ALUMINUM TOXICITY THROUGH PHOSPHATES

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DESCRIPTION: (Adapted from the investigator's abstract) In previous published work from the investigator's laboratory it has been established that at least one mode of aluminum toxic expression is through the formation of soluble aluminum complexes with biophosphates that compromises the ability of these phosphates to serve as substrates for subsequent enzymatic reactions. The principal mode of expression involves the displacement of the magnesium cofactor from the natural phosphomagnesium complexes that serve as intermediates of metabolism, thus attenuating the activity of the recipient biochemical pathway. The specific aims of the project are to:continue chemical investigation of the interactions between A1(III) and phosphates of biochemical origin, concentrating on key membrane-component phosphates, such as the phospholipids, and certain key phosphorylated residues, such as myo-inositol 1,4,5-trisphosphate; and model A1-phosphate interactions using the Molecular Systems BIOGRAF program, with the goal of elucidating the precise characteristics of phospho-aluminum and phospho-magnesium complexes. The purpose of the modeling experiments is to identify those ionic systems capable of interdicting the formation of toxic species, thus identifying avenues of research likely to lead toward effective therapeutic regimens.