Cytosine tautomeric forms

The tautomerisation of the purine bases adenine and guanine and of the pyrimidine bases thymine, cytosine, and uracil has important implications in molecular biology, and the occurrence of rare tautomeric forms of these bases has been suggested as a possible cause of spontaneous mutagenesis (Lowdin, 1965 Pullman and Pullman, 1971 Kwiatowski and Pullman, 1975). Three of the most likely tautomers for cytosine are shown in [87]—[89], together with the less likely imino forms [90] and [91] (Scanlan and Hillier,... 

Some of the impetus for studying tautomeric equilibria in heterocycles arises because of the postulate that point mutations in genetic material may be introduced when a given base exists in a tautomeric form during replication [279, 305-307], Cytosine, in particular, has imino and hydroxy tautomers that are within 3 kcal/mol of the global minimum illustrated above (because of the very large number of possible tautomers for the purines and pyrimidines, only the lowest energy tautomers are presented). This analysis has been made based on a... 

We should note particularly that uracil and thymine are dioxypyrimidines, whereas cytosine is an amino-oxypyrimidine. All three pyrimidines are thus capable of existing in several tautomeric forms (see Section 11.6.2). 

The bases are monocyclic pyrimidines (see Box 11.5) or bicyclic purines (see Section 11.9.1), and all are aromatic. The two purine bases are adenine (A) and guanine (G), and the three pyrimidines are cytosine (C), thymine (T) and uracil (U). Uracil is found only in RNA, and thymine is found only in DNA. The other three bases are common to both DNA and RNA. The heterocyclic bases are capable of existing in more than one tautomeric form (see Sections 11.6.2 and 11.9.1). The forms shown here are found to predominate in nucleic acids. Thus, the oxygen substituents are in keto form, and the nitrogen substituents exist as amino groups. 

The Mg+ complexes of cytosine, thymine and uracil are the most complex system studied via photodissociation spectroscopy to date . A complication for these systems is that these nucleobases can exist in various tautomeric forms and that complexation of a metal can change the stability order of the tautomers. DFT calculations located four tautomeric Mg(cytosine)+ complexes, and three of these (29, 30, and 31) were suggested to be responsible for the four reactive photofragment ions 32-35 observed at a wavelength of 360 nm (Scheme 4) . Related photofragmentation reactions were observed for the Mg(thymine)+" and Mg(uracil)+" complexes . ... 

The tautomeric studies of azacytosines are not so complete as those of cytosine itself. The contribution of other tautomeric forms of azacytosines to the tautomeric equilibrium has not been evaluated (because of lack of model tautomeric compounds). It appears that 6-aza-substi-tution causes a tautomeric shift from form 3 of cytosine toward its imine form, 6. Thus, upon 6-aza-substitution the contribution of the imine tautomers to the tautomeric equilibrium of cytosine increases, while that of tautomers 3 decreases. 

Table VI collects the theoretical quantities appropriate to the description of the tautomeric stability of cytosine, computed by methods including both -n- and cr-electrons. We have added to it the results of a 77-SCF MO approach (including cr-polarization effects) on heats of atomization of different tautomeric forms of cytosine. Bodor et al.liB have related the heat of atomization to the stability of the tautomers, and found that the most stable structure of the molecule is the amine-lactam 2 having the greatest heat of atomization (59.707 eV). They predict on this basis the following order of stability 2 > 3 > 6 > 1.

Effect of Substituent on the Stability of Tautomeric Forms of Cytosine... 

Figures 5 and 6 give the 77- and total electronic charges calculated by the CNDO/2 method for several tautomeric forms of cytosine, 5-F and 6-F-cytosine, and of N8-amino and N8-hydroxy substituted cytosines. The last two compounds as discussed before are important in the theory of mutagenesis, being products of reaction between cytosine and hydrazine or hydroxylamine, respectively.

Like cytosine, uracil (or thymine, its 5-methyl derivative) can exist in six tautomeric forms 27-32. A large amount of experimental evidence shows that uracil and thymine have the diketo (dilactam)... 

Cytosine, uracil, and guanine have tautomeric forms with aromatic hydroxyl groups. Draw these tautomeric forms. 

Fig. 15.4. Keto/enol and amino/imino tautomeric forms of uracil, cytosine, adenine, guanine. The keto and amino forms predominate, the enol and imino forms are only present in equilibrium at 0.01 Vo or less...

Jeffrey and Kinoshita have used a different numbering of the ring atoms of cytosine from that of Barker and Marsh, the latter being the same as the numbering used here. A superficial reading of the papers may lead to the erroneous conclusion that cytosine in the crystals take on different tautomeric forms depending upon the solvent used for recrystallization. 

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