (Figure 1)
As observed with ftsH mutants, a ∆lapB mutation can be tolerated when lipid A biosynthesis is reduced due to a mutation in either lpxA or lpxC or lpxD genes or in the early steps of LPS inner core biosynthesis [15]. This was based on the identification of suppressor mutations in either the lpxC gene, a mutation in either heptose biosynthesis or a single amino acid alteration WaaC T187K [15]
Summary
Gram-negative bacteria, such as Escherichia coli, are endowed with a cell envelope, which is comprised of an outer membrane (OM) and an inner membrane (IM) separated by the periplasm, containing a thin layer of peptidoglycan. We will discuss these processes in E. coli, with a particular emphasis on the regulation of the first committed step in LPS biosynthesis by LpxC as it is a topic of more recent studies with the discovery of the critical role played by the essential IM-anchored LPS assembly protein LapC, the identification of additional proteolytic control mechanisms exerted by HslUV protease at high temperatures and the regulation by the GcvB regulatory RNA (Figure 1). The second irreversible reaction becomes the first committed step in lipid A biosynthesis, catalyzed by Zn++ -dependent deacetylase LpxC, leading to the deacetylation of UDP-3-O-[(3R)-3-hydroxyacyl]-GlcNAc for the synthesis of UDP-3-O-[(3R)-3-hydroxyacyl]-GlcN, which in turn serves as a substrate for LpxD to yield UDP-2,3-diacylglucosamine [31,32,33,34,35] This intermediate is converted to the lipid IVA precursor by the further action of LpxH, LpxB and LpxK (Figure 1) [2,26]. Kdo2 -lipid IVA phosphotransferase lipid IVA 3-deoxy-α-D-manno-octulosonic acid transferase/
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