title: On the mechanism of 5-oxoproline overproduction in 5-oxoprolinuria.
abstract: The primary metabolic defect in 5-oxoprolinuria (pyroglutamic aciduria) is the lack of glutathione synthetase. The mechanism of the concomitant overproduction of 5-oxoproline was studied using cell-free extracts of erythrocytes from control individuals and from patients with 5-oxoprolinuria. Such extracts catalyzed the synthesis of 5-oxoproline from L-glutamate. Addition of ATP, Mg ions and alpha-aminobutyrate was needed for optimal activity. The conversion of glutamate to 5-oxoproline occurred in two steps, catalyzed by gamma-glutamyl-cysteine synthetase and gamma-glutamyl cyclotransferase, respectively. Extracts of erythrocytes from control subjects and patients with 5-oxoprolinuria had identical capacity to synthesize 5-oxoproline. The conversion of glutamate to 5-oxoproline was markedly inhibited by reduced glutathione, which exerted its effect on the gamma-glutamyl-cysteine synthetase step. The following mechanism is postulated for the overproduction of 5-oxoproline in 5-oxoprolinuria: the deficiency of glutathione synthetase causes a lack of glutathione which is an essential feed-back inhibitor in the initial step of its biosynthesis. Therefore gamma-glutamyl-cysteine is produced in excessive amounts and it is subsequently converted to 5-oxoproline (and cysteine) by gamma-glutamyl cyclotransferase. This overproduction of 5-oxoproline exceeds the capacity of the 5-oxoprolinase and 5-oxoproline accumulates in body fluids.
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010453:Peptide Synthases / Q000097:blood / Q000172:deficiency*; D011392:Proline / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism* / Q000652:urine
chemical_list: D011760:Pyrrolidinones; D011392:Proline; D010453:Peptide Synthases; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; D005998:Glycine