Inhibitory effects and metabolism of 5-fluoropyrimidine derivatives in pneumococcus.
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.
D000535:Aluminum; D001345:Autoradiography; D001426:Bacterial Proteins / Q000096:biosynthesis; D001431:Bacteriological Techniques; D002247:Carbon Isotopes; D002474:Cell-Free System; D011232:Chemical Precipitation; D002852:Chromatography, Ion Exchange; D002855:Chromatography, Thin Layer; D003124:Colorimetry; D003470:Culture Media; D003596:Cytosine / Q000378:metabolism; D004269:DNA, Bacterial / Q000096:biosynthesis; D005374:Filtration; D005467:Floxuridine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005615:Freezing; D008858:Microscopy, Phase-Contrast; D009713:Nucleotidyltransferases / Q000378:metabolism; D010087:Oxides; D011744:Pyrimidinones / Q000378:metabolism / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000096:biosynthesis; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D014238:Trichloroacetic Acid
D001426:Bacterial Proteins; D002247:Carbon Isotopes; D003470:Culture Media; D004269:DNA, Bacterial; D010087:Oxides; D011744:Pyrimidinones; D012329:RNA, Bacterial; D005467:Floxuridine; D014238:Trichloroacetic Acid; D003596:Cytosine; D000535:Aluminum; D009713:Nucleotidyltransferases; D005472:Fluorouracil; D013936:Thymidine