Three- thymidines

Figure 35-3. Base pairing between deoxyadenosine and thymidine involves the formation of two hydrogen bonds. Three such bonds form between deoxycytidine and deoxyguanosine.The broken lines represent hydrogen bonds.

A nucleoside consists of a purine or pyrimidine base linked to a pentose, either D-ribose to form a ribonucleo-side or 2-deoxy-D-ribose to form a deoxyribonucleoside. Three major purine bases and their corresponding ribo-nucleosides are adenine/adenosine, guanine/guanosine and hypoxanthine/inosine. The three major pyrimidines and their corresponding ribonucleosides are cytosine/ cytodine, uracil/uradine and thymine/thymidine. A nucleotide such as ATP (Fig. 17-1) is a phosphate or polyphosphate ester of a nucleoside. 

The typical test (illustrated in Figure 15.7) is performed using mice, normally female CBA mice 6-10 weeks of age. Female BALB/c and ICR mice have also been used. After animal receipt, they are typically acclimated to standard laboratory husbandry conditions for 7-10 days. The usual protocol will consist of at least two groups (vehicle control and test article treated) of five mice each. They are treated on the dorsal surface of both ears with 25 pi (on each ear) of test article solution for three consecutive days. Twenty-four to forty-eight hours after the last test article exposure, the animals are given a bolus (0.25 ml) dose of [3H]thymidine (20 pCi with a specific activity of 5.0-7.0 Ci/mmol) in phosphate buffered saline via a tail vein. Five hours after the injection, the animals are euthanized by C02 asphyxiation and the auricular lymph nodes removed. 

Like many reported A -transglycosylations, this reaction uses uncharacterized nucleoside phosphorylases from whole cells held at 50-60 °C, a temperature well above the range for viability of the parent microorganism. Remarkable temperature stability has been reported for three well-known NPs of E. coli purine nucleoside phosphorylase (PNP), uridine phosphorylase (URDP) and thymidine phosphorylase. ... 

Virustatic antimetabolites are false DNA building blocks (B) or nucleosides. A nucleoside (e.g., thymidine) consists of a nucleobase (e.g., thymine) and the sugar deoxyribose. In antimetabolites, one of the components is defective. In the body, the abnormal nucleosides undergo bioactivation by attachment of three phosphate residues (p.287). 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Acyclovir Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the L-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase converts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphosphate and then to the active compound, acyclovir triphosphate. Because viral thymidine kinase has a much greater affinity for acyclovir triphosphate than does mammalian thymidine kinase, acyclovir triphosphate accumulates only in virus-infected cells. 

Thymidine 267 9.6 0.6 Three dimers hydrate formation not measured Four dimers formed hydrate either formed in very low yield and/or very unstable... 

A mutant strain of Escherichia coli Y-10, defective in L-rhamnose synthesis, accumulates109 a considerable amount of thymidine diphosphate sugars. Three of them were identified110 as the esters of thymidine 5 -pyrophosphate with 6-deoxy-a-D-xyZo-hexopyranos-4-ulose (28), 6-deoxy-D-glucose, and D-fucose. The fourth component was found to be a 4-acetamido-4,6-dideoxy-D-galactose derivative111,112 (29) it occurs also in Pasteurella pseudotuberculosis102 and its... 

Fig. lA. Anabolic and catabolic pathways of 5-FU. DPD dihydropyrimidine dehydrogenase, DP di-hydropyrimidinase, pUP beta-ureidopropionase, UP uridine phosphorylase, OPRT orotate phospho-ribosyl transferase, UK uridine kinase, TP thymidine phosphorylase, TK thymidine kinase, RNR ribonucleotide reductase. The three active metabolites (shown in rectangles) are FdUMP (5-fluoro-2 -deoxyuridine 5 -monophosphate) inhibiting TS (thymidylate synthase), and FUTP (5-fluorouridine 5 -triphosphate) and FdUTP (5-fluoro 2 -deoxyuridine 5 -triphosphate) interfering with RNA and DNA, respectively. 

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by host cell enzymes (Figure 49-3). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates—only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms competition with deoxyGTP for the viral... 

RNA consists of long strings of ribonucleotides, polymerised in a similar way to DNA, but the chains are considerably shorter than those of DNA. RNA contains ribose rather than deoxyribose and also contains uracil instead of thymidine. This has important connotations in the secondary structure of RNA which does not form the long helices found in DNA. RNA is usually much more abundant than DNA in the cell and its concentration varies according to cell activity and growth. This is because RNA has several roles in protein synthesis. There are three major classes messenger RNA (mRNA) ribosomal RNA (rRNA) and transfer RNA (tRNA). 

Otero, G.C. and Hope, T.J. (1998) Splicing-independent expression of the herpes simplex virus type 1 thymidine kinase gene is mediated by three cis-acting RNA sub-elements. J. Virol, 72, 9889-9896. 

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