Acidity of Adenine and Adenine Derivatives and Biological Implications. A Computational and Experimental Gas-Phase Study

Sharma, Seema; Lee, Jeehiun K.

doi:10.1021/jo0204303

Cited by 44 publications

(152 citation statements)

References 62 publications

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“…22 Thus, as indicated by previous studies, gas-phase acidities can be informative regarding the leaving ability of a nucleobase within a hydrophobic active site, and may be relevant to the mechanism of substrate discrimination. 44,71 We therefore examined the dependence of hTDG activity on N1 acidity in a non-polar environment by calculating the gas phase N1 acidities of the nucleobases at 298 K (ΔG acid,g , Table S1, Supporting Information). (For comparison with other studies, the more commonly reported deprotonation enthalpies at 0 and 298 K are also given).…”

Section: Linear Free Energy Relationships For N-glycosidic Bond Hydromentioning

confidence: 99%

Specificity of Human Thymine DNA Glycosylase Depends on N-Glycosidic Bond Stability

et al. 2006

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Initiating the DNA base excision repair pathway, DNA glycosylases find and hydrolytically excise damaged bases from DNA. While some DNA glycosylases exhibit narrow specificity, others remove multiple forms of damage. Human thymine DNA glycosylase (hTDG) cleaves thymine from mutagenic G·T mispairs and recognizes many additional lesions, and has a strong preference for nucleobases paired with guanine rather than adenine. Yet, hTDG avoids cytosine, despite the millionfold excess of normal G·C pairs over G·T mispairs. The mechanism of this remarkable and essential specificity has remained obscure. Here, we examine the possibility that hTDG specificity depends on the stability of the scissile base-sugar bond by determining the maximal activity (k max ) against a series of nucleobases with varying leaving group ability. We find that hTDG removes 5-fluorouracil 78-fold faster than uracil and 5-chlorouracil 572-fold faster than thymine, differences that can be attributed predominantly to leaving group ability. Moreover, hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. A plot of log(k max ) versus leaving group pK a reveals a Brønsted-type linear free energy relationship with a large negative slope of β lg = −1.6 ± 0.2, consistent with a highly dissociative reaction mechanism. Further, we find that the hydrophobic active site of hTDG contributes to its specificity by enhancing the inherent differences in substrate reactivity. Thus, hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site.

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Section: Linear Free Energy Relationships For N-glycosidic Bond Hydromentioning

confidence: 99%

Specificity of Human Thymine DNA Glycosylase Depends on N-Glycosidic Bond Stability

et al. 2006

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“…Chen et al 8 measured a GPA of 14.1 eV (325.2 kcal/mol) for the most acidic site of gaseous adenine by using negative chemical ionization mass spectrometry. Lee et al 9 recently measured the gas-phase acidities of N9 and the NH 2 group by bracketing the gas-phase acidities (also in terms of deprotonation ∆H) of adenine, 9-ethyladenine, and 3-methyladenine by using a dualcell Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR). They concluded that 9H-adenine has two acidic sites: N9 and NH 2 .…”

Section: Introductionmentioning

confidence: 99%

Theoretical Estimations of the 298 K Gas-Phase Acidities of the Purine-Based Nucleobases Adenine and Guanine

Huang

Kenttämaa

2004

J. Phys. Chem. A

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Theoretical estimations at both the B3LYP/6-31+G(d)//B3LYP/6-31+G(d) and B3LYP/aug-cc-pVTZ// B3LYP/6-31+G(d) levels for the 298 K gas-phase acidities (GPA) of all the possible deprotonation sites of the most stable tautomers of adenine and guanine are reported in terms of the enthalpy change of deprotonation. The gas-phase acidities of the nucleobases estimated by direct calculations and derived from isodesmic reactions are very similar. At the B3LYP/aug-cc-pVTZ//B3LYP/6-31+G(d) level of theory, for the most stable adenine tautomer, 9H-adenine, the GPAs of N9, N4-H a , N4-H b , C8, and C2 sites are 337.8 ( 2.1, 355.6 ( 2.1, 355.3 ( 2.1, 375.7 ( 0.5, and 401.2 ( 0.5 kcal/mol, respectively. For the most stable guanine tautomer, 7H-keto-guanine, the GPAs of N3, N7, N2-H a , N2-H b , and C8 sites are 336.4 ( 2.2, 338.0 ( 2.1, 347.7 ( 2.1, 341.9 ( 2.1, and 376.0 ( 0.5 kcal/mol, respectively. For the second most stable tautomer, 9H-ketoguanine, the GPAs of N3, N9, N2-H a , N2-H b , and C8 are 338.6 ( 2.2, 337.4 ( 2.1, 343.8 ( 2.1, 338.4 ( 2.1, and 379.9 ( 0.5 kcal/mol, respectively. The GPAs of N9, hydroxyl group, N2-H a , N2-H b , and C8 of 9H-cis-enol guanine are 338.7 ( 2.1, 340.2 ( 2.1, 358.0 ( 2.1, 357.7 ( 2.1, and 378.3 ( 0.5 kcal/mol, respectively. The corresponding GPAs of 9H-trans-enol guanine are 336.5 ( 2.1, 339.8 ( 2.1, 359.1( 2.1, 359.5 ( 2.1, and 374.6 ( 0.5 kcal/mol, respectively. The errors given above are based on the experimental uncertainty in the reference values used in calculations involving isodesmic reactions. In general, N9 is the most acidic site for 9H-adenine, followed by the amino group, while C2 is the least acidic site. For both 7H-keto-and 9H-keto-guanine, N3 and N7 (or N9) are the most acidic sites, followed by the amino group. For enol guanine tautomers, N9 is the most acidic site, followed by the hydroxyl group and the amino group. For all guanine tautomers mentioned above, C8 is the least acidic site. Differing from the situation of 9H-adenine and 9H-enol guanine, the acidities of the two amino group hydrogen atoms are significantly different in 7H-keto-and 9H-keto-guanine.

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“…In this research, we conducted quantum mechanical computations aiming at quantifying the effects of structural variations in adenine on the hydrogen bonding interaction (pairing) with thymine. As already discussed in the introductory section, derivatives of the nucleobases have been shown to possess biological activities and potential for clinical applications [16][17][18][19][20][21][22][23][24][25][26][27][28]. It was also of interest to analyze the impact of structural changes on the geometries of the formed complexes.…”

Section: Resultsmentioning

confidence: 99%

“…Experimental and theoretical investigations on hydrogen bonding involving structural fragments of biopolymers are the subject of continuing interest [12][13][14][15]. Literature data reveal that structurally modified DNA bases may possess substantial biological activity [16][17][18][19][20][21][22][23][24][25][26][27][28]. For example, halogenated pyrimidines have been shown to possess well-expressed anti-tumor, anti-bacterial and anti-viral effects [20].…”

Section: Introductionmentioning

confidence: 99%

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Effects of structural variations on the hydrogen bond pairing between adenine derivatives and thymine

Nikolova¹,

Galabov²

2015

Maced. J. Chem. Chem. Eng.

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The hydrogen bonding between substituted adenines and thymine was investigated by density functional theory computations at the B3LYP/6-311+G(2d,2p) level. The effect of 20 different polar substituents at position 8 in adenine was examined in detail. Three different theoretical parameters, reflecting the electrostatics at the atoms involved in hydrogen bonding, were applied. An excellent correlation between electrostatic potentials at the bonding atoms in the monomer adenines and interaction energies was derived (Eqn. 2). It can be employed in designing bioactive adenine derivatives that are able to bind with a finely adjusted strength to thymine bioreceptor sites. NBO and Hirshfeld atomic charges are found to be less successful as reactivity predictors in these interactions.Keywords: DNA base pair; adenine; thymine; hydrogen bonding; electrostatic potential; atomic charges ЕФЕКТИ НА СТРУКТУРНИТЕ ВАРИЈАЦИИ ВРЗ СПАРУВАЊЕТО НА АДЕНИНСКИ ДЕРИВАТИ И ТИМИН СО ПОМОШ НА ВОДОРОДНО СВРЗУВАЊЕИстражувано е водородното сврзување помеѓу супституирани аденини и тимин со помош на пресметки според теоријата за функционал на електронската густина на нивото B3LYP/6-311+G(2d,2p). Детално е изучуван ефектот на 20 различни поларни супституенти на аденин во позицијата 8. Применети се три различни теоретски параметри кои ја рефлектираат електростатиката на атомите вклучени во водородното сврзување. Добиена е одлична корелација помеѓу електростатските потенцијали на сврзувачките атоми во мономерните аденини и интеракционите енергии (р-ка 2). Тоа може да се примени при дизајнирање на биоактивни аденински деривати кои можат да се сврзат со фино нагодена јачина со тиминските биорецепторски сајтови. Најдено е дека т.н. NBO и Хиршфилдовите (Hirshfeld) атомски полнежи се помалку успешни како претскажувачи на реактивноста во овие интеракции.Клучни зборови: ДНК базен пар; аденин; тимин; водородно сврзување; електростатски потенцијал; атомски полнежи  Dedicated to Academician Gligor Jovanovski on the occasion of his 70 th birthday.

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Acidity of Adenine and Adenine Derivatives and Biological Implications. A Computational and Experimental Gas-Phase Study

Cited by 44 publications

References 62 publications

Specificity of Human Thymine DNA Glycosylase Depends on N-Glycosidic Bond Stability

Specificity of Human Thymine DNA Glycosylase Depends on N-Glycosidic Bond Stability

Theoretical Estimations of the 298 K Gas-Phase Acidities of the Purine-Based Nucleobases Adenine and Guanine

Effects of structural variations on the hydrogen bond pairing between adenine derivatives and thymine

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