Response of rat liver glutaminase to pH, ammonium, and citrate: Possible regulatory role of glutaminase in ureagenesis

Liver glutaminase is stimulated by an increase in NH⁺₄ concentration and NH⁺₄ is an absolute requirement for activity at approximate physiological concentrations of phosphate and glutamine. Increases in the concentration of NH⁺₄ cannot, however, overcome the inhibitory effect of a decrease in pH. In addition, the concentration of NH⁺₄ required for half-maximal rate decreases as pH increases. This decrease is the result of two factors: a direct effect of pH on the apparent affinity of the enzyme for NH⁺₄, and an indirect effect of pH brought about by an increase in the apparent affinity of the enzyme for phosphate which results in a further decrease in the M_0.5 for NH⁺₄. In addition, liver glutaminase responds strongly to the concentration of citrate over a physiologically relevant range at approximate physiological concentrations of NH⁺₄, phosphate, and glutamine. An increase in citrate concentration stimulates glutaminase by increasing the affinity of the enzyme for glutamine. The apparent affinity of the enzyme for citrate increases as pH increases. The strong response of liver glutaminase to pH, NH⁺₄, and citrate and the fact that the hydrolysis of glutamine can supply metabolites and effectors for urea synthesis suggest a possible regulatory role of glutaminase in ureagenesis.