Inosine 2-deoxyinosine

As a demonstration of the validity of this theoretical result, we show in Figure 12.7 a fully developed isotachic train of inosine, deoxyinosine, adenosine, and deoxyadenosine [11]. This figiue illustrates how strongly the thickness of the shock layer between bands in the isotachic train depends on the relative retention, and how widely the size of the mixed zones can vary with a — 1, as predicted by Eq. 16.27. The main features of this displacement chromatogram are (i) the very close plateau concentrations of the first two and of the last two com-... 

A fully developed isotachic train of inosine, deoxyinosine, adenosine, and de-oxyadenosine is shown in Figure 12.7. The thickness of the mixed zones between the bands in this train is in qualitative agreement with what can be inferred re-... 

Hypoxanthine (6-oxypurine) Inosine Deoxyinosine Inosine monophosphate (IMP) Deoxyinosine monophosphate (dIMP)... 

These data demonstrate a marked abnormality in the ability of intact uremic RBC to metabolize adenosine (deoxyadenosine) to inosine (deoxyinosine) and hypoxanthine. The equivalent labelling by radioactive adenosine and deoxyadenosine of ATP pools suggests that the adenylate kinase pathway in uremic RBC is normal despite markedly elevated ATP levels. The latter may reflect decreased utilization of ATP in uremic RBC or an effect of high inorganic phosphate on ATP turnover (8). 

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. 

Adenosine deaminase (ADA) is a ubiquitous enzyme that is essential for the breakdown of the purine base adenosine, from both food intake and the turnover of nucleic acids. ADA hydrolyzes adenosine and deoxyadenosine into inosine and deoxyinosine, respectively, via the removal of an amino group. Deficiency of the ADA enzyme results in the build-up of deoxyadenosine and deoxyATP (adenosine triphosphate), both of which inhibit the normal maturation and survival of lymphocytes. Most importantly, these metabolites affect the ability of T-cells to differentiate into mature T-cells [656430], [666686]. ADA deficiency results in a form of severe combined immunodeficiency (SCID), known as ADA-SCID [467343]. 

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. 

A close look at this reaction reveals that in the opposite direction, the reaction is of the phosphorolysis type. For this reason, the enzymes catalyzing the reaction with ribose-l-phosphate are called phosphorylases, and they also participate in nucleic acid degradation pathways. Purine nucleoside phosphorylases thus convert hypoxanthine and guanine to either inosine and guanosine if ribose-l-phosphate is the substrate or to deoxyinosine and deoxyguanosine if deoxyribose-1-phosphate is the substrate. Uridine phosphorylase converts uracil to uridine in the presence of ribose-l-phosphate, and thymidine is formed from thymine and deoxyribose-l-phosphate through the action of thymidine phosphorylase. 

Patients that lack adenosine deaminase are unable to degrade adenosine to inosine, or deoxyadenosine to deoxyinosine. Accumulated deoxyadenosine (dAdo) is converted to nucleotides as follows ... 

Similarly, adenosine, inosine and 2 -deoxyinosine have been converted into their 8-trifluoromethyl derivatives by reaction with the copper complex formed from trifluoromethyl iodide and copper in hexamethylphosphorotriamide (80JCS(P1)2755). iV -Trifluoromethyl-purine riboside was also produced from 6-chloropurine riboside. Recently, guanosine has been shown to give the C (8)-substituted derivative (148) by reaction with a benz[a]anthracene 5,6-dioxide at pH 9.5 over 4 days at 37 °C (80CC82). 

The phosphorylase can catalyze the formation of inosine or deoxyinosine, and of guanosine or deoxyguano-sine, but not adenosine or deoxyadenosine. However, the last two nucleosides can be converted to inosine and deoxyinosine by adenosine deaminase. The normal function of the phosphorylase appears to be the formation... 

ADA deficiency causes death from massive infection before the patient reaches the age of 2 years. Some children with ADA or PNP deficiency have benefited from pe-riodie infusions of irradiated erythrocytes (which contain ADA and PNP). Irradiation of erythrocytes is necessary to inactivate any white blood cells that may be present and thereby to reduce the risk of graft-versus-host disease (Chapter 35). PNP deficiency usually causes hypouricemia and hypouricosuria and excretion of inosine, guanosine, deoxyinosine, and deoxyguanosine. 

Because of the uncertainties in the intrinsic effects for studies with inosine, because of high commitments, the experiments were repeated with 2 -deoxyinosine, a slow substrate. 

Guanine + D-ribosyl phosphate guanosine -f- phosphate Hypoxanthine + D-ribosyl phosphate inosine + phosphate Hypoxanthine 2-deoxy- D-ribosyl phosphate 2-deoxyinosine + phosphate... 

Adenosine deaminase is the enzyme that hydrolyzes adenosine (or deoxyadenosine) to inosine (or deoxyinosine) and is important for purine metabolism. High levels of adenosine are toxic to B cells of the immune system and can result in an immunocompromised state. Also, people who lack the gene for adenosine deaminase have the genetic condition of severe combined immunodeficiency and are extremely susceptible to opportunistic infections. Many cancer and antiviral agents also are degraded by this enzyme hence, there is a role tor the development of inhibitors of this enzyme (26). The mechanism proposed for adenosine deaminase is a nucleophilic attack of water at the 6-position of the purine base to form a tetrahedral intermediate (Fig. 5.13). The transition state presumably resembles this intermediate. 

Erythrocytes from a child with purine nucleoside phosphorylase (PNP) deficiency (Watson et al - this symposium) and high levels of inosine and guanosine, deoxyinosine and deoxyguanosine in plasma and urine do not show intracellular accumulation of any of these nucleosides. The finding of high intracellular levels of dAR in the ADA deficient erythrocyte is thus in accord with a unique transport system for adenosine-type compounds associated with both adenosine kinase (AK) and ADA in the human red cell. 

Adenosine deaminase (ADA) catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. The study of ADA in mammalian cells is of particular importance because of (a) its indicated association with combined immunodeficiency disease in which patients with a deficiency of ADA activity exhibit a loss of both B and T cell function (1) ... 

The fate of other purine-ribose compounds was studied in the rat and it was found that C Mabeled adenosine (211) and adenylic acid (212) were utilized for the s3Tithesis of RNA adenine and guanine, but to a much smaller extent than adenine (191). Similarly, growing yeast utilized the purine base, adenine, far more readily than the corresponding nucleoside or nucleotide (195). It was believed that the ribose derivatives were poorly utilized because they were first cleaved to free adenine, which was incorporated subsequently into polynucleotides. It is curious that the attachment of ribose or a ribose pho hate moiety to adenine or guanine did not facilitate their incorporation into nucleic acids. In contrast, inosine, the ribonucleoside of hypoxantbine, was utilized considerably by the rat as a nucleic acid precursor (211) the corresponding deoxyriboside, deoxyinosine, was not (213). 

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