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

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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

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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    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