Deoxyadenosine metabolism

Ullman B.y GudaSy L.J.y Cohen A. and Martiny Jr.y D.W.y 1978y Deoxyadenosine metabolism and cytotoxicity in. cultured mouse T lymphoma cells a model for immunodeficiency diseasey Celly 14 365. 

D. Perrett, A. Sahota, H.A. Simmonds, and K.Hugh-Jones. Deoxyadenosine metabolism in the erythrocytes of children with severe, combined immunodeficiency. Bioscience Reports 1 933 (1981)... 

The mechanism of inhibition of these protozoal infections by the most active drugs, puromycin and the aminonucleoside, is not known. Puromycin and nucleocidin both interfere with protein synthesis, but the aminonucleoside does not. It is known to be demethylated to 3 -amino-3-deoxyadenosine, which is phosphorylated and interferes with nucleic acid metabolism (see above). Whether puromycin must be converted to the aminonucleoside before it can inhibit protozoa has not been established. Some purine analogues known to interfere with nucleic acid metabolism, however, are less effective as antiprotozoal agents, even in vitro, perhaps because their effects are primarily on the de novo pathway which many, if not all, protozoa do not use [406]. 

The biologic action of gemcitabine on its own is due almost completely to its effects on DNA metabolism. Early studies of this drug in leukemic cell lines showed that notable decreases in cellular dNTPs occurred with the use of the drug (8). These decreases were most impressive in terms of the levels of 2 -deoxycytidine 5 -triphosphate (dCTP), however, 2 -deoxyadenosine 5 -triphosphate (dATP) and 2 -deoxyguanosine 5 -triphosphate (dGTP) were also affected. It is felt that part of this is due to the inhibitory effects of... 

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... 

Didanosine (ddl) is a synthetic analog of deoxyadenosine (Figure 49-2). Oral bioavailability is approximately 40% dosing on an empty stomach is optimal, but buffered formulations are necessary to prevent inactivation by gastric acid (Table 49-3). Cerebrospinal fluid concentrations of the drug are approximately 20% of seram concentrations. Serum half-life is 1.5 hours, but the intracellular half-life of the activated compound is as long as 20-24 hours. The drug is eliminated by both cellular metabolism and renal excretion. 

A Abe ACE ACh ADME ADR Ala Arg Asp ATP dATP AUC Adenine Abequose Angiotensin-converting enzyme Acetyl choline Absorption, distribution, metabolism and elimination Adverse drug reaction Alanine Arginine Aspartate Deoxyadenosine triphosphate Adenosine triphosphate Area under the curve... 

A deficiency of Adenosine Deaminase (ADA) decreases metabolism of deoxyadenosine causing dATP to accumulate. 

The PAH benzo[g/z/(fluoranthene (35) undergoes metabolism to an epoxide (36) which can form adducts with DNA, for example, by binding to a deoxyadenosine residue (equation 1). In Section V.A the structure of four possible diastereoisomers of the deoxyadenosine adduct (37) is discussed29. 

Vinyl chloride. A chemical used in the manufacture of plastics which is carcinogenic and causes various toxic effects including liver injury, damage to bones and skin. Liver haemangiosarcomas are produced in animals and humans. Vinyl chloride undergoes metabolic activation by cytochrome P-450 to an epoxide which may interact with DNA and form adducts (etheno-deoxyadenosine and etheno-deoxycytidine) which leads to mutations. Also reaction with glutathione occurs. 

Disruption of AdoMet metabolism is a key element also in the action of 5 - [(Z)-5-amino-2-butenyl]methylamino 5 -deoxyadenosine (MDL73811), an AdoMet decarboxylase inhibitor which is a highly effective trypanocide (53). Treatment of trypanosomes with MDL73811 caused a 20-fold increase in the trypanosome AdoMet level after only 1 h of exposure. In comparison, AdoMet levels in cultured mammalian cells rose only 1.5-fold after similar treatment with MDL73811 (48). This analog is rapidly concentrated by trypanosomes through the purine transport system (54). 

Although it is still not clear which potential mechanism best explains the arrested development of immune cells, it is clear that elevated levels of adenosine and deoxyadenosine are toxic. The biochemical disorders of purine and pyrimidine metabolism discussed in this chapter are summarized in Table 41.4. 

S ATP + deoxyadenosine <1, 3, 5, 6> (<1> involved in biosynthesis of nucleoside monophosphates from preformed deoxyribonucleosides [4] <3> key anaboHc enzyme for activation of purine and pyrimidine deoxyriho-nucleosides as weU as cytosine arabinoside and other anti-tumour drugs [9] <5> involved in nucleoside metabolism [11] <6> dGK/dAK plays an essential role in generating the dexyribonucleotide precursors, dGTP and dATP, for DNA metabolism [12]) (Reversibility <1, 3, 5, 6> [4, 9, 11, 12]) [4, 9, 11, 12]... 

Jenuth, J.P. Mably, E.R. Snyder, F.F. Modeling of purine nucleoside metabolism during mouse embryonic development. Relative routes of adenosine, deoxyadenosine, and deoxyguanosine metabolism. Biochem. Cell Biol., 74, 219-225 (1996)... 

Szabados, E. Duggleby, R.G. Christopherson, R.I. Metabolism of adenosine and deoxyadenosine by human erythrocytes and CCRF-CEM leukemia cells. Int. J. Biochem. Cell Biol., 28, 1405-1414 (1996)... 

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. 

Cordycepin, J deoxyadenosine, adenine 9-cordy-ceposide a purine antibiotic synthesized by Cordy-ceps militaris and Aspergillus nidulans (see Nucleoside antibiotics). JM, 251.24, m.p. 225-226 C, [a] —47° (water). As an antimetabolite of adenosine, it inhibits purine biosynthesis, but is not very toxic. It is phosphorylated metabolically to the monophosphate. 

Figure 1-3 shows a number of nucleoside antibiotics which contain adenine and an unusual sugar at the 9-position. Cordycepin (3 -deoxy-adenosine) is a cytostatic agent and is converted to the 5 -mono-, di-, and triphosphate derivatives in mouse tumor cells. Cordyceps militaris, the organism which produces cordycepin, also produces a related analogue with antitumor activity, 3 -amino-3 -deoxyadenosine this compound is also metabolized by way of phosphate derivatives. The angustmycins, psicofuranine and decoyinine, are, respectively, the 9-j3-D-psicofuranosyl... 

Although cells derive their deoxyribonucleotides primarily by reduction of ribonucleotides, the deoxyribonucleosides can be utilized to some extent by way of kinase reactions. Phosphorylation of deoxyribonucleosides represents the only known point of entry into the sequences of deoxyribonucleotide metabolism other than the main entry point, ribonucleotide reduction. Pyrimidine deoxyribonucleosides may be incorporated into DNA in animal cells by this route. The conversion of deoxyadenosine and deoxyguanosine into deoxyribonucleotides and thence into DNA would also appear possible by a kinase-initiated sequence, because the enzymatic phosphorylation of these compounds has been demonstrated. However, this route has not been well studied in animal cells and its assessment is complicated by very active deamination and phosphorolytic cleavage reactions which compete with the reactions leading to DNA. E. coli cells appear to possess only one kinase capable of phosphorylating deoxyribonucleosides, thymidine kinase. 

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