Effects of acivicin and pala, singly and in combination, on de novo pyrimidine biosynthesis

Thomas W. Kensler, Hiremagalur N. Jayaram, David A. Cooney

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The inhibitory activities of two oncolytic amino acid analogs, acivicin and n-(phosphonacetyl)-l-aspartate, on pyrimidine biosynthesis have been examined in a murine tumor line, the Lewis lung carcinoma. Acivicin, an antimetabolite elaborated by Streptomyces sviceus, inhibits a spectrum of l-glutamine utilizing enzymes including carbamoyl phosphate synthetase II, the inaugurating enzyme of de novo pyrimidine biosynthesis. Profound inhibition of carbamoyl phosphate synthetase II activity by acivicin is demonstrated in vitro as well as in vivo. n-(Phosphonacetyl)-l-aspartate, a rationally-designed transition-state analog of the reaction catalyzed by l-aspartate transcarbamylase, the second enzyme of the pathway, is a potent and specific inhibitor of l-aspartate transcarbamylase. Both agents, at therapeutic doses, exert marked inhibitions of their respective target enzymes and impede flux through the pathway as monitored by inhibition of pyrazofurin-provoked accumulation of orotate and orotidine. Additionally, synergistic effects are observed when acivicin and n-(phosphonacetyl)-l-aspartate are used in combination, both in terms of biochemical and therapeutic endpoints. The salient features of the actions of these drugs on pyrimidine biosynthesis in the Lewis lung carcinoma are summarized in Table 6. Comparison of the effects of acivicin with those of n-(phosphonacetyl)-l-aspartate suggest divergent actions on nucleotide biosynthesis. In spite of its pronounced sensitivity to acivicin, carbamoyl phosphate synthetase II appears not to be a critical target for the antineoplastic activity of this drug.

Original languageEnglish (US)
Pages (from-to)57-73
Number of pages17
JournalAdvances in Enzyme Regulation
Volume20
Issue numberC
DOIs
StatePublished - 1982
Externally publishedYes

Fingerprint

acivicin
Biosynthesis
Carbamyl Phosphate
Aspartic Acid
Ligases
Aspartate Carbamoyltransferase
Lewis Lung Carcinoma
pyrazofurin
Enzymes
Antimetabolites
Streptomyces
Glutamine
Pharmaceutical Preparations
Antineoplastic Agents
pyrimidine
Tumors
Nucleotides
Fluxes
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Effects of acivicin and pala, singly and in combination, on de novo pyrimidine biosynthesis. / Kensler, Thomas W.; Jayaram, Hiremagalur N.; Cooney, David A.

In: Advances in Enzyme Regulation, Vol. 20, No. C, 1982, p. 57-73.

Research output: Contribution to journalArticle

Kensler, Thomas W. ; Jayaram, Hiremagalur N. ; Cooney, David A. / Effects of acivicin and pala, singly and in combination, on de novo pyrimidine biosynthesis. In: Advances in Enzyme Regulation. 1982 ; Vol. 20, No. C. pp. 57-73.
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