Suppression of cytidylate biosynthesis by protein synthesis antagonists
When protein synthesis is effectively inhibited in Novikoff cell cultures by various drugs, there is a marked suppression of labeling of cytidiane nucleotides (mainly CTP) from exogenously supplied (/sup 3/H)uridine. The inhibition could be caused by a reduced activity of CTP synthetase, the enzyme catalyzing the conversion of UTP to CTP, since (/sup 3/H)UTP is readily produced. The variety of the drugs used appears to argue against a direct effect of the drugs on CTP synthetase, since three different glutarimide antibiotics (cycloheximide, streptimidone, and emetine) and puromycin, which has a quite different chemical structure, are equally effective. An increase of the cytidine nucleotide pool size is observed in most instances of drug treatment; however, feedback inhibition of CTP synthetase is considered unlikely because of a lack of correlation between the degree of inhibition of (/sup 3/H)CTP production and the extent of accumulation of the cytidine nucleotides. There is a marked inhibition of RNA synthesis when all protein synthesis inhibitors are present; but almost complete inhibition of RNA synthesis by actinomycin D produces only a slight inhibition in (/sup 3/H)CTP production, indicating that the block in the conversion of UTP to CTP results from inhibited protein synthesis rather than from inhibited RNA synthesis. Examination of the labeling pattern of both RNA and DNA nucleotides following drug treatment gave further evidence for inhibited CTP production. Inhibition of protein synthesis elicited a much greater reduction of the suppression ratio (experimental/control ratio) for RNA-CMP labeling than for RNA-UMP labeling and an even greater reduction of the suppression ratio for DNA-dCMP labeling compared to DNA-dTMP labeling. The effect was also obtained in HeLa cell cultures, but is not restricted to neoplastic cell lines since it was seen with normal human diploid fibroblast cultures.
- Research Organization:
- East Tennessee State Univ., Johnson City
- DOE Contract Number:
- W-7405-ENG-26
- OSTI ID:
- 5308513
- Journal Information:
- J. Biol. Chem.; (United States), Vol. 255:8
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BIOSYNTHESIS
INHIBITION
CYCLOHEXIMIDE
BIOLOGICAL EFFECTS
CYTIDYLIC ACID
PUROMYCIN
ACTINOMYCIN
BIOCHEMICAL REACTION KINETICS
DNA
FIBROBLASTS
HELA CELLS
LABELLED COMPOUNDS
RNA
TRITIUM
URIDINE
ANIMAL CELLS
ANTIBIOTICS
ANTIMITOTIC DRUGS
AZINES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CONNECTIVE TISSUE CELLS
DRUGS
FUNGICIDES
HETEROCYCLIC COMPOUNDS
HYDROGEN ISOTOPES
HYDROXY COMPOUNDS
ISOTOPES
KINETICS
LIGHT NUCLEI
NUCLEI
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PESTICIDES
PYRIMIDINES
RADIOISOTOPES
REACTION KINETICS
RIBOSIDES
SOMATIC CELLS
SYNTHESIS
URACILS
YEARS LIVING RADIOISOTOPES
550200* - Biochemistry
550300 - Cytology