Variation, Modification and Engineering of Lipid A in Endotoxin of Gram-Negative Bacteria.

Kazuyoshi Kawahara

doi:10.3390/ijms22052281

Abstract

Lipid A of Gram-negative bacteria is known to represent a central role for the immunological activity of endotoxin. Chemical structure and biosynthetic pathways as well as specific receptors on phagocytic cells had been clarified by the beginning of the 21st century. Although the lipid A of enterobacteria including Escherichia coli share a common structure, other Gram-negative bacteria belonging to various classes of the phylum Proteobacteria and other taxonomical groups show wide variety of lipid A structure with relatively decreased endotoxic activity compared to that of E. coli. The structural diversity is produced from the difference of chain length of 3-hydroxy fatty acids and non-hydroxy fatty acids linked to their hydroxyl groups. In some bacteria, glucosamine in the backbone is substituted by another amino sugar, or phosphate groups bound to the backbone are modified. The variation of structure is also introduced by the enzymes that can modify electrostatic charges or acylation profiles of lipid A during or after its synthesis. Furthermore, lipid A structure can be artificially modified or engineered by the disruption and introduction of biosynthetic genes especially those of acyltransferases. These technologies may produce novel vaccine adjuvants or antagonistic drugs derived from endotoxin in the future.

Highlights

The term “endotoxin” implies a toxin produced by bacteria, it has another biochemical name, “lipopolysaccharide”
Its central role in endotoxin activity in the 1980s when the structure of E. coli-type lipid A was chemically synthesized by Shiba, Kusumoto, and their colleagues at Osaka
Another member of β-Proteobacteria, Comamonas testosteroni, a resident of soil and water environments, has a lipid A of a symmetric structure with only a shorter 3-hydroxy fatty acid, 3-OH-C10:0, at all of the 2, 20, 3, and 30 positions, and the hydroxyl groups of those at the 2 and 20 positions are substituted by C14:0 and C12:0, respectively (Figure 3b) [33]

Summary

Introduction

The term “endotoxin” implies a toxin produced by bacteria, it has another biochemical name, “lipopolysaccharide”. The history of endotoxin study, especially the establishment of the chemical structure of lipid. The term “lipopolysaccharide”, abbreviated as LPS, was first used by Shear in the study using Serratia marcescens [3]. Despite these early studies, we had to wait for confirmation of the chemical structure of lipid A and its central role in endotoxin activity in the 1980s when the structure of E. coli-type lipid A was chemically synthesized by Shiba, Kusumoto, and their colleagues at Osaka. We can realize that the history of endotoxin research started in the 19th century, and the platform of knowledge necessary for further applicational study had been established at the beginning of the 21st century

Diversity of Lipid A Structure in Various Taxonomic Groups of

Structural Modification of Lipid A after the Synthesis of LPS

Construction of Novel Lipid A Structure by Genetic Engineering

Closing Remarks