- Pyroglutamic acid is the last step of the glutathione cycle and is thought to be related to cysteine insufficiency or glycine availability.
- Drug-induced reversible inhibition of glutathione synthetase, such as from acetaminophen, leads to elevated pyroglutamic acid.
- Researchers noted that glutathione depletion of septic patients may be noted with higher serum levels of pyroglutamate, and lower levels of erythrocyte glutathione peroxidase.
Pyroglutamic acid (5-oxoproline) is produced and utilized in the gamma-glutamyl cycle. This cycle is needed to assist in the production and recycling of glutathione (GSH), a powerful antioxidant.
Glutathione is a tripeptide, consisting of glutamate, cysteine, and glycine. Using the gamma-glutamyl cycle, GSH is divided into cysteinyl glycine and a gammaglutamyl molecule which attaches to another amino acid for transport across a membrane or into a cell. Gammaglutamyl transferase then splits off that attached amino acid, and the glutamate becomes pyroglutamic acid (5-oxoproline).
Cysteinyl glycine is also broken down and transported into the cell as cysteine and glycine. The entire GSH molecule needs to be reformed intracellularly from pyroglutamic acid by recombining cysteine, glycine, and glutamic acid using GSH synthetase.
This enzymatic reformation requires cofactors such as ATP and magnesium.
References:
- Emmett M. Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle. Clin J Am Soc Nephrol. 2014;9(1):191-200.
- Metges CC, Yu YM, Cai W, et al. Oxoproline kinetics and oxoproline urinary excretion during glycine- or sulfur amino acid-free diets in humans. Am J Physiol Endocrinol Metab. 2000;278(5):E868-876.
- Persaud C, Forrester T, Jackson AA. Urinary excretion of 5-L-oxoproline (pyroglutamic acid) is increased during recovery from severe childhood malnutrition and responds to supplemental glycine. J Nutr. 1996;126(11):2823-2830.
Because pyroglutamic acid formation is dependent on glutathione entering the gamma-glutamyl cycle, an insufficient amount of GSH or its precursors and necessary cofactors can result in low pyroglutamic acid.
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Elevations in pyroglutamic acid can reflect lack of precursors (glycine, cysteine, glutamine) or nutrient cofactors for GSH recycling (magnesium). Most specifically, pyroglutamic acid has been proposed as a measure of glycine availability.
Oxidative stress, in general, can upregulate the detoxification pathways and result in elevated pyroglutamic aciduria.
Significant toxic exposures, such as medication toxicities, can deplete ATP, interrupting GSH recycling and causing elevations in pyroglutamic acid. In rare cases, this can result in metabolic acidosis.
Deficiency in glutathione synthetase has also been described in literature as presenting with pyroglutamic aciduria.
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