Degree Name

Doctor of Philosophy


Department of Chemistry


The unusual structure of y-glutamyl amino acids makes them resistant to hydrolysis by peptidases. Instead they are degraded by y-glutamyltransferase (y-GT) and y-glutamyl amino acid cyclotransferase.

In this study the compounds excreted by patients with the rare disorder, y-GT deficiency, demonstrated the probable physiological substrates and role of y-GT in the human kidney. Abnormal metabolites excreted were reduced glutathione, y-glutamylcysteine, y-glutamylglutamine, y-glutamyl-a-aminobutyrylglycine and cysteine. The last three have not been previously described in this disorder. Cystine, a proven in vitro substrate of y-GT, was found in normal amounts. Disulphides and mixed disulphides of the above thiols were present even in fresh urine but may have been products of thiol-thiol oxidation and thiol-disulphide exchange in the bladder. Plasma levels of the y-glutamyl compounds and cysteine seemed not to be increased.

pgamma-Giutamylglutamine was positively identified in plasma and cerebrospinal fluid from hyperammonaemic patients with urea cycle defects and was reabsorbed by the kidney even when plasma levels of y-glutamylglutamine were >214 f.Lmoi/L. However in patients with phenylalanine hydroxylase deficiency, y-glutamylphenylalanine was detected in their urine but not their plasma. This contrast in the renal handling of y-glutamyl amino acids may occur because y-glutamylphenylalanine, unlike y-glutamylglutamine, is a poor substrate for intracellular y-glutamyl amino acid cyclotransferase.

Enzyme studies on serum, urine and fibroblasts from the two Australian patients confirmed that y-GT activity was deficient and that the y-glutamyl amino acid cyclotransferase activity in their red cells was normal.

Human lens, a tissue model for the degradation of y-glutamyl compounds, was analysed for y-glutamyl amino acid cyclotransferase activity. The investigation found that this activity was located on the periphery of the lens, was higher in a child compared with adults and was lower in a cataractous (and probably GSH depleted) lens compared with lenses from normal controls of similar age.

This study has shown for the first time that y-glutamylglutamine, ophthalmic acid and cysteine are physiological substrates of human renal y-GT. Hence both the hydrolysis of y-glutamyl compounds and the transpeptidation of cysteine appear to be important physiological functions of human y-GT in the renal tubule, allowing for direct synthesis of y-glutamylcysteine and some role in renal ammonium metabolism.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.