Theoretical Study of the Effects of Amino Acids on. One-electron Oxidation of a Nucleobase: Adenine Residue Can be a Hole-trapping Site

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Pure and Applied Chemical Sciences, Vol. 2, 2014, no. 1, HIKARI Ltd, Theoretical Study of the Effects of Amino Acids on One-electron Oxidation
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Pure and Applied Chemical Sciences, Vol. 2, 2014, no. 1, HIKARI Ltd, Theoretical Study of the Effects of Amino Acids on One-electron Oxidation of a ucleobase: Adenine Residue Can be a Hole-trapping Site Kazutaka Hirakawa* Department of Applied Chemistry and Biochemical Engineering Graduate School of Engineering, Shizuoka University Johoku 3-5-1, aka-ku, Hamamatsu, Shizuoka , Japan Mami Yoshida Department of Radiation Chemistry and Radioprotection Life Science Research Center, Mie University Edobashi 2-174, Tsu, Mie , Japan Copyright 2014 Kazutaka Hirakawa and Mami Yoshida. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract DA damage by oxidative stress has been extensively investigated, but the effect of interaction with histone protein on the DA oxidation has not been well-understood. The effects of amino acids on DA oxidation induced by one-electron oxidants were examined by ab initio molecular orbital calculation at Hartree-Fock 6-31G* level. The calculated ionization potentials of nucleobases suggest that guanine is protected by interaction with amino acids from oxidative damage, whereas oxidation of adenine is enhanced through interaction with several kinds of amino acids. These findings suggest that adenine can be easily oxidized under the interaction with certain amino acid in chromatin rather than guanine, which can be most easily oxidized in isolated DA. The effect of amino acids on DA oxidation may explain the mutation at adenine residue induced by oxidative stress due to ultraviolet A irradiation. Keywords: Ab initio molecular orbital calculation, Ionization potential, DA damage, Amino acid, Oxidation 42 Kazutaka Hirakawa and Mami Yoshida 1 Introduction DA damage caused by one-electron oxidation of nucleobases has been extensively studied from the viewpoint of mutagenesis and carcinogenesis [1-5]. Since guanine is the most easily oxidized base among DA nucleobases, the guanine radical cation is the initial product of DA one-electron oxidation in a wide variety of isolated DA systems [1-5]. The electron-loss center created in a DA duplex by one-electron oxidation ultimately moves to end up at the hole-trapping site via hole migration through the DA π-stack [2,5-8]. Various experimental [4,9-12] and theoretical [13,14] studies have revealed that GG, GGG, and GGGG sequences can be the hole-trapping site in the B-form DA, leading to the formation of oxidative products of guanine. However, the approach to evaluate the genomic DA damage has not been well established. Genomic DA is packed into nucleosomes that further fold to form a higher-order chromatin structure. Therefore, the interaction between a nucleobase and an amino acid of a histone protein should play an important role in the oxidation of a nucleobase in vivo [15]. Indeed, oxidative DA damage in vivo cannot be completely explained from the result of the study using isolated DA systems [16,17]. In this study, the effect of an amino acid on DA oxidation was examined using an ab initio molecular orbital (MO) calculation. 2 Methods The ab initio MO calculations at the Hartree-Fock 6-31G* level were performed to elucidate the effect of amino acid on the ionization potential (IP) of nucleobases using Spartan 02 for Windows (Wavefunction Inc., CA, USA). The geometry of adenine-thymine (A-T) and guanine-cytosine (G-C) base pairs was constructed using Spartan 02 with standard B-form geometrical parameters optimized by the X-ray crystallographic analysis of relevant monomers and X-ray diffraction data of a polymer [18,19]. All the sugar backbones were replaced by methyl groups, keeping the position of all the atoms fixed. The equilibrium geometry of amino acid, which approaches the A-T or G-C base pair from the inter-planer direction, as shown in Fig. 1, was determined using molecular mechanics calculation. The geometry of base pairs was fixed during the calculation. Theoretical study of the effects of amino acids 43 Figure 1 Scheme of the calculation model of the interaction between the nucleobase and the amino acid. Table 1 Calculated IP (ev) of nucleobases associated with amino acids without interaction Gly Ala Val Leu Pro Tyr Gln Asp Glu Arg A T G C ±0.00 The italics indicate the IP difference between the nucleobase associated with the amino acid and that without interaction. 44 Kazutaka Hirakawa and Mami Yoshida 3 Results and Discussion The histone protein is commonly composed of the amino acids listed in Table 1 [20]. Table 1 shows the calculated IP of nucleobases associated with the amino acids. The IPs of adenine and guanine in all models are lower than those of thymine and cytosine, respectively, indicating that adenine or guanine can be the hole-trapping site in a DA-amino acid system, rather than thymine and cytosine. The IP of guanine associated with each amino acid becomes larger than that without an amino acid, showing that the interaction with an amino acid results in protection of guanine from oxidation. On the other hand, the IP of adenine was lowered by the interaction with glycine, alanine, tyrosine, glutamine, asparagine, glutamic acid, and arginine, showing that the amino acid can enhance the oxidation of adenine. Especially, the IP of adenine associated with arginine is lower than that of guanine. The IP of adenine monotonically decreased with a shortening of the distance between nucleobase and arginine, whereas that of guanine increased (Fig. 2). O O H2 CH C OH H2 CH C OH CH2 CH2 CH2 CH 2 Arg CH2 CH 2 Arg H H H2 C H2 C H H O d/å H 2 d/å H H2 G CH3 A CH3 Adenine IP / ev Guanine d / Å Figure 2 Calculated IPs of adenine and guanine interacted with arginine. Theoretical study of the effects of amino acids 45 Although these calculations were based on the simplified model, the obtained results qualitatively demonstrated that the effect of interaction between adenine and arginine is quite different from that of guanine. The calculation of the equilibrium geometry of an intermolecular complex between base pairs and arginine showed their complexes through hydrogen bonding (Fig. 3). These calculations suggest that lowering the IP of adenine is due to the proton-donating character of the amino group of adenine through hydrogen bonding with the amino acid. Similarly, the increase of the IP of guanine should be due to the proton-accepting character of the carbonyl O and the -7 of guanine in the hydrogen bonding with the amino acid. These results suggest that partly denatured site of DA strand might be also a hole-trapping site through the interaction with amino acid. Figure 3 Equilibrium geometry of intermolecular complexes between arginine and guanine or adenine. In general, a guanine radical cation is finally formed through hole migration, when one-electron oxidation in isolated DA is induced by an oxidant, such as a photoexcited photosensitizer. The present study has shown that the oxidation potential of an adenine residue may become lower than the neighboring guanine residues by interaction with a histone protein. Thus, a nucleobase radical cation formed in DA may be finally localized on an adenine residue through hole migration or direct oxidation under certain conditions. Similarly to the reaction of a guanine radical cation [1,3], the formed adenine radical cation might react with a water molecule to form the C-8 OH adduct radical, followed by oxidation, leading to 8-oxo-7,8-dihydroadenine (8-oxo-A) [1]. An ab initio MO calculation has shown that 8-oxo-A forms a stable base pair with G (Fig. 4, formation enthalpy: ΔH= kcal mol -1 ), which is comparable to the Watson-Crick A-T base pair (ΔH= kcal mol -1 ) and may cause an A-T C-G transversion. 46 Kazutaka Hirakawa and Mami Yoshida UVA radiation induces DA oxidation through Type I (electron transfer) and Type II (singlet oxygen) mechanisms by activation of various endogenous photosensitizers [1-5,10-12] because UVA is hardly absorbed by DA. UVA frequently induces A-T C-G transversion, rather than G-C T-A and G-C C-G transversions [16,17]. Thus, the oxidation of adenine associated with amino acids may play an important role in UVA-induced mutation. The mutation at adenine residue by UVA could not be explained from the experimental and theoretical studies using isolated DA. Figure 4 Calculated equilibrium geometry of a G : 8-oxo-A base pair. 4 Conclusions In summary, this study suggests that adenine associated with a certain amino acid can be easily oxidized and is comparable to guanine in chromatin DA. The lowering of IP of adenine is possibly due to the proton-donating character of the amino group of adenine through hydrogen bonding with the amino acid. UVA-induced mutation at adenine residue may be explained by the enhancement of oxidation of adenine by an interaction with the amino acid of histone protein. Acknowledgements. The presented work was partially supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of the Japanese Government. References [1] C.J. Burrows and J.G. Muller, Oxidative nucleobase modifications leading to strand scission, Chemical Reviews, 98 (1998), [2] F.D. Lewis and Y. Wu, Dynamics of superexchange photoinduced electron transfer in duplex DA, Journal of Photochemistry and Photobiology C: Photochemistry Reviews, 2 (2001), 1-16. Theoretical study of the effects of amino acids 47 [3] J.-L. Ravanat, T. Douki and J. Cadet, Direct and indirect effects of UV radiation on DA and its components, Journal of Photochemistry and Photobiology B: Biology, 63 (2001), [4] S. Kawanishi, Y. Hiraku and S. Oikawa, Mechanism of guanine-specific DA damage by oxidative stress and its role in carcinogenesis and aging, Mutation Research, 488 (2001), [5] K. Hirakawa, DA damage through photo-induced electron transfer and photosensitized generation of reactive oxygen species, in ew Research on DA damage, ed. by H. Kimura and A. Suzuki, ova Science Publishers, ew York, Chapter 9, pp , [6] D.B. Hall, R.E. Holmlin and J.K. Barton, Oxidative DA damage through long-range electron transfer, ature, 382 (1996), [7] R.. Barnett, C.L. Cleveland, A. Joy, U. Landman and G.B. Schuster, Charge migration in DA: ion-gated transport, Science, 294 (2001), [8] M. Bixon and J. Jortner, Charge transport in DA via thermally induced hopping, Journal of the American Chemical Society, 123 (2001), [9] F.D. Lewis, J. Liu, X. Liu, X. Zuo, R.T. Hayes and M.R. Wasielewski, Dynamics and energetics of hole trapping in DA by 7-deazaguanine, Angewandte Chemie International Edition in English, 4 (2002), [10] K. Hirakawa, M. Aoshima, Y. Hiraku and S. Kawanishi, Photohydrolysis of methotrexate produces pteridine, which induces poly-g-specific DA damage through photoinduced electron transfer, Photochemistry and Photobiology, 76 (2002), [11] K. Hirakawa, H. Suzuki, S. Oikawa and S. Kawanishi, Sequence-specific DA damage induced by ultraviolet A-irradiated folic acid via its photolysis product, Archives of Biochemistry and Biophysics, 410 (2003), [12] K. Hirakawa, M. Yoshida, S. Oikawa and S. Kawanishi, Base oxidation at 5' site of GG sequence in double-stranded DA induced by UVA in the presence of xanthone analogues: relationship between the DA-damaging abilities of photosensitizers and their HOMO energies, Photochemistry and Photobiology, 77 (2003), [13] H. Sugiyama and I. Saito, Theoretical studies of GG-specific photocleavage of DA via electron transfer: significant lowering of ionization potential and 5'-localization of HOMO of stacked GG bases in B-form DA, Journal of the American Chemical Society, 118 (1996), [14] Y. Yoshioka, Y. Kitagawa, Y. Takano, K. Yamaguchi, T. akamura and I. Saito, Experimental and theoretical studies on the selectivity of GGG triplets toward one-electron oxidation in B-form DA, Journal of the American Chemical Society, 121 (1999), [15] M.E. unez, K.T. oyes and J.K. Barton, Oxidative charge transport through DA in nucleosome core particles, Chemistry & Biology, 9 (2002), 48 Kazutaka Hirakawa and Mami Yoshida [16] E.A. Drobetsky, J. Turcotte and A. Chateauneuf, A role for ultraviolet A in solar mutagenesis, Proceedings of the ational Academy of Sciences of the United States of America, 92 (1995), [17] E. Sage, B. Lamolet, E. Brulay, E. Moustacchi, A. Chteauneuf and E.A. Drobetsky, Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells, Proceedings of the ational Academy of Sciences of the United States of America, 93 (1996), [18] S. Arnott and D.W. Hukins, Optimised parameters for A-DA and B-DA, Biochemical and Biophysical Research Communications, 47 (1972), [19] S. Arnott and E. Selsing, Structures for the polynucleotide complexes poly(da) with poly (dt) and poly(dt) with poly(da) with poly (dt), Journal of Molecular Biology, 88 (1974), [20] K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent and T.J. Richmond, Crystal structure of the nucleosome core particle at 2.8 Å resolution, ature, 389 (1997), Received: February 15, 2014
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