Deacylation of bacterial endotoxins by neutrophils and macrophages: early observations and hypotheses.
Gram-negative bacterial lipopolysaccharides (LPS) are thought to play a role in immunomodulation by providing signals to cells such as macrophages, lymphocytes and neutrophils. Recent structure-activity studies indicate that many of the bioactivities of lipid A, the bioactive region of LPS, can be produced by a lipid A precursor. The precursor is a glucosamine disaccharide that is phosphorylated at 1 and 4' and that has 3-hydroxytetradecanoate residues linked to the glucosamine backbone at 2, 3, 2', and 3'. In contrast, certain toxic activities (pyrogenicity, complement activation and the ability to produce the Shwartzman reaction) appear to require complete lipid A, which additionally has nonhydroxylated fatty acids substituted to the hydroxyl groups of some of the 3-hydroxytetradecanoate residues. Earlier studies have identified enzymes (acyloxyacyl hydrolases) in neutrophils and macrophages that remove the nonhydroxylated fatty acids from complete lipid A, thus converting the lipid A to a precursor-like structure. Based on the structure-activity studies described above, it is speculated that acyloxyacyl hydrolysis reduces the toxicity of lipid A. It is also possible that enzymatic removal of the nonhydroxylated fatty acids is required for some of the stimulatory activities of lipid A.
Munford
R S
RS
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006090:Gram-Negative Bacteria; D006801:Humans; D006868:Hydrolysis; D008050:Lipid A / Q000378:metabolism / Q000633:toxicity; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004731:Endotoxins; D005227:Fatty Acids; D008050:Lipid A; D008070:Lipopolysaccharides; D002265:Carboxylic Ester Hydrolases; C048964:acyloxyacyl hydrolase