Molecular aspects of endotoxic reactions.

The most common procedure in searching for active sites in biological macromolecules is partial hydrolysis. In a few cases, acidic, alkaline, or enzymatic breakdown of the macromolecule results in the removal of the inert sites of the complex, reducing the size of the remainder to the active core structure. Similar treatments frequently serve as steps of purification by removing noncovalently bound contaminants. Isolation of the active materials in a homogeneous state often decreases biological activity by separating either the solubilizing factor or a carrier constituent, or by removing a cofactor the presence of which is essential for full biological potency. Several examples are also known wherein dissociation of the macromolecular complex with mild methods, such as the use of surfactants, depolymerizes the structure without introducing hydrolytic cleavage of covalent bonds. These depolymerized structures were shown to have altered biological effectiveness, indicating that these activities require a certain organization of subunits. Blocking some parts of the molecule has been successfully used in enzymology. The existence of functional groups and their specific steric arrangement in the structure is the molecular explanation of their activity. The same statement can be applied to a very large number of other biologically active substances. Interference with this steric arrangement by alteration of the functional groups achieved by their blockage or removal, or by substitution, leads to changes in activity. Similarly, modification between the distances of the important functional groups by distortion of the structure also results in changes in biological properties. Most of these approaches have been applied in the investigation of gram-negative endotoxins. The present review of the achievements will not include a discussion in detail of the chemical aspects of endotoxin research, because several extensive surveys were recently published on this subject. The most impressive array of different