Title: Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate
Abstract: The two major sites for glyconeogenesis in mammals are liver and kidney (2, 3).Both of these organs contain the specific enzyme, fructose 1,6-diphosphatase, which catalyzes the following reaction (4-6).n-Fructose 1,6-diphosphate Mg++ f n-fructose B-phosphateThis enzymatic step is presumed to be obligatory for glyconeogenesis in order to bypass the highly exergonic phosphofructokinase reaction (7).A sensitive mechanism for the regulation of fructose 1,6-diphosphatase activity would be of importance in control of the direction of flow of carbohydrate metabolism in these organs, i.e. catabolism via glycolysis or glycogenolysis ver.sus the anabolic process of glyconeogenesis.We have recently reported three possible mechanisms for the regulation of liver fructose 1,6-diphosphatase activity under physiological conditions (8): (a) the specific and reversible inhibition by adenosine 5'-monophosphate, (b) the reversible inhibition of the enzyme by substrate at concentrations greater than 0.1 mM, and (c) the reversible inactivation of fructose 1,6diphosphatase by reaction with ATP or ADP.This latter process could be clearly distinguished from inhibition by AMP, since the inactivation did not occur in the presence of either substrate, phosphate, or ethylenediaminetetraacetate and was not reversible by either dilution or overnight dialysis at 4".Our detailed studies on the first two of these mechanisms is the subject of the present report.Recent reports from several other laboratories have confirmed the widespread role of both AMP and fructose 1,6-diphosphate as inhibitors of fructose 1,6-diphosphatase from different sources.Weber (9) first reported inhibition of rat liver fructose 1,6-diphosphatase by excess substrate, and Newsholme (10) and Newsholme and Krebsl have obtained results similar to ours with rat liver extracts.Mendicino and Vasarhely (6) and Salas, Vifiuela, and Sols (11) have shown that both rat kidney and frog