Structure-Activity Relationship of Lipid A: Comparison of Biological Activities of Natural and Synthetic Lipid A's with Different Fatty Acid Compositions1

Abstract

To investigate the structure-activity relationships, various biological activities, including pyrogenicity, lethal toxicity, elicitation of Shwartzman reaction, mitogenicity and tumor necrosis factor (TNF)-inducing activity, were compared among natural and synthetic lipid A's differing in fatty acid composition. In all these tests, natural lipid A's from Escherichia coli and Salmonella minnesota and synthetic LA-15-PP, which carries 3-hydroxy- and 3-acyloxy-tetradecanoyl groups at the 2, 3 and 2', 3' positions, respectively, showed the strongest activities among the tested lipid A's. In contrast, LA-16-PP, in which the amide-bound 3-hydroxytetradecanoic acid at position 2 of LA-15-PP is replaced by 3-hexadecanoyloxytetradecanoic acid, exhibited lower activity than LA-15-PP and natural lipid A's. Although LA-16-PP has been assumed to have a typical Salmonella lipid A structure (and, in fact, it has a structure corresponding to one of the components of Salmonella lipid A), the activity of this synthetic compound was not comparable to that of natural Salmonella lipid A. LA-17-PP, in which tetradecanoic acid is the sole fatty acid component, exhibited relatively strong mitogenicity and TNF-inducing activity, but very low pyrogenicity. The activities of LA-18-PP, which has ester-bound tetradecanoic acid and amide-bound 3-hydroxytetradecanoic acid, were lower than those of LA-17-PP. The results indicate that the differences in fatty acid composition of lipid A's have important influences on the biological activities studied.

Salmonella-Type Heptaacylated Lipid A Is Inactive and Acts as an Antagonist of Lipopolysaccharide Action on Human Line Cells

“…Both of these lipid As, the Salmonella-type heptaacylated and E. coli-type hexaacylated forms, had been successfully synthesized chemically in the past (12)(13)(14), and their biological properties had been carefully tested by many investigators (15)(16)(17)(18)(19)(20). The Salmonella-type lipid A had been demonstrated to be very active in mice and rabbits and subsequently had been thought to be a typical lipid A (18 -20) along with that from E. coli.…”

“…Escherichia coli-and Salmonella-type lipid A have the most typical lipid A structures so far defined, and both have been synthesized chemically (12)(13)(14) and well characterized biologically by many investigators (15)(16)(17)(18)(19)(20). The chemical structure of these lipid As consists of a hexa-and heptaacylated diglucosamine bearing six and seven fatty acids, respectively, as shown in Fig.…”

Predominant role of the substituents on the hydroxyl groups of 3‐hydroxy fatty acids of non‐reducing glucosamine in lipid A for the endotoxic and antagonistic activity

“…Fatty acids especially play an essential role in the activity. Their number, binding site and the kind appear to be critical determinants of the capacity for the activity [5][6][7]. In fact, some of the non-toxic lipid A preparations so far found have the characteristic fatty acids with the usual diglucosamine backbone and phosphates [8][9][10].…”

Lipid content of Salmonella typhimurium.

“…The fatty acid and total lipid composition of numerous microorganisms have been determined (8,9,12). The bacterial components most often studied, the structural fatty acids, are subject to variation with changing experimental parameters.…”