DATP 2 -deoxyadenosine

Dansyl-CaM, dansyl-calmodulin Dansyl-CaM-FC, Ca2 1 -dependent dansyl-calmodulin fluorescence change dATP, 2 -deoxyadenosine 5 -triphosphate DB, diabetic... 

Regulation of ribonucleotide reductase is complex. The binding of dATP (deoxyadenosine triphosphate) to a regulatory site on the enzyme decreases catalytic activity. The binding of deoxyribonucleoside triphosphates to several other enzyme sites alters substrate specificity so that there are differential increases in the concentrations of each of the deoxyribonucleotides. This latter process balances the production of the 2 -deoxyribonucleotides required for cellular processes, especially that of DNA synthesis. 

The consequence of ADA deficiency is accumulation of adenosine and 2 -deoxyadenosine, substances toxic to lymphocytes, important cells in the immune response. 2 -Deoxyadenosine is particularly toxic because its presence leads to accumulation of its nucleotide form, dATP, an essential substrate in DNA synthesis. Elevated levels of dATP actually block DNA replication and cell division by inhibiting synthesis of the other deoxynncleoside 5 -triphosphates (see Chapter 27). Accumulation of dATP also leads to selective depletion of cellular ATP, robbing cells of energy. Children with ADA SCID fail to develop normal immune responses and are susceptible to fatal infections, unless kept in protective isolation. 

Pentostatin (deoxycoformycin Fig. 4) is a purine isolated from cultures of Streptomyces antibioticus. Its mode of action involves inhibition of adenosine deaminase, which plays a key role in purine salvage pathways and DNA synthesis. As a consequence, deoxyadenosine triphosphate (dATP) is accumulated, which is highly toxic to lymphocytes. This is associated with augmented susceptibility to apoptosis, particularly in T cells. 

Adenine Deoxyadenosine Deoxyadenyiic acid Deoxyadenosine monophosphate (dAMP) Deoxyadenosine diphosphate (dADP) Deoxyadenosine triphosphate (dATP)... 

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... 

One form of SOD is caused by inherited insufficiency of adenosine deaminase leading to accumulation of its substrate, deoxyadenosine, which is derived from DNA degradation and is converted to dATP, an allosteric inhibitor of ribonucleotide reductase. 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

The basic cause of the severe immunodeficiency symptoms is uncertain. However, adenosine deaminase also catalyzes hydrolysis of 2 -deoxyadenosine, and in the absence of the enzyme both this compound and its trinucleotide precursor 2 -deoxy-ATP (dATP) accumulate in tissues.312 Ribonucleotide reductase is... 

When two acid molecules condense by elimination of a molecule of water, the product is called an acid anhydride, as can be seen in Figure 12.60. Acid anhydrides are always very reactive, or high-energy, compounds. When deoxy-adenosine monophosphate forms an anhydride with phosphoric acid, we have deoxyadenosine diphosphate (dADP). Of course, if we add an additional phosphate group, we have deoxyadenosine triphosphate (dATP). 

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. 

Deoxyadenosine 5 -Triphosphate (dATP) 100 mM solution, pH 7.5 (Pharmacia Biotech, Piscataway, NJ)... 

Radiochemicals tritiated 2 -deoxythymidine 5 -triphosphate [me/fty/-3H]dTTP, 2 -deoxyadenosine 5 -triphosphate [2,8-3H]dATP, 2 -deoxyguanosine 5 -triphos-phate [8-3H]dGTP or 2 -deoxycytidine 5 -triphosphate [5-3H]dCTP. The radiospecificities of the deoxy nucleotides usually range between 15 and 30 Ci/mmol. They can be obtained from several companies such as Amersham (Buckinghamshire, UK), ICN (Costa Mesa, CA), NEN (DuPont Ltd., Hertfordshire, UK), Moravek Biochemicals (Brea, CA), and so forth. They can be used at 2 pCi/assay. 

AcK acetate kinase AcP acetyl phosphate AdK adenylate kinase AP A p ,pn-di(adenosine 5 -) n-phosphate ARS aminoacyl tRNA synthetase ATP, ADP, AMP adenosine 5 -tri-, di-, monophosphate ATP-u-S (Sp)-adenosine 5 -0-(l-thiotriphos-phate), ATP-y-S adenosine 5 -0-(3-thiotriphosphate) CK carbamyl kinase CP carbamyl phosphate CrK creatine kinase CTP, CDP, CMP cytidine 5 -tri-, di-, monophosphate dATP, dAMP deoxyadenosine 5 -tri-, monophosphate DNA deoxyribonucleic acid AG change in free energy GK glycerol kinase GTP, GDP, GMP guanosine 5 -tri-, di-, monophosphate HK hexokinase IUB International Union of Biochemistry MCP methoxycarbonyl phosphate NTP, NDP, NMP nucleoside 5 -tri-, di-, monophosphate PC phosphocreatine PEP phosphoenol pyruvate P orthophosphate PK pyruvate kinase P polyphosphate PnK poly-... 

For example, the rate of reaction of ribonucleotide reductase is regulated by deoxyadenosine triphosphate (dATP) which is a product of the pathway for which ribonucleotide reductase is the committing step (Fig. 8.9). Note that dATP is neither a substrate nor a product of ribonucleotide reductase itself rather, it is an allosteric inhibitor. If the pathway (NDP dNTP) is running at a rate too high for the rate at which dNTPs are being used (for DNA synthesis), the concentrations of the dNTPs will rise, including [dATP], The increase will "feed back" to ribonucleotide reductase by the... 

Persons with severe combined immune deficiency (SCID) are totally unable to mount an immune response to antigens. Both the B and T lymphocytes are affected. The disease arises from an inherited lack of a degradative enzyme, adenosine deaminase (ADA). The reaction shown here illustrates the pathways affected. Lack of ADA allows deoxyadenosine triphophosphate (dATP) to accumulate from the degradation of DNA. High dATP levels inhibit production of the other dNTPs needed for DNA replication because of their allosteric effects on the enzyme ribonucleotide reductase. 

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