2 -Deoxyadenosine 5 -triphosphate

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)... 

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. 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

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... 

Vela, J.E. et al. Simultaneous quantitation of the nucleotide analog adefovir, its phos-phorylated anabolites and 2 -deoxyadenosine triphosphate by ion-pairing LC/MS/MS. /. Chromatog. B. 2007, 848, 335-343. 

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. 

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... 

Deoxyadenosine monophosphate Deoxyadenosine diphosphate Deoxyadenosine triphosphate Adenosine monophosphate Adenosine diphosphate Adenosine triphosphate... 

Adefovir is an antiviral agent that inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Adefovir is indicated in the treatment of chronic hepatitis B in adults with evidence of active viral replication and evidence of persistent elevations in serum aminotransferases or histologically active disease. Adefovir dipivoxil (9-[2-[bis[(pivaloyloxy)methoxy] phosphinyl]methoxyl]ethyl]adenine, bis-POM PMEA) is a diester prodrug of adefovir, an acyclic phosphonate nucleotide analog of adenosine monophosphate. 

Vidarabine is an inhibitor of viral DNA synthesis. Cellular enzymes phosphorylate vidarabine to the triphosphate, which inhibits viral DNA polymerase activity in a manner that is competitive with deoxyadenosine triphosphate. Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator. Vidarabine triphosphate also inhibits ribonucleoside reductase, RNA polyadenylation, and 5 -adenosylhomocysteine hydrolase, an enzyme involved in transmethylation reactions. Resistant variants due to mutations in viral DNA polymerase can be selected in vitro. 

Deoxyribonucleotides are also called deoxyribonucleoside mono-, di-, or triphosphates if they contain 1, 2, or 3 phosphates, respectively. Deoxyadenosine triphosphate, for example, is a nucleoside triphosphate. 

Pemetrexed and its polyglutamates have a somewhat different spectrum of biochemical actions. Like methotrexate, it inhibits DHFR, but as a poly glutamate, even more potently inhibits glycinamide ribonucleotide formyltransferase (GART) and TS. Unlike methotrexate, it produces little change in the pool of reduced folates, indicating that the distal sites of inhibition (TS and GART) predominate. Its pattern of deoxynucleotide depletion also differs, with little effect on deoxyadenosine triphosphate (dATP), a profile more characteristic of primary TS inhibition. 

If the sugar is deoxyribose rather than ribose, the nucleoside has "deoxy" as a prefix (e.g., deoxyadenosine). Nuoleotides are given the name of the nucleoside plus mono, di, or triphosphate (e.g., adenosine triphosphate or deoxyadenosine triphosphate). 

Radioactive sulfur isotope linked to deoxyadenosine triphosphate S-nitroso-A -acetyl-D, L-penicUlamine Thyrotropin-releasing hormone Thyroid-stimulating hormone Vasoactive intestinal peptide... 

Pentostatin (Fig. 42.25) is a ring-expanded purine ribonuoleoside that inhibits adenosine deaminase and is used in the treatment of hairy cell leukemia. The elevated levels of deoxyadenosine triphosphate that result from inhibition of this degradative enzyme inhibit the action of ribonucleotide reductase (the enzyme that converts ribose diphosphate to deoxyribose diphosphate), thus halting DNA synthesis within the tumor cell. 

Antimetabolites may also inhibit the synthesis of cofactors and substrates required for purine bios mthesis. As mentioned above (Chapter 6), PP-ribose-P s3mthesis can be inhibited by 3 -deoxyadenosine triphosphate. 

Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency, Proc. Natl. Acad. Sci. USA, 75 472. 

There are three plausible mechanisma to explain malaria parasite killing following vivo deoxycoformycin inhibition of ADA. First, there could be an IE deficiency of the catabolite hypoxanthine which is needed by the parasite for nucleotide synthesis. Second, there may be direct toxicity to critical parasite enzymes from accumulated adenosine or deoxyadenosine. Increased levels of 2 -deoxyadenosine, for example, have been shown to irreversibly inactivate S-adenosylhomocysteine hydrolase due to accumulation of S-adenosylhomocysteine which inhibits methyltrans-ferase reactions (9). Third, there could be an accumulation of deoxyadenosine triphosphate, dATP, such as has been observed in ADA associated severe combined immunodeficiency disease (SCID) CIO). DeoxyATP could act to inhibit ribonucleotide reductase and thereby interfere with DNA synthesis (11). In line with this third mechanism we observed an accumulation of both dADP and dATP in nucleotide profiles (24 hr) of PEBC following in vivo 2 -deoxycof ormycin treatment of the IP. knowlesi infected rhesus monkeys. 

Michailidis E, Marchand B, Kodama EN (2009) Mechanism of inhibition of HIV-1 reverse transcriptase by 4 -ethynyl-2-fluoro-2 -deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. J Biol Chem 284 35681-35691... 

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