Abstract
Abstract N-(phosphonacetyl)-l-aspartate (PALA), a transition state analogue for aspartate transcarbamylase, is an effective inhibitor of the enzyme in a number of tissues when administered to mice. After a single injection of 1 mg of [3H]PALA (1 µCi per mg), PALA concentrations reach a peak of 1.5 x 10-6 m within 2 hours in spleen, and remain at a constant level of 5 x 10-7 m for at least 72 hours in both spleen and liver. PALA concentrations in jejunum are maintained at 10-7 m for at least 72 hours following a single subcutaneous injection. More than 90% of the tissue radioactivity can be recovered as unchanged PALA. The drug is equally effective when given either orally or by subcutaneous injection. Using the activity of aspartate transcarbamylase as a measure of the effective concentration of PALA in the tissue, a single oral dose of as little as 100 µg gives maximum inhibition of the enzyme. Aspartate transcarbamylase activity is maximally inhibited within 15 min of administration and 72 hours later the enzyme activity in spleen is still substantially inhibited. Addition of 1 x 10-7 m PALA in vitro to an extract of spleen inhibits by 80% the incorporation of radioactivity from CO2 into UMP and CMP; approximately 10-6 m PALA is required to give comparable inhibition of incorporation from carbamyl-P. Mice injected with 1 mg of PALA 1 hour before injection with isoproterenol incorporated [14C]thymidine into the DNA of their submaxillary glands at a rate no greater than that of control animals, whereas incorporation by mice injected with isoproterenol alone was markedly stimulated, indicating that PALA effectively blocks the supply of pyrimidine nucleotides required for DNA synthesis in this instance of drug-stimulated proliferation.
Highlights
(PALA), a transition state analogue for aspartate transcarbamylase, is an effective inhibitor of the enzyme in a number of tissues when administered to mice
Distribution of tritium between the acid-soluble and acid-precipitable fractions of liver, spleen, kidney, and jejunum 1, 8, and 24 hours after injection of 1 mg of [aH]PALA was used as a measure of the degree of breakdown of PALA by the tissue since hydrolysis of PALA would result in the formation of n-aspartate, which would be available for incorporation into protein
Antimetabolites which interfere with pyrimidine metabolism are widely used in treating neoplastic disease because rapidly proliferating cells are dependent on an increased supply of pyrimidine nucleotides for nucleic acid biosynthesis
Summary
(less than 0.1 rnM> prevent cell division (1, Z), apparently by IV-(phosphonacetyl)~L-aspartate (PALA), a transition state analogue for aspartate transcarbamylase, is an effective inhibitor of the enzyme in a number of tissues when administered to mice. Mice injected with 1 mg of PALA 1 hour before injection with isoproterenol incorporated [14C]thymidine into the DNA of their submaxillary glands at a rate no greater than that of control animals, whereas incorporation inhibiting de wo pyrimidine nucleotide biosynthesis at the level of orotate phosphoribosyltransferase [2]. In another example, PALAl and 4,5dicarboxy-2ketopentyl phosphonate are toxic to cells in culture by inhibiting aspartate transcarbamylase [3]. By mice injected with isoproterenol alone was markedly stimulated, indicating that PALA effectively blocks the supply
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