Pyroglutamic aciduria: Rate of formation and degradation of pyroglutamate

(1) Our patient with pyroglutamic aciduria excretes about 35 g of l-pyroglutamate in the urine per 24 h. The serum concentration has been determined to be about 50 mg/100 ml, explaining the major part of the metabolic acidosis present. Tracer studies with [14C]glutamate and [14C]pyroglutamate have brought forth data which permit dynamic interpretation of the pyroglutamate metabolism in the patient. (2) The endogenous production of l-pyroglutamate is more than 2 times greater than the amount excreted in the urine. (3) The patient, as well as healthy controls and dogs, are able to degrade pyroglutamic acid to a considerable extent. The initial step in the degradation is probably a hydrolysis to l-glutamic acid. No evidence has been obtained showing different rates of glutamic acid degradation in the patient and in normal controls. (4) The most likely defect in the patient appears to be an abnormal rate of formation of l-pyroglutamic acid. Proline is not a precursor of pyroglutamate in our patient. Of the known routes of formation only the γ-glutamyl- or γ-glutamyl-glutamin-lactamase action on ample amounts of γ-glutamyl substrates seems capable of producing the amounts of pyroglutamic acid seen in the patient. Accordingly, the metabolic defect in the patient may be related to the further metabolism of γ-glutamyl peptides, giving rise to increased amounts of γ-glutamyl substrates, with the subsequent formation of pyroglutamic acid.