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Isoguanine Formation from Adenine

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Isoguanine Formation from Adenine FULL PAPER DOI: 10.1002/chem.201102415 Isoguanine Formation from Adenine Qianyi Cheng,[a] Jiande Gu,*[b] Katherine R. Compaan,[a] and Henry F. Schaefer, III*[a] Abstract: Several possible mechanisms tautomer (isoG1 or isoG2). The local favored. The other option is indirect underlying isoguanine formation when and activation barriers for the two hydrogen transfer involving microsol- OH radical attacks the C2 position of pathways are very similar. This evi- vation by one water molecule. The adenine (AC2) are investigated theoreti- dence suggests that the two pathways water lowers the reaction barrier by cally for the first time. Two steps are are competitive. After dehydrogena- over 20 kcalmolÀ1, indicating that involved in this process. In the first tion, there are two possible routes for water-mediated hydrogen transfer is C step, one of two low-lying AC2···OH re- the second step of the reaction. One is much more favorable. Both A+ OH ! actant complexes is formed, leading to direct hydrogen transfer, via enol–keto isoG+ HC reactions are exothermic and C2ÀH2 bond cleavage. Between the two tautomerization, which has high local spontaneous. Among four isoguanine reactant complexes there is a small iso- barriers for both tautomers and is not tautomers, isoG1 has the lowest merization barrier, which lies well energy. Our findings explain why only below separated adenine plus OH radi- the N H and O H tautomers of isolated Keywords: adenine · nucleobases · 1 2 cal. The complex dissociates to free isoguanine and isoguanosine have been radicals · tautomerization molecular hydrogen and an isoguanine observed experimentally. Introduction pair with a non-standard hydrogen-bonding pattern. They can formally only pair with each other, not with other nucle- Isoguanine is one of the components in the non-standard obases.[10] It is thought that this base pair makes ribonucleic isoguanine·isocytosine base pair, and it naturally occurs in acids more versatile as catalysts by adding diversity to the butterfly wings,[1,2] croton beans,[3,4] and mollusks.[5] It was structure,[11] and expands the genetic alphabet.[12,13] DNA first isolated by Cherbuliez and Bernhard in 1932 from the containing a string of isoguanine forms a stable parallel tet- croton bean.[3] Isoguanine exists as the aglycone fragment of raplex structure,[14] and it may contribute to an extracellular the glycoside 2-oxy-6-aminopurine-d-riboside.[3,4,6] Oxidation growth factor containing RNA.[15] of adenine to isoguanine was proposed based on studies of Isoguanine, isoguanine derivatives[16–19] and isoguanosine purine metabolism[7] and direct oxidation of adenine[8] in derivatives[10, 20–22] have been synthesized, and they are con- vivo, during Browns mechanistic studies of the conversion sidered to be involved in DNA lesions. These studies also of adenine to guanine.[9] A scheme involving the oxidation suggest that the formation of isoguanine from adenine plays of adenine at the C2 position was suggested by Bendich and an important role in A!T and A!C transversions in cellu- co-workers.[8] However, the detailed mechanism is unknown. lar DNA,[17–19] inducing mutations at various stages of In the standard Watson–Crick base pairing scheme, ade- cancer.[19] Thus, isoguanine is one important form of DNA nine (A) pairs with thymine (T) and guanine (G) pairs with damage produced by reactive oxygen species. Understanding cytosine (C) via hydrogen-bonding. These form the two nat- the detailed mechanism of formation of isoguanine from ad- ural base pairs in DNA that stabilize its double helix struc- enine could aid in studying DNA damage and understanding ture. However, isoguanine (2-hydroxyladenine or isoG) and human longevity. Reactions of OH radicals with adenine isocytosine (2-aminouracil or isoC) form an interesting base have been studied experimentally,[23–27] but most of the at- tention has been focused on the C4,C5, and C8 positions. An C experimental investigation of direct OH addition at the C2 position was carried out by 60Co g-irradiating aqueous solu- [a] Dr. Q. Cheng, K. R. Compaan, Prof. Dr. H. F. Schaefer, III m m 3À tions containing 0.1–1.0 m adenine, 0.0–1.0 m Fe(CN)6 , Center for Computational Quantum Chemistry m University of Georgia, Athens, GA 30602 (USA) and 1.0 m phosphate (pH 7), which were saturated with [25] E-mail: [email protected] N2O. HPLC with electrochemical detection revealed no [b] Dr. J. Gu isoguanine. Taking the radiation dose and detection limit Drug Design & Discovery Center into account, they estimated that no more than 2% of the State Key Laboratory of Drug Research C OH radicals add at C2. However, one possible mechanism Shanghai Institute of Materia Medica of this rare reaction has been mentioned. It is analogous to Shanghai Institutes for Biological Sciences, CAS C C Shanghai 201203 (P. R. China) the conversion of A8-OH , which is formed by OH addition [25] E-mail: [email protected] directly at C8, to 8-OH-A by losing a hydrogen atom. The Chem. Eur. J. 2012, 18, 4877 – 4886 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4877 tautomerization following the formation of 2-OH-A (isogua- ies[46] of a wide range of electron affinities. In the present nine) is also of great interest. Keto (N1H, N3H)–enol (O2H) study, for purposes of reproducibility, there are 220 contract- tautomerism of 9-substituted isoguanosine has been exam- ed functions for the adenine molecule, 245 functions for ad- ined by UV absorption spectra at low pK1 in aqueous enine-OH complexes, 270 functions for adenine-2OH com- medium. N1H has a long wavelength absorption near plexes, and 239 functions for isoguanine molecule and its 310 nm, and the enol form absorbs around 270 nm.[28] tautomers. Neutral adenine[29] and five dehydrogenated adenine radi- Optimized geometries, harmonic vibrational frequen- cal derivatives[30] have been studied theoretically. However, cies,[47–49] and intrinsic reaction coordinates (IRC)[50–53] were there are few studies on adenine and OH radical reactions. computed with the QChem 3.2 package.[54] A 1998 study reported the relative energies of four hydroxy- lated adenine species.[31] In 2010, Cheng and co-workers ex- amined the dehydrogenation of adenine by COH using densi- Results and Discussion ty functional theory (DFT).[32] From their work, it is clear that OH radical attacking the C2 position is energetically fa- The structure and numbering Scheme for adenine are shown vorable, evidenced by formation of a low energy in Figure 1. Isoguanine N1H and N3H tautomers are also [32] A(C2)···OH complex. Based on the extremely high local shown in Figure 1, adopting numbering similar to adenine. C reaction barrier, dehydrogenation [(A-H) +H2O] of this complex is unlikely. Instead of dehydrogenation, the present mechanistic study reveals the possible formation of isogua- nine from this adenine starting complex, as well as the tau- tomerization between several isoguanine tautomers. These results should give new insights into related biochemical ex- periments. Theoretical Methods The generalized gradient approximation exchange-correla- tion B3LYP functional was employed in this work, which is a combination of Beckes 3-parameter HF/DFT hybrid ex- change functional (B3)[33] with the dynamical correlation functional of Lee, Yang, and Parr (LYP).[34] This method has been used in various DNA related computational studies, and has provided reasonable results for DNA bases, base pairs, and anions.[31,35–44] The B3LYP method is adopted along with double-z quali- ty basis sets with polarization and diffuse functions (denoted Figure 1. IUPAC numbering of atoms for adenine, similar numbering as DZP + +). The DZP+ + basis sets are generated by aug- adopted for isoguanine N1H and N3H tautomers. menting the Huzinaga–Dunning set of contracted double-z Gaussian functions with one set of p-type polarization func- tions for each H atom and one set of five d-type polarization functions for each first-row atom. Besides that, one even- Hydroxyl radical attacks adenine C2: When hydroxyl radical tempered diffuse s function was added to each H atom, attacks the C2–H2 region of adenine, it may be more favor- ACHTUNGRE while even-tempered s and p diffuse functions were centered able for the electron-rich oxygen to attack the C2 atom, on every heavy atom to complete the DZP + + basis. The which is more positively charged than the hydrogen. Seven even-tempered orbital exponents were determined accord- intermediate AC2···OH complexes, including three transition ing to the prescription of Lee:[45] states, are shown in Figure 2. The numbering schemes corre- spond to increasing energy, relative to separated A and OH À1 adiffuse ¼ 1=2 ða1=a2 þ a2=a3Þa1 ð1Þ radical. All energies are in kcalmol , with ZPVE corrected values in parentheses. A summary of the relative energies is where a1, a2, and a3 are the three smallest Gaussian orbital presented in Table 1. exponents of the s- or p-type primitive functions for a given Complexes 1 and 2 may be formed immediately in the atom (a1 <a2 <a3). The final DZP + + set contains six func- OH adenine reaction, since both of them lie much lower in tions per H atom (5s1p/3s1p) and nineteen functions per C, energy than separated reactants A plus OH. Between the N, or O atom (10s6p1d/5s3p1d). This combination of func- two complexes, there is a transition state TS1 along the iso- tionals and basis sets has the tactical advantage that it has merization path. This reaction (1!TS1!2) is displayed in previously been used in comprehensive benchmark stud- Figure 3. Following the formation of 1 or 2, dehydrogenation 4878 www.chemeurj.org 2012 Wiley-VCH Verlag GmbH & Co.
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