Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1974 Apr;71(4):1026–1029. doi: 10.1073/pnas.71.4.1026

Accumulation of 5-Oxoproline in Mouse Tissues After Inhibition of 5-Oxoprolinase and Administration of Amino Acids: Evidence for Function of the γ-Glutamyl Cycle*

Paul Van Der Werf 1, Ralph A Stephani 1, Alton Meister 1
PMCID: PMC388154  PMID: 4151516

Abstract

5-Oxoprolinase catalyzes the conversion of 5-oxo-L-proline (L-pyroglutamate, L-2-pyrrolidone-5-carboxylate) to L-glutamate with concomitant stoichiometric cleavage of ATP to ADP and inorganic orthophosphate. In this reaction, a step in the γ-glutamyl cycle, 5-oxoproline (formed by the action of γ-glutamylcyclotransferase on γ-glutamyl amino acids, which are in turn formed by transpeptidation of amino acids with glutathione), is made available for glutathione synthesis. When mice are injected with L-2-imidazolidone-4-carboxylate, a competitive inhibitor of 5-oxoprolinase, they accumulate 5-oxoproline in their tissues (kidney, liver, brain, and eye) and excrete it in the urine. Mice given the inhibitor together with one of several L-amino acids accumulate and excrete much more 5-oxoproline than when they are given the inhibitor alone. Such augmentation of 5-oxoproline accumulation offers evidence for the function of the γ-glutamyl cycle in vivo and supports the view that 5-oxoproline is a quantitatively significant metabolite.

Keywords: pyroglutamate, pyrrolidone carboxylate, glutathione, amino-acid transport

Full text

PDF
1026

Images in this article

1027Image
on p.1027

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Eldjarn L., Jellum E., Stokke O. Pyroglutamic aciduria: studies on the enzymic block and on the metabolic origin of pyroglutamic acid. Clin Chim Acta. 1972 Sep;40(2):461–476. doi: 10.1016/0009-8981(72)90359-2. [DOI] [PubMed] [Google Scholar]
  2. Hagenfeldt L., Larsson A., Zetterström R. Pyroglutamic aciduria. Studies in an infant with chronic metabolic acidosis. Acta Paediatr Scand. 1974 Jan;63(1):1–8. doi: 10.1111/j.1651-2227.1974.tb04342.x. [DOI] [PubMed] [Google Scholar]
  3. Jellum E., Kluge T., Börresen H. C., Stokke O., Eldjarn L. Pyroglutamic aciduria--a new inborn error of metabolism. Scand J Clin Lab Invest. 1970 Dec;26(4):327–335. doi: 10.3109/00365517009046241. [DOI] [PubMed] [Google Scholar]
  4. MEISTER A., BUKENBERGER M. W. Enzymatic conversion of D-glutamic acid to D-pyrrolidone carboxylic acid by mammalian tissues. Nature. 1962 May 12;194:557–559. doi: 10.1038/194557a0. [DOI] [PubMed] [Google Scholar]
  5. MEISTER A., BUKENBERGER M. W., STRASSBURGER M. THE OPTICALLY-SPECIFIC ENZYMATIC CYCLIZATION OF D-GLUTAMATE. Biochem Z. 1963;338:217–229. [PubMed] [Google Scholar]
  6. Meister A. On the enzymology of amino acid transport. Science. 1973 Apr 6;180(4081):33–39. doi: 10.1126/science.180.4081.33. [DOI] [PubMed] [Google Scholar]
  7. Orlowski M., Meister A. The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A. 1970 Nov;67(3):1248–1255. doi: 10.1073/pnas.67.3.1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. PASCHER G. Die Wasserlöslichen Bestandteile der peripheren Hornschicht (Hautoberfläche); quantitative Analysen. III. Alpha-Pyrrolidoncarbonsäure. Arch Klin Exp Dermatol. 1956;203(3):234–238. [PubMed] [Google Scholar]
  9. POLGAR P., MEISTER A. A CONVENIENT PROCEDURE FOR THE DETERMINATION OF PYRROLIDONECARBOXYLIC ACID AND RELATED COMPOUNDS. Anal Biochem. 1965 Aug;12:338–343. doi: 10.1016/0003-2697(65)90100-4. [DOI] [PubMed] [Google Scholar]
  10. Ross L. L., Barber L., Tate S. S., Meister A. Enzymes of the gamma-glutamyl cycle in the ciliary body and lens. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2211–2214. doi: 10.1073/pnas.70.8.2211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Strömme J. H., Eldjarn L. The metabolism of L-pyroglutamic acid in fibroblasts from a patient with pyroglutamic aciduria: the demonstration of an L-pyroglutamate hydrolase system. Scand J Clin Lab Invest. 1972 May;29(3):335–342. doi: 10.3109/00365517209080249. [DOI] [PubMed] [Google Scholar]
  12. Tate S. S., Ross L. L., Meister A. The -glutamyl cycle in the choroid plexus: its possible function in amino acid transport. Proc Natl Acad Sci U S A. 1973 May;70(5):1447–1449. doi: 10.1073/pnas.70.5.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Van der Werf P., Orlowski M., Meister A. Enzymatic conversion of 5-oxo-L-proline (L-pyrrolidone carboxylate) to L-glutamate coupled with cleavage of adenosine triphosphate to adenosine diphosphate, a reaction in the -glutamyl cycle. Proc Natl Acad Sci U S A. 1971 Dec;68(12):2982–2985. doi: 10.1073/pnas.68.12.2982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Van der Werf P., Stephani R. A., Orlowski M., Meister A. Inhibition of 5-oxoprolinase by 2-imidazolidone-4-carboxylic acid. Proc Natl Acad Sci U S A. 1973 Mar;70(3):759–761. doi: 10.1073/pnas.70.3.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Wilk S., Orlowski M. The occurrence of free L-pyrrolidone carboxylic acid in body fluids and tissues. FEBS Lett. 1973 Jul 1;33(2):157–160. doi: 10.1016/0014-5793(73)80182-6. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES