Deamination of adenosine

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

The Deamination of Adenosine 20 g of adenosine are dissolved in one liter of water by warming, and after cooling to room temperature 120 g of barium nitrite (monohydrate) are added to the solution. Under stirring there is added in time intervals of one hour 160 cc of 2N sulfuric acid after each time interval. After the third addition, the reaction mass is allowed to stand for 3 hours at room temperature. The solution is then tested for barium, and if some barium is still present a slight excess of sulfuric acid is added. 300 cc of methanol is then added. In order to drive off the excess of nitrous acid, CO is conducted... 

RNA-editing is a posttranscriptional mechanism mediated by RNA editases, which results in a site-selective deamination of adenosine to inosine. This alters codons and splicing in nuclear transcripts and thereby alters the structure and function of proteins. 

Adenosine deaminase (ADA) is an amino hydrolase that catalyzes the deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyinosine, respectively. High activity of ADA is seen in thymus and other lymphoid tissues. ADA has been shown in many different physical forms. A small form of the enzyme predominates in the spleen, stomach, and red blood cells, whereas the large form predominates in the kidney, liver, and skin fibroblasts. The small form of the catalytic subunit can be converted to the large form by complexing with a protein termed binding protein or complexing protein. 

One of the distinctive features of TMN neurons is that they contain high levels of adenosine deaminase, a key enzyme involved in deamination of adenosine, a mediator of homeostatic sleep regulation (Thakkar et al, 2003a, b). 

The involvement of isobutylhydroxylamine, (CH3)2CHCH2NH—OH (4), and of HA (NH2OH) in the biosynthesis of the antibiotics valanimycin (5) and nebularine (6), respectively, has been demonstrated in Streptomyces species (see Section n.B). In the case of nebularine, HA is released in the final step of its production by enzymatically induced deamination of adenosine, while the isobutylhydroxylamine is a precursor for the biosynthesis of valanimycin. In cyanobacterium, the presence of free and bound HA was demonstrated to be a product of enzyme-mediated glutamine oxidation ... 

Production of HA during the biosynthesis of the antibiotic nebularine (6) was demonstrated in another Streptomyces species. The formation of HA was confirmed both by chemical reactions designed to detect it and by MS analysis. An unusual enzymic deamination of adenosine was suggested, which resulted in release of HA, rather than of NH3, as a key step in the production of nebularine (equation 6). 

The abnormal T- and B-cell functions in patients with SCID are the result of ADA dehciency. The ADA gene has been mapped to chromosome 20q.l3, and a number of point and deletion mutations have been identihed in SCID patients [5-7]. ADA catalyses the irreversible deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyi-nosine as a part of purine nucleoside metabolism. Adenosine and deoxyadeno-sine are suicide inachvators of S-adenosyl-homocysteine (SAH) hydrolase, and lead indirectly to intracellular accumulation of SAH, which is a potent inhibitor of methy-lation reactions. Cellular methylation function is essential for detoxihcation of adenosine and deoxyadenosine. As a result ADA dehciency leads to accumulation to... 

The structure of the urease active center is similar to that of adenosine deaminase, an enzyme containing one zinc(II) per active site (though see 48). This enzyme catalyzes the deamination of adenosine to inosine and NH3 (see Scheme 9), a reaction mechanistically related... 

Adenosine deaminase catalyzes the hydrolytic deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyinosine respectively. Inhibition of adenosine deaminase leads to an accumulation of its substrates which results in adenosine receptor-mediated effects. Most inhibitors are not reported to have antinociceptive properties, but 2 -deoxycoformycin was proven to have an inhibitory effect on pain transmission (Poon and Sawynok, 1999), and Fujisawa Pharmaceuticals claim adenosine deaminase inhibitors to be active against chronic pain. 

Pteridine is changed by, the enzyme adenosine deaminase to the levorotatory form of the hydrate, 3,4-dihydro-4-hydroxypteridine. When this reaction was approached from the other direction, the same enzyme dehydrated this enantiomer most rapidly, leaving a net positive optical rotation at equilibrium.65 Specimens of the enzyme from both mammalian and fungal sources, although of very different molecular weight, were found to catalyze the stereospecific hydration of pteridine also pteridine inhibited the deamination of adenosine by both enzyme specimens. Assuming that the first step in the deamination of adenosine is the formation of a tetrahedral hydrated intermediate, it was argued that both the hydration of pteridine and the deamination of adenosine were parallel phenomena.65... 

The kinetic parameters Km, V, ax, pH optima, and energy of activation (2 act) for deamination of adenosine catalyzed by homogeneous preparations of adenosine aminohydrolase are summarized in Table III 82-86, 98). Except for the unusually low specific activities observed for both the chicken duodenal and calf serum enzymes, and the significantly higher energy of activation reported for the former, the reaction param-... 

Carbon-14 and nitrogen-15 heavy-atom KIEs in the hydrolytic deamination of adenosine 5-monophoshate (AMP 513) with AMP deaminase... 

Adenosine deaminase catalyzes the deamination of adenosine to form inosine and ammonia. The inosine (Ino) can be degraded further to hypoxanthine (Hyp) by nucleoside phosphorylase, an activity often present in extracts. Therefore, in many cases, the assay involves a determination of either the loss of adenosine (Ado) or the formation of both inosine and hypoxanthine. An early study by Uberti et al., 1977, was followed by another by Hartwick et al., 1978. 

Both compounds exhibit pronounced positive Cotton effects and a considerable hypochromic-ity (12a 19% 12b 13%). Both isomers are substrates formammalian adenosine deaminase. The diastereoisomer 12b is deaminated stepwise due to the difference in configuration. Moreover 12b is a strong competitive inhibitor for the deamination of adenosine by adenosine deaminase. 

The first base of an anticodon determines whether a particular tRNA molecule reads one, two, or three kinds of codons C or A (one codon), U or G (two codons), or I (three codons). Thus, part of the degeneracy of the genetic code arises from imprecision (wobble) in the pairing of the third base of the codon with the first base of the anticodon. We see here a strong reason for the frequent appearance of inosine, one of the unusual nucleosides, in anticodons. Inosine maximizes the number of codons that can be read by a particular tRNA molecule. The inosines in tRNA are formed by deamination of adenosine after synthesis of the primary transcript. 

Nitrosyl chloride in iV,iV-dimethylfonnamide at low temperature has been used for the convenient deamination of adenosine, adenosine 5 -phosphate, adenosine 5 -triphosphate, and their iV -oxides to the corresponding inosine derivatives. Nitrous anhydride (N2O3) has been used to convert the coenzyme adenine-nicotinamide dinucleotide into hypo-xanthine-nicotinic acid dinucleotide. 

In an attempt to shed some light on the mutagenic effects of nitrous acid on nucleic acids, Shapiro re-investigated the deamination of adenosine, cytidine, and guanosine with nitrous acid. Whereas adenosine and cytidine gave the expected products (namely, inosine and uridine, respectively), guanosine afforded, in addition to xanthosine, a small proportion of 2-nitroinosine (227), which was isolated as the ammonium salt. 

Roth, E., Jr., Ogasawara, N., and Schulman, S. (1989). The deamination of adenosine and adenosine monophosphate in Plasmodium falciparu m-i n fee ted human erythrocytes In vitro use of 2 deoxycoformycin and AMP deaminase-deficient red cells. Blood 74, 1121-1125. 

The bases are modified at the same time the endonucleolytic cleavage reactions are occurring (see Fig. 14.20, circle 3). Three modifications occur in most tRNAs (1) Uracil is methylated by S-adenosylmethionine (SAM) to form thymine (2) one of the double bonds of uracil is reduced to form dihydrouracil , and (3) a uracil residue (attached to ribose by an A-glycosidic bond) is rotated to form pseudouridine, which contains uracil linked to ribose by a carbon-carbon bond, (see Fig. 14.17). Other, less common but more complex, modifications also occur and involve bases other than uracil. Of particular note is the deamination of adenosine to form the base inosine. 

The use of biological methods has a small but significant niche in synthetic heterocyclic chemistry, being used both on a research scale and for fine chemicals production. The processes may use isolated enzymes or whole microorganisms, the main reactions being oxidations of a heterocyclic nucleus or of side-chains. Some other reaction types are referred to later in the book, for example enzyme-catalysed base exchange in nucleosides and the deamination of adenosine. 

Selective quenching allows also to put into evidence and to study a conformational change within a protein. ADAR2 (adenosine deaminase that acts on RNA) is a -80-kDa protein that efficiently deaminates the R/G site of GluR-B pre-mRNA sequences in vitro (O Connell et al. 1997). This enzyme has an RNA binding domain (RBD)l located in the C-terniinal catalytic domain. Deamination of adenosine (A) in the mRNA results in inosine (I) at that position. Because inosine is translated as guanosine (G), the editing reaction causes a functional A to G replacement. 

Inosine can be converted directly to inosinate by inosine kinase. This enzyme has been shown to exist in human cells, but at a low level (P2). It undoubtedly does not play a major role. Inosine phosphorylase cleaves inosine to hypoxanthine and ribose I-phosphate (Kl). Inosine is formed by the deamination of adenosine catalyzed by adenosine deaminase, an enzyme found in varying concentrations in essentially all normal mammalian cells examined. Studies with an inhibitor of adenosine deaminase, ribosyl-4-amino-5-imidazole carboxamide, on several strains of Escherichia coli revealed a major role for the enzyme. In cells with a block in purine synthesis a condition of guanine deprivation occurred after growth with adenine as purine source, and there was a derepression of the enzymes that convert IMP to XMP and XMP to GMP (K17). 

In eukaryotes, the different types of tRNA are made by RNA polymerase III inside the nucleus (Fig. 68.1). The primary products of transcription undergo various modifications. All transcripts have a C-C-A group added to the 3 hydroxyl end. Some precursors of tRNA have introns that are removed. Various bases are modified, forming unusual products (Fig. 58.2). For example, uracil can be altered to form pseudouridine ( /) or reduced to form dihydrouracil (D). Another example is inosine (I) formed by the deamination of adenosine. 

Adenosine deaminase (adenosine aminohydro-lase EC 3.5.4.4) catalyses the deamination of adenosine and deoxyadenosine. Thioglycollate-stimulated C57BL/6 mouse peritoneal macrophages contained high levels of adenosine deaminase activity (Chan 1979). In the presence of deoxycoformy-cin (1 pg/ml), a potent inhibitor of adenosine deaminase (Agarwal et al. 1977), thioglycoUate-stimulated mouse peritoneal macrophages excreted deoxyadenosine (Chan 1979). 

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