Proton-dependent inhibition of yeast and brain hexokinases by aluminum in ATP preparations.

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Abstract
The Al present as a contaminant in ATP preparations can cause strong inhibition of yeast hexokinase P-II activity at pH 7.0 or below but has little or no inhibitory effect at a pH of 7.5 or greater. The inhibition is reversed by citrate, 3-phosphoglycerate, malate, phosphate, and catecholamines, all of which have previously been described as activators of hexokinase at low pH. These agents may activate the enzyme only by virtue of their ability to coordinate with Al present in the assay system. The presence of Al is also responsible for the "negative cooperativity" observed at low pH with respect to Mg.cntdot.ATP concentration, i.e., the inhibition by Al is uncompetitive at low Mg.cntdot.ATP concentrations but becomes competitive at high Mg.cntdot.ATP concentrations. The inhibition is thought to be due to formation of a complex of Al.cntdot.ATP with the enzyme, with a dissociation constant (Ki) of 0.1 .mu.M. Yeast hexokinase P-I is somewhat less sensitive to Al than is hexokinase P-II, and yeast glucokinase is not detectably affected. The hexokinase in rat brain (type I) shows a pH-dependent inhibition by Al similar to that observed with the yeast hexokinases, whereas the rat muscle (type II) enzyme is less sensitive, suggesting a possible relationship to Al encephalopathy in man.