Hypoxanthine nucleoside

Silyl derivatives of purines are commonly used in the same way as in a synthesis of 9-(a, -D-glucopyranosyl)adenine from AT -benzoyl-9-bis(trimethylsilyl)adenine and 2,3,4,6-tetra-O-acetyl-a-D-glucosyl chloride at 150-160 °C over 4 hours to produce, after deblocking, a mixture of anomeric nucleosides (B-68MI40901,p. 135). The hypoxanthine nucleosides may be obtained in a similar fashion or by deamination of the adenine derivatives. 

This new sugar had the formula C5Hio04- In other words, it possesses one atom of oxygen less than does a pentose. Analysis of its benzyl-phenylhydrazone, of its guanine and hypoxanthine nucleosides, and of its thymine and cytosine nucleosides, confirmed this composition. It therefore appeared probable that the sugar might be a desoxypentose. 

The reaction of a hypoxanthine nucleoside 2 3 -dimethanesulphonate with sodium benzoate in DMF to give a 3 -deoxy-2 -keto-nucleoside has already been noted (Scheme 136), and analogous reactions with the cytidine and uridine derivatives (408) also gave the 3 -deoxy-2 -keto-nucleosides (409). Attempted... 

The molyhdopterin cofactor, as found in different enzymes, may be present either as the nucleoside monophosphate or in the dinucleotide form. In some cases the molybdenum atom binds one single cofactor molecule, while in others, two pterin cofactors coordinate the metal. Molyhdopterin cytosine dinucleotide (MCD) is found in AORs from sulfate reducers, and molyhdopterin adenine dinucleotide and molyb-dopterin hypoxanthine dinucleotide were reported for other enzymes (205). The first structural evidence for binding of the dithiolene group of the pterin tricyclic system to molybdenum was shown for the AOR from Pyrococcus furiosus and D. gigas (199). In the latter, one molyb-dopterin cytosine dinucleotide (MCD) is used for molybdenum ligation. Two molecules of MGD are present in the formate dehydrogenase and nitrate reductase. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Figure 34-8. Formation of uric acid from purine nucleosides byway of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathwayand enzymes,all of which existin the mucosa of the mammalian gastrointestinal tract.

Figure 12 Gradient separation of bases, nucleosides and nucleoside mono- and polyphosphates. Column 0.6 x 45 cm. Aminex A-14 (20 3 p) in the chloride form. Eluent 0.1 M 2-methyl-2-amino-l-propanol delivered in a gradient from pH 9.9-100 mM NaCl to pH 10.0-400 mM NaCl. Flow rate 100 ml/hr. Temperature 55°C. Detection UV at 254 nm. Abbreviations (Cyt) cytosine, (Cyd) cytidine, (Ado) adenosine, (Urd) uridine, (Thyd) thymidine, (Ura) uracil, (CMP) cytidine monophosphate, (Gua) guanine, (Guo) guanosine, (Xan) xanthine, (Hyp) hypoxanthine, (Ino) inosine, (Ade) adenosine, (UMP) uridine monophosphate, (CDP) cytidine diphosphate, (AMP) adenosine monophosphate, (GMP) guanosine monophosphate, (IMP) inosine monophosphate, (CTP) cytidine triphosphate, (ADP) adenosine diphosphate, (UDP) uridine monophosphate, (GDP) guanosine diphosphate, (UTP) uridine triphosphate, (ATP) adenosine triphosphate, (GTP), guanosine triphosphate. (Reproduced with permission of Elsevier Science from Floridi, A., Palmerini, C. A., and Fini, C., /. Chromatogr., 138, 203, 1977.)...

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. 

FIGURE 1 7-3 Adenosine metabolites. Adenosine is converted to inosine by adenosine deaminase. Removal of the ribose by nucleoside phos phorylase produces hypoxanthine, which is sequentially oxidized to xanthine and uric acid by xanthine oxidase. 

Answer C. The child most likely has severe combined immunodeficiency caused by adenosine deaminase defidency. This enzyme deaminates adenosine (a nudeoside) to form inosine (another nucleoside). Hypoxanthine and xanthine are both purine bases, and the monophosphates are nucleotides. 

The synthesis of purine nucleotides (1) starts from IMP. The base it contains, hypoxanthine, is converted in two steps each into adenine or guanine. The nucleoside monophosphates AMP and CMP that are formed are then phos-phorylated by nucleoside phosphate kinases to yield the diphosphates ADP and GDP, and these are finally phosphorylated into the triphosphates ATP and CTP. The nucleoside triphosphates serve as components for RNA, or function as coenzymes (see p. 106). Conversion of the ribonucleotides into deoxyribo-nucleotides occurs at the level of the diphosphates and is catalyzed by nucleoside diphosphate reductase (B). 

Purine nucleoside phosphorylase (PNP, E.C. 2.4.2.1) catalyzes the reversible phosphorylysis of ribonucleosides and 2 -deoxyribonucleosides of guanine, hypoxanthine, and related nucleoside analogs [1]. It normally acts in the phosphorolytic direction in intact cells, although the isolated enzyme catalyzes the nucleoside synthesis under equilibrium conditions. Figure 1 shows the chemical reaction. 

Table 7.1.4 Concentration range of purine and pyrimidine metabolites in urine (pmol/mmol creatinine) from patients. ADA Adenosine deaminase, APRT adenine phosphoribosyltransferase, ASA adenylosuccinate lyase, DHP dihydropyrimidinase, DPD dihydropyrimidine dehydrogenase, HGPRT hypoxanthine-guanine phosphoribosyltransferase, PNP purine nucleoside phosphorylase, TP thymidine phosphorylase, UMPS uridine monophosphate synthase, / -UP fi-ureidopropionase... 

The activity of hypoxanthine-guanine phosphoribosyltransferase, adenine phos-phoribosyltransferase, adenosine deaminase, and purine nucleoside phosphorylase can be determined in dried blood spots using an HPLC-linked assay [3]. 

The nomenclature for the minor bases can be confusing. Like the major bases, many have common names— hypoxanthine, for example, shown as its nucleoside inosine in Figure 8-5. When an atom in the purine or pyrimidine ring is substituted, the usual convention (used... 

Purine nucleoside phosphorylase converts inosine and guanosine into their respective purine bases, hypoxanthine and guanine. 

Purines that result from the normal turnover of cellular nucleic acids can be reconverted into nucleoside triphosphates and used by the body. Thus, they are "salvaged" instead of being degraded to uric acid. PRPP is the source of the ribose-phosphate, and the reactions are catalyzed by adenine phosphoribosyltransferase, and hypoxanthine-guanine phosphoribosyltransferase (HPRT). 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

The conversions of inosine to hypoxanthine (Fig. 25-17, step e), of guanosine to guanine (step g), and of other purine ribonucleosides and deoxyribonucleo-sides to free purine bases are catalyzed by purine nucleoside phosphorylase.318 321b Absence of this enzyme also causes a severe immune deficiency which involves the T cells. However, B cell function is not impaired.312 315 322... 

The first surprise was that these molecules are much longer than seems necessary for the formation of adapters. In addition, 10-20% of their bases are modified greatly from their original form.171 Another surprise was that the anticodons are not all made up of "standard" bases. Thus, hypoxanthine (whose nucleoside is inosine) occurs in some anticodons. Conventional "cloverleaf" representations of tRNA, which display their secondary structures, are shown in Figs. 5-30 and 29-7. However, the molecules usually have an L shape rather than a cloverleaf form (Figs. 5-31 and 29-6),172 and the L form is essential for functioning in protein synthesis as indicated by X-ray and other data.173 Three-dimensional structures, now determined for several different tRNAs,174 175 are all very similar. Structures in solution are also thought to be... 

Until recently the lactol ring structure of 2-desoxy-D-ribose in nucleic acid had been proved conclusively only for the thymidine nucleoside component and in this case it was furanose in form.26 Subsequently Brown and Lythgoe,27 by application of the periodate oxidation procedure to the 2 -desoxy ribosides of guanine, hypoxanthine, cytosine and thymine, afforded proof of the presence of a furanose sugar in each compound. 

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