The regulation of lipid A biosynthesis.

Gram-negative bacteria surround their inner membrane and cell wall with an asymmetric outer membrane which contains lipopolysaccharide (LPS) in its outer leaflet. In addition to serving as a potent permeability barrier, the LPS-rich outer membrane also contributes to the structural integrity of the cell envelope and, thus, the ability to synthesize LPS is essential in most Gram-negative bacteria. Although the cell must make enough LPS to support growth, its biosynthesis must be tightly regulated as overproduction of the acylated disaccharide domain of LPS, lipid A, is deleterious to bacterial viability. The committed enzyme of the lipid A biosynthetic pathway, LpxC, serves as a major regulatory node to control flux through the pathway and ensure that the cell has enough, but not too much, LPS. The regulation of LpxC in the model organism Escherichia coli has been the subject of immense study, which has led to a detailed understanding of the regulation of LPS biogenesis that has served as a paradigm for other organisms. Recent work, however, has revealed diverse mechanisms used by different species to regulate LpxC and highlights that regulation at alternative points in the LPS biosynthetic pathway have the potential to influence LPS production. Here, the discovery and subsequent molecular dissection of the varied strategies used to regulate LPS biosynthesis are reviewed as well as the physiological consequences of LPS dysregulation.