Biopolym. Cell. 2000; 16(2):124-137.
Structure and Function of Biopolymers
Prototropic molecular-zwitterionic tautomerism of xanthine and hypoxanthine: unexpected biological view
1Kondratyuk I. V., 1Samijlenko S. P., 1Kolomiets I. M., 1Potyahaylo A. L., 1Hovorun D. M.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


The prototropic molecular-zwitterionic tautomerism of xanthine and hypoxanthine has been investigated by the semi-empirical quantum-chemical AMI method. Geometric, energetic and other physico-chemical features of their complete molecular-zwitterionic families of tautomers have been established. The influence of the environment with universal solvatation mechanism on the tautomeric equilibrium has been evaluated at Otizager approximation. The comparison of the calculations with the 1H NMR data favours the N7H Xan and the N9H Hyp tautomers in DMSO solutions. A possible biochemical role of tautomeric (especially zwitterionic) forms of Xan and Hyp is discussed. The stabilizing influences of both environment and specific interactions with proteins on rare tautomeric forms are considered. The biological significance of high energy tautomers is discussed.


[1] Shabarova ZA, Bogdanov AA. Chemistry of nucleic acids and their components. M.: Chimiya, 1978. 582 p.
[2] Poltev VI, Bruskov VI, Shuliupina NV, Rein R, Shibata M, Ornstein R, Miller J. Genotoxic modification of nucleic acid bases and biological consequences of it. Review and prospects of experimental and computational investigations. Mol Biol (Mosk). 1993;27(4):734-57.
[3] Saenger W. Principles of nucleic acid structure. New York: Springer, 1984; 556 p.
[4] Rossi C, Picchi M, Tiezzi E, Corbini G, Corti P. Conformational and dynamic investigation in solution of inosine and its molecular complex, inosiplex, by proton and carbon NMR spectroscopy. Magn Reson Chem. 1990;28(4):348–54.
[5] Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986;83(6):1911-5.
[6] Norinder U. A theoretical reinvestigation of the nucleic bases adenine, guanine, cytosine, thymine and uracil using AM1. J Mol Struct. 1987;151:259–69.
[7] Sabio M, Topiol S, Lumma WC. An investigation of tautomerism in adenine and guanine. J Phys Chem. 1990;94(4):1366–72.
[8] Nowak MJ, Lapinski L, Kwiatkowski JS, Leszczy?ski J. Molecular structure and infrared spectra of adenine. Experimental matrix isolation and density functional theory study of adenine 15N isotopomers. J Phys Chem. 1996;100(9):3527–34.
[9] Nowak MJ, Lapinski L, Kwiatkowski JS. An infrared matrix isolation study of tautomerism in purine and adenine. Chem Phys Lett. 1989;157(1-2):14–8.
[10] Nowak MJ, Rostkowska H, Lapinski L, Kwiatkowski JS, Leszczynski J. Tautomerism N(9)H - N(7)H of purine, adenine, and 2-chloroadenine: combined experimental IR matrix isolation and ab initio quantum mechanical studies. J Phys Chem. 1994;98(11):2813–6.
[11] Szczepaniak K, Szczesniak M, Person WB. Infrared studies and the effect of ultraviolet irradiation on the tautomers of 9-methylguanine isolated in an argon matrix. Chem Phys Lett. 1988;153(1):39–44.
[12] Kwiatkowski JS, Person WB. The tautomerism of the nucleic acid bases revisited: from non-interacting to interacting bases. Theor biochem Mol Biophys. Eds D. L. Beverige, R. Lovery. New York: Adenine press, 1990: 153-171.
[13] Szczepaniak K, Szczesniak M. Matrix isolation infrared studies of nucleic acid constituents: Part 4. Guanine and 9-methylguanine monomers and their keto—enol tautomerism. J Mol Struct. 1987;156(1-2):29-42.
[14] Brown RD, Godfrey PD, McNaughton D, Pierlot AP. A study of the major gas-phase tautomer of adenine by microwave spectroscopy. Chem Phys Lett. 1989;156(1):61–3.
[15] Leszczynski J. The Potential Energy Surface of Guanine Is Not Flat: An ab Initio Study with large basis sets and higher order electron correlation contributions. J Phys Chem A. 1998;102(13):2357–62.
[16] LeBreton PR, Yang X, Urano S, Fetzer S, Yu M, Leonard NJ, et al. Photoemission properties of methyl-substituted guanines: photoelectron and fluorescence investigations of 1,9-dimethylguanine, O6,9-dimethylguanine, and 9-methylguanine. J Am Chem Soc. 1990;112(6):2138–47.
[17] Gould IR, Vincent MA, Hillier I, Lapinski L, Nowak MJ. A new theoretical prediction of the infrared spectra of cytosine tautomers. Spectrochim Acta A. 1992;48(6):811–8.
[18] Cavalieri LF, Fox JJ, Stone A, Chang N. On the Nature of Xanthine and Substituted Xanthines in Solution 1 . J Am Chem Soc. 1954;76(4):1119–22.
[19] Lichtenberg D, Bergmann F, Neiman Z. Tautomeric forms and ionisation processes in xanthine and its N-methyl derivatives. J Chem Soc. 1971;1676-82.
[20] Mizuno H, Fujiwara T, Tomita K. The Crystal and Molecular Structure of the Sodium Salt of Xanthine. Bull Chem Soc Jpn. 1969;42(11):3099–105.
[21] Sponer J, Leszczy?ski J. Tautomerism of xanthine: The second-order Moller-Plesset study. Struct Chem. 1995;6(4-5):281–6.
[22] Bergmann F, Kleiner M, Neiman Z, Rashi M. The ionisation sequence of hypoxanthine and 6-mercaptopurine. Isr J Chem. 1964;2(5):185–96.
[23] Lin J, Yu C, Peng S, Akiyama I, Li K, Lee LK, et al. Ultraviolet photoelectron studies of the ground-state electronic structure and gas-phase tautomerism of purine and adenine. J Am Chem Soc. 1980;102(14):4627–31.
[24] Munns AR, Tollin P. The crystal and molecular structure of inosine. Acta Crystallogr B. 1970;26(8):1101-13.
[25] Krishnan R, Seshadri TP. Crystal Structure of Sodium Deoxyinosine Monophosphate. Nucleosides Nucleotides. 1992;11(5):1047–57.
[26] Sheina GG, Stepanian SG, Radchenko ED, Blagoi YP. IR spectra of guanine and hypoxanthine isolated molecules. J Mol Struct. 1987;158:275–92.
[27] Musui Q, Yuoxin J, Wenqin L, Junru B, Peijuan G, Renlong W, Keqin Z, Debao W. Biological function of modified nucleotides in tRNA molecules-synthesis and biological activity of the analogues of yeast alanyl tRNA with 134 replaced by A34 or G34. Scientia Sinica, Ser. B. 1988;31: 695-701.
[28] Zheltovsky NV, Samiylenko SP, Kolomiets IN, Kondratyuk IV, Stepanyugin AV. The investigation of interactions of hypoxanthine, xanthine and their methyl and glycosyl derivatives with amino acid carboxylic group by spectroscopic methods. Biopolym Cell. 1993; 9(3):17-22.
[29] Zheltovsky NV, Samoilenko SA, Kondratyuk IV, Kolomiets IN, Stepanyugin AV. Recognition of purine bases and nucleosides by the amino acid carboxylic group. J Mol Struct. 1995;344(1-2):53–62.
[30] Costas ME, Acevedo-Ch?vez R. Density functional study of the neutral hypoxanthine tautomeric forms. J Phys Chem. 1997;101(44):8309–18.
[31] Hern?ndez B, Luque FJ, Orozco M. Tautomerism of xanthine oxidase substrates hypoxanthine and allopurinol. J Org Chem. 1996;61(17):5964–71.
[32] Samijlenko SP, Kolomiets IM, Kondratyuk IV, Stepanyugin AV. Model considerations on physico-chemical nature of protein-nucleic acid contacts through amino acid carboxylic groups: Spectroscopic data. Biopolym Cell. 1998; 14 (1):47-53.
[33] Morozov JuV, Bazhulina NP. Electronic structure, spect­roscopy and reactivity of the molecules. Moscow: Mir, 1989. 288 p.
[34] Govorun DM, Kondratyuk IV, Zheltovsky NV. Acidic-basic properties of molecular xanthine and its complex formation ability. Biopolym Cell. 1994; 10(6):61-4.
[35] Maslova RN, Lesnik EA, Varshavski? IaM. Kinetics and mechanism of the 3H to 1H in C(8)H groups of purine derivatives. Mol Biol (Mosk). 1975;9(2):310-20.
[36] Eads JC, Scapin G, Xu Y, Grubmeyer C, Sacchettini JC. The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP. Cell. 1994;78(2):325-34.
[37] Aoki K. Metal binding effects on nucleic acid structures. Comprehensive supramolecular chemistry. Eds J. L. Alwood, J. E. D. Davies, D. D MacNicol, F. Vogtle, J. M. Lehn. New York: Pergamon press, 1996. Chapter 8: 269-94.
[38] Konevega LV, Kalinin VL. Lethal and mutagenic effects of tritium incorporated into position 8 of the purines in phage lambda DNA and the role of the Fpg protein. Genetika. 1998;34(7):897-902.