Cytosine discovery

Early work on DNA polymerase I led to the definition of two central requirements for DNA polymerization. First, all DNA polymerases require a template. The polymerization reaction is guided by a template DNA strand according to the base-pairing rules predicted by Watson and Crick where a guanine is present in the template, a cytosine deoxynucleotide is added to the new strand, and so on. This was a particularly important discovery, not only because it provided a chemical basis for accurate semiconservative DNA replication but also because it represented the first example of the use of a template to guide a biosynthetic reaction. 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

The discovery in the 1980s that RNA molecules often have catalytic properties and may serve as true enzymes (ribozymes Chapter 12) stimulated new thinking about evolution. Although RNA catalysts are not as fast as the best enzymes they are able to catalyze a wide variety of different reactions. Could it be that in the early evolution of organisms RNA provided both the genetic material and catalysts The "RNA world" would have been independent of both DNA and protein.a b Later DNA could have been developed as a more stable coding molecule and proteins could have evolved as more efficient catalysts. Plausible reactions by which both cytosine and uracil could have arisen in drying ponds on early Earth have been demonstrated.6... 

The discovery of the presence of glucose in the nucleoside of 5-(hydroxy-methyl)cytosine was as unexpected as the original finding of the presence36 of 5-(hydroxymethyl)cytosine and the absence of cytosine.36 As Cohen suggests,84 other viruses contain cytosine they therefore lack the hydroxy -... 

Bromo- and chloroacetaldehyde react readily with adenine and cytosine, either free or as constituents of nucleosides and nucleotides (Figure 5)63. The etheno adducts so formed are highly fluorescent, a discovery that has made this reaction a very valuable research... 

Erwin Chargaff s discovery that DNA contains equimolar amounts of guanine and cytosine and also equimolar amounts of adenine and thymine has come to be known as Chargaff s rule ... 

In 1933, Klein discovered that sodium arsenate inhibits the action of the nucleotidase" of intestinal mucosa. Consequently, Klein and Thannhauser were enabled to hydrolyze thymus nucleic acid by means of intestinal desoxyribonucleinase without subsequent dephosphorylation of the liberated nucleotides. Making use, also, of Klein s discovery of the deaminase-inhibiting activity of silver ions, they were successful in isolating the adenine nucleotide. Hence the phosphodesoxyribosyl nucleotides of adenine, guanine, thymine, and cytosine were isolated and characterized. 

Interest in G C tetrad forming base-pairs comes from the discovery of the fragile X syndrome and the associated d(CGG)n d(CCG) repeats. Initial structural prediction for the CG rich repeat sequences identified a parallel stranded motif stabilized by the methylation of the cytosine residues. Subsequent structural analyses by NMR methods on a sequence that contained CG2 repeats, linked by thymine bases, revealed a head-to-tail hairpin arrangement... 

The discovery of both DNA secondary-structure formation within the NHE nil region of the c-myc promoter and proteins that bind specifically to the cytosine-rich strand, guanine-rich strand, or the duplex of the same region has led to a model of how the NHE IIIi controls c-myc expression (Figure 6). The model suggests the presence of three different DNA structural populations within the NHE IIIi two that cause activation and one that results in repression of c-myc transcription. First, when the NHE IIIi assumes a normal... 

Because of complementary base pairing, the amount of adenine in a molecule of DNA always equals the amount of thymine, and the amount of cytosine always equals the amount of guanine. In 1953, James Watson and Francis Grick used this observation to make one of the greatest scientific discoveries of the twentieth century when they determined the double-helix structure of DNA. They accomplished this feat without performing many laboratory experiments themselves. Instead, they analyzed and synthesized the work of numerous scientists who had carefully carried out studies on DNA. 

Flucytosine is a powerful antifungal agent used in the treatment of serious systemic fungal infections, such as Cryptococcus neoformans and Candida spp (Table 40.2). Flucytosine itself is not cytotoxic but, rather, is a pro-drug that is taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine deaminase (Fig. 40.11) (51). Then, 5-FU is converted to 5-fluorodeoxyuridine, which as a thymidylate synthase inhibitor interferes with both protein and RNA biosynthesis. 5-Fluorouracil is cytotoxic and is employed in cancer chemotherapy (see Chapter 42). Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism. Resistance rapidly develops to flucytosine when used alone, so it is almost always used in conjunction with amphotericin B. Use of flucytosine has declined since the discovery of fluconazole. 

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