DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo

Richard J. Rosenbluth, David A. Cooney, Hiremagalur N. Jayaram, Harry A. Milman, Elton R. Homan

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Abstract

The inhibition in vivo of l-asparagine synthetase (l-glutamine hydrolyzing. EC 6.3.5.4) from l-asparaginase-resistant leukemia 5178Y (L5178Y/AR) and from mouse pancreas by the ketoamino acids DON (l-DON; 6-diazo-5-oxo-l-norleucine), CONV (l-CONV; 2-amino-5-chlorolevulinic acid; 5-chloro-4-oxo-l-norvaline) and DONV (l-DONV; 5-diazo-4-oxo-l-norvaline) was investigated using both l-glutamine and ammonium chloride as substrates. In the L5178Y/AR system, DON was shown to inhibit the utilization of l-glutamine by l-asparagine synthetase in vivo to a degree comparable to that previously observed in vitro. CONV, however, was less effective in vivo than in vitro and DONV exerted no demonstrable inhibitory effect in the intact organism. In the case of the analogous enzyme from mouse pancreas, both DON and CONV effectively inhibited the utilization of l-glutamine in vivo. DONV was relatively inert in this experimental setting. The pattern of inhibition of l-asparagine synthetase was generally mirrored by the effects of these ketoamino acids on the organ pool-sizes of l-asparagine. However, CONV, alone of the three, demonstrated inhibition of the incorporation of l-asparagine into tumoral and pancreatic protein in vivo. Both DON and CONV inhibited the incorporation of [14C]formate into nucleic acid purines; this effect, in turn, most likely reflected the strong inhibition by these agents of several of the amidotransferases concerned with purine biosynthesis.

Original languageEnglish (US)
Pages (from-to)1851-1858
Number of pages8
JournalBiochemical Pharmacology
Volume25
Issue number16
DOIs
StatePublished - Aug 15 1976
Externally publishedYes

Fingerprint

Aspartate-Ammonia Ligase
asparagine synthetase (glutamine-hydrolyzing)
Glutamine
formic acid
Asparagine
Pancreas
Diazooxonorleucine
Asparaginase
Ammonium Chloride
Purines
Acids
Organ Size
Norleucine
Nucleic Acids
Biosynthesis
Leukemia
Enzymes
Proteins
Substrates
norvaline

ASJC Scopus subject areas

  • Pharmacology

Cite this

Rosenbluth, R. J., Cooney, D. A., Jayaram, H. N., Milman, H. A., & Homan, E. R. (1976). DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo. Biochemical Pharmacology, 25(16), 1851-1858. https://doi.org/10.1016/0006-2952(76)90189-1

DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo. / Rosenbluth, Richard J.; Cooney, David A.; Jayaram, Hiremagalur N.; Milman, Harry A.; Homan, Elton R.

In: Biochemical Pharmacology, Vol. 25, No. 16, 15.08.1976, p. 1851-1858.

Research output: Contribution to journalArticle

Rosenbluth, RJ, Cooney, DA, Jayaram, HN, Milman, HA & Homan, ER 1976, 'DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo', Biochemical Pharmacology, vol. 25, no. 16, pp. 1851-1858. https://doi.org/10.1016/0006-2952(76)90189-1
Rosenbluth RJ, Cooney DA, Jayaram HN, Milman HA, Homan ER. DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo. Biochemical Pharmacology. 1976 Aug 15;25(16):1851-1858. https://doi.org/10.1016/0006-2952(76)90189-1
Rosenbluth, Richard J. ; Cooney, David A. ; Jayaram, Hiremagalur N. ; Milman, Harry A. ; Homan, Elton R. / DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo. In: Biochemical Pharmacology. 1976 ; Vol. 25, No. 16. pp. 1851-1858.
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abstract = "The inhibition in vivo of l-asparagine synthetase (l-glutamine hydrolyzing. EC 6.3.5.4) from l-asparaginase-resistant leukemia 5178Y (L5178Y/AR) and from mouse pancreas by the ketoamino acids DON (l-DON; 6-diazo-5-oxo-l-norleucine), CONV (l-CONV; 2-amino-5-chlorolevulinic acid; 5-chloro-4-oxo-l-norvaline) and DONV (l-DONV; 5-diazo-4-oxo-l-norvaline) was investigated using both l-glutamine and ammonium chloride as substrates. In the L5178Y/AR system, DON was shown to inhibit the utilization of l-glutamine by l-asparagine synthetase in vivo to a degree comparable to that previously observed in vitro. CONV, however, was less effective in vivo than in vitro and DONV exerted no demonstrable inhibitory effect in the intact organism. In the case of the analogous enzyme from mouse pancreas, both DON and CONV effectively inhibited the utilization of l-glutamine in vivo. DONV was relatively inert in this experimental setting. The pattern of inhibition of l-asparagine synthetase was generally mirrored by the effects of these ketoamino acids on the organ pool-sizes of l-asparagine. However, CONV, alone of the three, demonstrated inhibition of the incorporation of l-asparagine into tumoral and pancreatic protein in vivo. Both DON and CONV inhibited the incorporation of [14C]formate into nucleic acid purines; this effect, in turn, most likely reflected the strong inhibition by these agents of several of the amidotransferases concerned with purine biosynthesis.",
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N2 - The inhibition in vivo of l-asparagine synthetase (l-glutamine hydrolyzing. EC 6.3.5.4) from l-asparaginase-resistant leukemia 5178Y (L5178Y/AR) and from mouse pancreas by the ketoamino acids DON (l-DON; 6-diazo-5-oxo-l-norleucine), CONV (l-CONV; 2-amino-5-chlorolevulinic acid; 5-chloro-4-oxo-l-norvaline) and DONV (l-DONV; 5-diazo-4-oxo-l-norvaline) was investigated using both l-glutamine and ammonium chloride as substrates. In the L5178Y/AR system, DON was shown to inhibit the utilization of l-glutamine by l-asparagine synthetase in vivo to a degree comparable to that previously observed in vitro. CONV, however, was less effective in vivo than in vitro and DONV exerted no demonstrable inhibitory effect in the intact organism. In the case of the analogous enzyme from mouse pancreas, both DON and CONV effectively inhibited the utilization of l-glutamine in vivo. DONV was relatively inert in this experimental setting. The pattern of inhibition of l-asparagine synthetase was generally mirrored by the effects of these ketoamino acids on the organ pool-sizes of l-asparagine. However, CONV, alone of the three, demonstrated inhibition of the incorporation of l-asparagine into tumoral and pancreatic protein in vivo. Both DON and CONV inhibited the incorporation of [14C]formate into nucleic acid purines; this effect, in turn, most likely reflected the strong inhibition by these agents of several of the amidotransferases concerned with purine biosynthesis.

AB - The inhibition in vivo of l-asparagine synthetase (l-glutamine hydrolyzing. EC 6.3.5.4) from l-asparaginase-resistant leukemia 5178Y (L5178Y/AR) and from mouse pancreas by the ketoamino acids DON (l-DON; 6-diazo-5-oxo-l-norleucine), CONV (l-CONV; 2-amino-5-chlorolevulinic acid; 5-chloro-4-oxo-l-norvaline) and DONV (l-DONV; 5-diazo-4-oxo-l-norvaline) was investigated using both l-glutamine and ammonium chloride as substrates. In the L5178Y/AR system, DON was shown to inhibit the utilization of l-glutamine by l-asparagine synthetase in vivo to a degree comparable to that previously observed in vitro. CONV, however, was less effective in vivo than in vitro and DONV exerted no demonstrable inhibitory effect in the intact organism. In the case of the analogous enzyme from mouse pancreas, both DON and CONV effectively inhibited the utilization of l-glutamine in vivo. DONV was relatively inert in this experimental setting. The pattern of inhibition of l-asparagine synthetase was generally mirrored by the effects of these ketoamino acids on the organ pool-sizes of l-asparagine. However, CONV, alone of the three, demonstrated inhibition of the incorporation of l-asparagine into tumoral and pancreatic protein in vivo. Both DON and CONV inhibited the incorporation of [14C]formate into nucleic acid purines; this effect, in turn, most likely reflected the strong inhibition by these agents of several of the amidotransferases concerned with purine biosynthesis.

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