The GM2 activator protein, a novel inhibitor of platelet-activating factor

The GM2 activator protein is required as a substrate-specific cofactor for P-hexosaminidase A to hydrolyze GM2 ganglioside. The GM2 activator protein reversibly binds and solubilizes individual GM2 ganglioside molecules, maki ng them available as sub strate, Although GM2 ganglioside is the strongest binding ligand for the activator protein, it can also bind and transport be tween membranes a series of other glycolipids, even at neutral pH. Biosynth etic studies have shown that a large portion of newly synthesized GM2 activ ator molecules are not targeted to the lysosome, but are secreted and can t hen be recaptured by other cells through a carbohydrate independent mechani sm. Thus, the GM2 activator protein may have other in vivo functions. We fo und that the GM2 activator protein can inhibit, through specific binding, t he ability of platelet activating factor (PAF) to stimulate the release of intracellular Ca2+ pools by human neutrophils, PAF is a biologically potent phosphoacylglycerol, Inhibitors for PAF's role in the pathogenesis of infl ammatory bowel disease and asthma have been sought as potential therapeutic agents. The inherent stability and protease resistance of the small, monom eric GM2 activator protein, coupled with the ability to produce large quant ities of the functional protein in transformed bacteria, suggest it may ser ve as such an agent. (C) 1999 Academic Press.