Ethacrynic acid-an inhibitor of l-asparagine synthetase

Hiremagalur N. Jayaram, David A. Cooney, Harry A. Milman, Elton R. Homan, Valarie M. King, Edward J. Cragoe

Research output: Contribution to journalArticle

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Abstract

Ethacrynic acid, a clinically useful diuretic, has been shown to inhibit l-asparagine synthetase from leukemia 5178Y resistant to l-asparaginase (L5178Y/AR) in vitro. This inhibition is thought to involve the formation of an adduct between ethacrynic acid and sulfhydryl functions on the enzyme; the adduct is not readily reversible even when another thiol, such as dithiothreitol, is used to displace the acid. A series of analogs of ethacrynic acid were examined as inhibitors of l-asparagine synthetase. Only one proved to be superior to the title compound; it was 2 2-(1-carboxymethoxy-4-chloro-2-naphthyl)3,6-diethyl-6-(1-carboxymethoxy- 4-chloro-2-naphthoyl)-5,6-dihydro-[4H]-pyran (Compound D). There was no correlation between the diuretic or natriuretic potency of the series of compounds examined and their ability to inhibit l-asparagine synthetase activity. There was also no correlation between the ability of these agents to inhibit l-asparaginase from Dasyprocta agouti (another sulfhydryl enzyme) and l-asparagine synthetase from L5178Y/AR. In every case, ethacrynic acid and its analogs interrupted the utilization of ammonia by l-asparagine synthetase to a greater degree than the utilization of l-glutamine. In vivo, the inhibition by l-asparagine synthetase from L5178Y/AR by ethacrynic acid was feeble, while the analogous enzyme from pancreas was inhibited to a significant degree.

Original languageEnglish (US)
Pages (from-to)1787-1792
Number of pages6
JournalBiochemical Pharmacology
Volume24
Issue number19
DOIs
StatePublished - Oct 1 1975
Externally publishedYes

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Aspartate-Ammonia Ligase
Ethacrynic Acid
Asparaginase
Diuretics
Enzymes
Pyrans
Dithiothreitol
Glutamine
Ammonia
Sulfhydryl Compounds
Pancreas
Leukemia
Acids

ASJC Scopus subject areas

  • Pharmacology

Cite this

Jayaram, H. N., Cooney, D. A., Milman, H. A., Homan, E. R., King, V. M., & Cragoe, E. J. (1975). Ethacrynic acid-an inhibitor of l-asparagine synthetase. Biochemical Pharmacology, 24(19), 1787-1792. https://doi.org/10.1016/0006-2952(75)90458-X

Ethacrynic acid-an inhibitor of l-asparagine synthetase. / Jayaram, Hiremagalur N.; Cooney, David A.; Milman, Harry A.; Homan, Elton R.; King, Valarie M.; Cragoe, Edward J.

In: Biochemical Pharmacology, Vol. 24, No. 19, 01.10.1975, p. 1787-1792.

Research output: Contribution to journalArticle

Jayaram, HN, Cooney, DA, Milman, HA, Homan, ER, King, VM & Cragoe, EJ 1975, 'Ethacrynic acid-an inhibitor of l-asparagine synthetase', Biochemical Pharmacology, vol. 24, no. 19, pp. 1787-1792. https://doi.org/10.1016/0006-2952(75)90458-X
Jayaram HN, Cooney DA, Milman HA, Homan ER, King VM, Cragoe EJ. Ethacrynic acid-an inhibitor of l-asparagine synthetase. Biochemical Pharmacology. 1975 Oct 1;24(19):1787-1792. https://doi.org/10.1016/0006-2952(75)90458-X
Jayaram, Hiremagalur N. ; Cooney, David A. ; Milman, Harry A. ; Homan, Elton R. ; King, Valarie M. ; Cragoe, Edward J. / Ethacrynic acid-an inhibitor of l-asparagine synthetase. In: Biochemical Pharmacology. 1975 ; Vol. 24, No. 19. pp. 1787-1792.
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