Function of renal γ-glutamyltransferase: Significance of glutathione and glutamine interactions

Abstract

The membrane bound γ-glutamyltransferase (γ-GT) is capable of utilizing both glutathione, GSH, and glutamine, gln, as the natural γ-glutamyl donor. The enzyme is oriented in the membrane to react with extracellular substrates and is present on both the brush border and peritubular capillaries. The reaction catalyzed by γ-GT is critically dependent upon the ratio of γ-glutamyl donor/γ-GT which under near physiological conditions results in the formation of γ-glutamyl peptide and glu on the blood and urine side respectively; this effectively establishes an osmotic gradient which could contribute to transepithelial and transcapillary water fluxes. Interestingly, utilization of extrarenal γ-glutamyl substrates are quantitatively more significant in the microvascular than brush border location. Delivery of gln to these enzyme sites is some 20 times greater than GSH. Gln utilization unlike GSH is limited by the reaction with the γ-glutamyl donor site; thus reactivity is greatly enhanced by the maleate like activator hippurate which may account for the acidosis-induced adaptation in ammonia formation from gln by this enzyme. Coupled to a role in ammoniagenesis the brush border enzyme appears to play a role in the reabsorption of filtered gln. The hydrolysis of filtered GSH as well as its utilization in transfer reactions involved in amino acid reabsorption at the brush border may reflect the role of the enzyme in eliminating osmotically active solutes from the urine and thereby facilitating water fluxes. However the role of gln as γ-glutamyl donor relative to GSH will depend upon the quantitative significance of tubular GSH synthesis and secretion.