Conversion of uracil deoxyriboside to thymidine of deoxyribonucleic acid.
TL;DR: Evidence is presented that uracil deoxyriboside, which structurally is the simple demethylated form of thymidine, may indeed be the primary acceptor of the methyl group.
About: This article is published in Journal of Biological Chemistry.The article was published on 1956-06-01 and is currently open access. It has received 77 citations till now. The article focuses on the topics: Uracil & Thymidine.
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423 citations
01 Jan 1961
TL;DR: The pathways of purine and pyrimidine metabolism have been greatly aided by tracer research, nutritional and genetic studies with intact organisms, and tissue studies in vitro as mentioned in this paper, and their biosynthesis was complicated by the increased formation of free bases from the breakdown of tissue nucleic acids and nucleotides upon homogenization of the tissue.
Abstract: Publisher Summary This chapter provides an overview of purines and pyrimidines and their biosynthesis. The pathways of purine and pyrimidine metabolism have been greatly aided by tracer research, nutritional and genetic studies with intact organisms, and tissue studies in vitro. The study of purine synthetic reactions was complicated by the increased formation of purine bases from the breakdown of tissue nucleic acids and nucleotides upon homogenization of the tissue. The utilization of free purines is accomplished by reaction with PRPP to form nucleotides directly. The bases have also been converted to nucleotides via the nucleosides. Nucleosides are produced by reaction of free bases with ribose 1-phosphate in the presence of nucleoside phosphorylase. The extensive utilization of dietary adenine and the nonutilization of guanine in rat have been explained in terms of the relative absence of the enzyme adenase and the presence of much guanase in rat tissues. The synthesis of purines de novo was initiated by the formation of 5-phosphoribosylamine by reaction of glutamine with 5-phosphoribosylpyrophosphate. The nucleotides that are constituents of nucleic acids, namely, guanylic acid and adenylic acid, were formed from inosinic acid.
250 citations
Journal Article•
TL;DR: It is concluded that these fluorinated pyrimidines inhibit the metabolic methylation of deoxyuridine monophosphate to thymidine monphosphate and was also incorporated into RNA in these cell suspensions.
Abstract: Summary 1.A study of the effects of fluorinated pyrimidines on nucleic acid biosynthesis has been carried out in suspensions of Ehrlich ascites cells incubated anaerobically with various labeled substrates. The drugs did not inhibit glycolysis. 2.The conversion of formate-C14 into DNA thymine was inhibited in increasing order of potency by 5-fluoroorotic acid, 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2′-deoxyuridine. This inhibition by 5-fluorouracil and 5-fluoroorotic acid was reversed by deoxyuridine. However, formate incorporation into nucleic acid adenine was not inhibited. 3.In studies of permeability it was found that 5-fluorouracil was taken up by the ascites cells to a greater extent than were uracil, orotic acid, and fluoroorotic acid. 5-Fluorouridine caused an increased cellular uptake of uracil and orotic acid. 4.The fluorinated pyrimidines did not affect the conversion of thymidine-6-H3 into DNA thymine, nor the incorporation of phosphate-P32 into DNA or RNA in these cell suspensions. 5.The fluorinated pyrimidines inhibited the metabolic conversion of uracil-2-C14 and orotic-6-C14 acid into DNA thymine and, with the exception of 5-fluoro-2′-deoxyuridine, inhibited the incorporation of the same precursors into RNA uracil. The metabolic transformation of uracil and orotic acid into nucleic acid cytosine was not greatly affected by the drugs. 6.5-Fluorouracil-2-C14 was converted into 5-fluoro-2′-deoxyuridine monophosphate and was also incorporated as such into RNA in these cell suspensions. 7.It is concluded that these fluorinated pyrimidines inhibit the metabolic methylation of deoxyuridine monophosphate to thymidine monophosphate. With the exception of 5-fluoro-2′-deoxyuridine, the compounds inhibit the conversion of pyrimidines into RNA uracil. The exact metabolic locus of this block has not yet been determined. These biochemical observations have been discussed in the light of the tumor-inhibitory properties of these drugs.
248 citations
Cites background from "Conversion of uracil deoxyriboside ..."
...It is known from the excellent work of Friedkin (9) and Cohen (3) that the methylation reaction leading to thymidylic acid is catalyzed by a tetrahydrofolic acid coen/yme....
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TL;DR: In the current study, this in vitro system appeared useful to test the potential efficacy of agents (such as methionine) which might be used to improve or retard improvement of patients with megaloblastic anaemia.
Abstract: Summary. The synthesis of thymine DNA from deoxyuridine and uridine was studied by culturing human bone marrow for 1–3 hours in the presence of radioactive-labelled nucleosides. In the current study, this in vitro system appeared useful to test the potential efficacy of agents (such as methionine) which might be used to improve or retard improvement of patients with megaloblastic anaemia.
In the bone marrow from patients with B12-deficient or folate-deficient megaloblastic anaemia, there was defective incorporation of deoxyuridine into thymine DNA. This defect was partially corrected by added B12 in the B12-deficient but not the folate-deficient marrows, and completely corrected by folic acid (pteroylglutainic acid) in both types of deficient marrow. The folate antagonist rnethotrexate blocked the corrective effect of B12. Incorporation of labelled uridine into DNA of B12-deficient megaloblastic marrow was enhanced less by B12 than by PGA. Vitamin B12 antagonists failed to depress the incorporation of labelled uridine into DNA in bone marrows from both normal and B12-deficient patients.
These results support the concept that inadequate DNA synthesis in B12 deficiency is due in large measure to blockade in folate metabolism brought about by lack of B12. 5-Methyl-tetrahydrofolate, which may accumulate in B12 deficiency, failed to correct the defect in DNA synthesis, adding further evidence to the concept of metabolic trapping of this form of folate in B12 deficiency. Thus, riboside reduction in man may be independent of B12, as it is in E. coli, rather than dependent on B12, as it is in L. leichmannii.
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TL;DR: DNA of calf thymus has been subjected to controlled chemical degradation, suggesting a certain similarity in the behavior of APA and of pentose nucleic acid toward alkali and the composition and properties of the degradation products were investigated.
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