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Inhibitory effects and metabolism of 5-fluoropyrimidine derivatives in pneumococcus
Abstract:
5-Fluorouracil (FU), 5-fluorocytosine, and the riboside and deoxyriboside derivatives of these fluoropyrimidines each exhibit a different spectrum of inhibitory effects in pneumococci. The biochemical basis of this finding seems to be the extremely low level of nucleoside phosphorylase (hydrolase) and N-trans-deoxyribosylase activity in pneumococcus and the consequent, relatively limited metabolic interconversion of the different fluoropyrimidines, which can therefore selectively affect one or the other of the several drug-sensitive biochemical reactions in this bacterium. Special attention was paid to the effect of fluoropyrimidines on the metabolism of cytosine and thymidine. In spite of the fact that FU is converted to both fluorouridine triphosphate and fluorocytidine triphosphate, only fluorouridylate but no fluorocytidylate can be detected in the ribonucleic acid Exogenous FU and fluorouridine also inhibit the synthesis of cytosine nucleotides from supplied uridine in a pyrimidine auxotroph. Thymidine was found to be a poor reversing agent for any of the fluoropyrimidine inhibitions. In both the wild type and in a thymidine-requiring (thymidylate-synthetase deficient) mutant, growing with supplied thymidine in the medium, fluorodeoxyuridine (FUdR) treatment caused cell death and inhibition of the incorporation of radioactive thymidine, adenosine, or uracil into deoxyribonucleic acid. It is suggested that FUdR (or a metabolic derivative) inhibits the transport of phosphorylation of thymidine in this microorganism.
Insights
5-Fluorouracil (FU) and its derivatives show varied effects on pneumococci due to limited metabolic conversion. These fluoropyrimidines selectively inhibit drug-sensitive reactions, impacting DNA and RNA synthesis.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Pneumococci exhibit limited metabolic interconversion of fluoropyrimidines due to low nucleoside phosphorylase and N-trans-deoxyribosylase activity.
- This limited metabolism allows different fluoropyrimidines to selectively target specific biochemical pathways in pneumococci.
Purpose of the Study:
- To investigate the differential inhibitory effects of 5-Fluorouracil (FU) and its derivatives on pneumococci.
- To elucidate the biochemical basis for these varied effects, focusing on fluoropyrimidine metabolism and its impact on nucleotide synthesis.
Main Methods:
- Assessing the inhibitory effects of various fluoropyrimidines (FU, 5-fluorocytosine, riboside, and deoxyriboside derivatives) on pneumococci.
- Analyzing the incorporation of radioactive precursors (thymidine, adenosine, uracil) into DNA and RNA.
- Investigating the effects on cytosine and thymidine metabolism in both wild-type and mutant pneumococcal strains.
Main Results:
- Different fluoropyrimidines displayed distinct inhibitory spectra against pneumococci.
- 5-Fluorouracil (FU) was converted to fluorouridine triphosphate and fluorocytidine triphosphate, but only fluorouridylate was detected in RNA.
- Fluorodeoxyuridine (FUdR) treatment led to cell death and inhibited DNA synthesis, suggesting interference with thymidine transport or phosphorylation.
Conclusions:
- The limited metabolic interconversion of fluoropyrimidines in pneumococci underlies their differential inhibitory effects.
- Fluoropyrimidines can selectively disrupt essential biochemical pathways, including DNA and RNA synthesis.
- FUdR appears to inhibit thymidine metabolism, contributing to its cytotoxic effects in pneumococci.