Increased anion gap metabolic acidosis as a result of 5-oxoproline
(pyroglutamic acid): a role for acetaminophen.
Earlier studies of the total urinary content of amino acids released by acid hydrolysis (24) indicated an upper limit for peptide excretion of 1 g/day, a large proportion of which might be accounted for by abundant amino acid derivatives such as hippuric acid, 5-oxoproline, and phenylacetylglutamine (25-27).
Low peptide excretion was also observed for the size range of 250-750 Da, and high recovery of amino acids was achieved only for the fraction containing molecules under 250 Da, which would include free amino acids and amino acid derivatives such as hippuric acid and 5-oxoproline.
Urinary excretion of 5-oxoproline
(pyroglutamic aciduria) as an index of glycine insufficiency in normal man.
However, two adult subjects with metabolic acidosis, one with an increased anion gap, have been described in whom 5-oxoproline (pyroglutamic acid) was responsible for the acidosis (1, 2).
This method measures total 5-oxoproline concentrations (sum of n- and L-isomers), as well as detecting numerous other organic acids.
Total 5-oxoproline was grossly increased above the reference range in urine, ranging from 0.
Subject 1 was given an acetaminophen challenge after recovery, and the excretion of 5-oxoproline was within the reference range before and after the challenge.
An inherited deficiency of either of these two enzymes results in an increased production and plasma concentration of 5-oxoproline that is reflected as an increase in urinary excretion (5-oxoprolinuria).
This accumulation of [gamma]-glutamyl cysteine does not, however, persist, because it is converted via a less favorable alternative pathway by the enzyme [gamma]-glutamyl cyclotransferase back to 5-oxoproline, which is only slowly utilized forward through the cycle by the rate-limiting enzyme 5-oxoprolinase; hence, marked accumulation of 5-oxoproline persists.
1, 5-oxoprolinase is involved in the decyclization conversion of 5-oxoproline to L-glutamate.
We highlight the case of a 35-year-old woman who presented initially with an uncomplicated staphylococcal pneumonia but who went on to develop a transient but severe high anion gap metabolic acidosis associated with markedly increased urinary excretion of 5-oxoproline but with no clinical evidence of any of the features of the inherited disorders of glutathione synthesis.