Studies on the specificity and mechanism of action of adenosine deaminase

Baer, Hans P.; Drummond, George I.; Gillis, Jean

doi:10.1016/0003-9861(68)90116-1

Cited by 45 publications

(27 citation statements)

References 15 publications

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“…However, ~20% of O 6 -Me-dG in the DNA digest was demethylated by adenosine deaminase (unpublished studies, J. Guo). Adenine deaminase possesses O 6 -demethylase activity, 44 and the hydrolysis of various groups at the 6-position of purine ribonucleosides, including 6-methoxyguanosine, by adenosine deaminase, has been reported by Baer and coworkers. 44 However, adenosine deaminase treatment had no effect on the level of O 6 -POB-dG (unpublished studies, J. Guo).…”

Section: Discussionmentioning

confidence: 95%

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Multiclass Carcinogenic DNA Adduct Quantification in Formalin-Fixed Paraffin-Embedded Tissues by Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

et al. 2016

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DNA adducts are a measure of internal exposure to genotoxicants and an important biomarker for human risk assessment. However, the employment of DNA adducts as biomarkers in human studies is often restricted because fresh frozen tissues are not available. In contrast, formalin-fixed paraffin embedded (FFPE) tissues with clinical diagnosis are readily accessible. Recently, our laboratory reported that DNA adducts of aristolochic acid, a carcinogenic component of Aristolochia herbs used in traditional Chinese medicines world-wide, can be recovered quantitatively from FFPE tissues. In this study, we have evaluated the efficacy of our method for retrieval of DNA adducts from archived tissue by measuring DNA adducts derived from four other classes of human carcinogens: polycyclic aromatic hydrocarbons (PAHs), aromatic amines, heterocyclic aromatic amines (HAAs), and N-nitroso compounds (NOCs). The deoxyguanosine (dG) adducts of the PAH benzo[a]pyrene (B[a]P), 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-benzo[a]pyrene (dG-N2-B[a]PDE); the aromatic amine 4-aminobiphenyl (4-ABP), N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP); the HAA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP); and the dG adducts of the NOC, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), O6-methyl-dG (O6-Me-dG) and O6-pyridyloxobutyl-dG (O6-POB-dG) formed in liver, lung, bladder, pancreas, or colon were recovered in comparable yields from fresh frozen and FFPE preserved tissues of rodents treated with the procarcinogens. Quantification was achieved by Ultra-Performance Liquid Chromatography-Electrospray Ionization-Ion Trap-Multistage Mass Spectrometry (UPLC-ESI-IT-MS3). These advancements in the technology of DNA adduct retrieval from FFPE tissue clear the way for the use of archived pathology samples in molecular epidemiology studies designed to assess the causal role of exposures to hazardous chemicals with cancer risk.

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Section: Discussionmentioning

confidence: 95%

“…44 O 6 -Me-dG and O 6 -POB-dG were enriched by a Strata-X SPE cartridge pre-conditioned with CH 3 OH and H 2 O before sample loading. The DNA digest was washed with H 2 O (2 mL), 10% CH 3 OH (1 mL), 25% CH 3 OH (2× 1 mL), and adducts were eluted with CH 3 OH (1 mL).…”

Section: Methodsmentioning

confidence: 99%

Multiclass Carcinogenic DNA Adduct Quantification in Formalin-Fixed Paraffin-Embedded Tissues by Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

et al. 2016

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“…The enzyme adenosine deaminase (ADA), which is present at high concentrations in human serum, is involved in the catabolism of dA and its analogs (27,28). ADA is responsible for the deamination of adenosine or deoxyadenosine analogs to inosine-or deoxyinosine-based products (27,(29)(30)(31)(32)(33) and can therefore affect the activation pathway and intracellular concentration of dA-based compounds. For example, ADA converts dideoxyadenosine (ddA) to ddI, leading to a different and indirect activation pathway for ddA (28,34,35).…”

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confidence: 99%

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Kirby

Michailidis

Fetterly

et al. 2013

Antimicrob Agents Chemother

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i Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) is a highly effective NRTI; however, the reasons for the potent antiviral activity of EFdA are not well understood. Here, we use a combination of structural, computational, and biochemical approaches to examine how substitutions in the sugar or adenine rings affect the incorporation of dA-based NRTIs like EFdA into DNA by HIV RT and their susceptibility to deamination by adenosine deaminase (ADA). Nuclear magnetic resonance (NMR) spectroscopy studies of 4=-substituted NRTIs show that ethynyl or cyano groups stabilize the sugar ring in the C-2=-exo/C-3=-endo (north) conformation. Steady-state kinetic analysis of the incorporation of 4=-substituted NRTIs by RT reveals a correlation between the north conformation of the NRTI sugar ring and efficiency of incorporation into the nascent DNA strand. Structural analysis and the kinetics of deamination by ADA demonstrate that 4=-ethynyl and cyano substitutions decrease the susceptibility of adenosinebased compounds to ADA through steric interactions at the active site. However, the major determinant for decreased susceptibility to ADA is the 2-halo substitution, which alters the pK a of N1 on the adenine base. These results provide insight into how NRTI structural attributes affect their antiviral activities through their interactions with the RT and ADA active sites. There are 10 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) that are currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infections (1-5). Several more nucleoside analog drugs are approved or being studied for the treatment of viruses, such as herpes simplex virus (HSV), hepatitis C virus (HCV), and hepatitis B virus (HBV), or as anticancer agents (6-10). NRTIs are among the most effective anti-HIV drugs. All approved anti-HIV NRTIs lack a 3=-hydroxyl moiety and, thus, act as chain terminators following their incorporation by the viral reverse transcriptase (RT) into the nascent DNA chain. However, the absence of a 3=-OH, while essential for the inhibition of DNA synthesis, also imparts detrimental properties to these inhibitors, including reduced intracellular phosphorylation to the active triphosphate form and reduced RT binding affinity (11). Prolonged exposure to NRTI-based treatments causes mitochondrial toxicity (12-14) and leads to the development of NRTI resistance mutations (15-18), giving rise to complications in the treatment of HIV-infected patients.Ideally, an NRTI should have a strong binding affinity for the RT target, a high barrier for the development of resistance, and low toxicity. We have reported that a series of 4=-substituted nucleosides in which the 3=-OH is retained has exceptional inhibitory activity against HIV-1 RT (19). Among these compounds, 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) is a highly active RT inhibitor that prevents translocation of the nucleic acid from the n...

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“…These enzymes have some properties in common, but according to the published reports follow different kinetic mechanisms [Baer et al, 1968;Orsi et al, 1972] and show different thermodynamic properties [Hoagland and Fisher, 1967], With regard to some catalytic properties (pH profile, Km and cofactor requirements) the enzyme from bovine skeletal muscle is similar to that isolated from a number of other sources and it even appears to require a thiol residue for full activity as other aminohydrolases [Pfrogner, 1967;Orsi et al, 1972]. In spite of these similarities, it is pos sible that bovine skeletal muscle adenosine Since 1939, when it was first identified in human erythrocytes by Conway and Cooke, adenosine deaminase (adenosine aminohy drolase, EC 3.5.4.4) has been isolated from a wide variety of microorganisms, plants and animal tissues such as chicken duodenum [Hoagland and Fisher, 1967] and liver [Ma and Fisher, 1968], calf intestine [Brady and O'Connell, 1962] and spleen [Pfrogner, 1967], etc.…”

Section: Introductionmentioning

confidence: 99%

“…Most of the kinetic and thermodynamic data until now reported for the adenosine deaminases have been obtained with calf du odenum [Orsi et al, 1972;Baer et al, 1968], chickèn duodenum [Hoagland and Fisher, deaminase shows, as the above mentioned enzymes, substantial differences with respect to the reaction mechanism and thermody namic parameters.…”

Section: Introductionmentioning

confidence: 99%

Bovine Skeletal Muscle Adenosine Deaminase: Kinetic and Thermodynamic Studies

Martínez

Jm²,

Diez³

1988

Enzyme

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Adenosine deaminase from bovine skeletal muscle catalyzes the hydrolytic deamination of adenosine to inosine and ammonia via an ordered Uni-Bi mechanism, if water is not considered as a true second substrate, as deduced from the inhibition pattern products. The inhibition constants (K(i)) obtained for inosine and ammonia were 316 jxmol/l and 2 mol/1, respectively. The activation energy of the reaction has been calculated as 10 kcal/mol, ΔH* and ΔF* as 7.9 and 15.6 kcal/mol, respectively, and ΔS* as-23 cal/mol/°K.

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Studies on the specificity and mechanism of action of adenosine deaminase

Cited by 45 publications

References 15 publications

Multiclass Carcinogenic DNA Adduct Quantification in Formalin-Fixed Paraffin-Embedded Tissues by Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

Multiclass Carcinogenic DNA Adduct Quantification in Formalin-Fixed Paraffin-Embedded Tissues by Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Bovine Skeletal Muscle Adenosine Deaminase: Kinetic and Thermodynamic Studies

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