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High-resolution crystal structure of the intramolecular d(TpA) thymine-adenine photoadduct and its mechanistic implications.

Davies RJ, Malone JF, Gan Y, Cardin CJ, Lee MP, Neidle S - Nucleic Acids Res. (2007)

Bottom Line: This is consistent with d(TpA)* arising by valence isomerization of a precursor cyclobutane photoproduct with cis-syn stereochemistry that is generated by [2 + 2] photoaddition of the thymine 5,6-double bond across the C6 and C5 positions of adenine.This mode of photoaddition should be favoured by the stacked conformation of adjacent T and A bases in B-form DNA.It is probable that the primary photoreaction is mechanistically analogous to pyrimidine dimerization despite having a much lower quantum yield.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, School of Chemistry and Chemical Engineering, Queen's University, Belfast BT7 1NN, UK. j.davies@qub.ac.uk

ABSTRACT
A high-resolution crystal structure is reported for d(TpA)*, the intramolecular thymine-adenine photoadduct that is produced by direct ultraviolet excitation of the dinucleoside monophosphate d(TpA). It confirms the presence of a central 1,3-diazacyclooctatriene ring linking the remnants of the T and A bases, as previously deduced from heteronuclear NMR measurements by Zhao et al. (The structure of d(TpA)*, the major photoproduct of thymidylyl-(3'-5')-deoxyadenosine. Nucleic Acids Res., 1996, 24, 1554-1560). Within the crystal, the d(TpA)* molecules exist as zwitterions with a protonated amidine fragment of the eight-membered ring neutralizing the charge of the internucleotide phosphate monoanion. The absolute configuration at the original thymine C5 and C6 atoms is determined as 5S,6R. This is consistent with d(TpA)* arising by valence isomerization of a precursor cyclobutane photoproduct with cis-syn stereochemistry that is generated by [2 + 2] photoaddition of the thymine 5,6-double bond across the C6 and C5 positions of adenine. This mode of photoaddition should be favoured by the stacked conformation of adjacent T and A bases in B-form DNA. It is probable that the primary photoreaction is mechanistically analogous to pyrimidine dimerization despite having a much lower quantum yield.

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Structure of d(TpA)* and the precursor cyclobutane photoadduct (1).
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Figure 1: Structure of d(TpA)* and the precursor cyclobutane photoadduct (1).

Mentions: Initial characterization of d(TpA)* suggested that it was a cyclobutane derivative (of uncertain stereochemistry) generated by [2 + 2] photoaddition of the 5,6-double bond of thymine across the C6 and C5 positions of adenine (11,15). A subsequent investigation of its solution structure by multi-dimensional 1H NMR and molecular modelling methods (14) led to the conclusion that it was a trans–syn cyclobutane adduct akin to structure (1) in Figure 1 (which is drawn with cis–syn stereochemistry). However, this assignment was later shown to be incompatible with the 13C NMR spectrum by Zhao et al. (16) who deduced that d(TpA)* results from strain-relieving ring expansion of the precursor cyclobutane adduct to give the more stable valence isomer incorporating an 8-membered heterocyclic ring that is depicted in Figure 1. In this structure, the configuration at the original thymine C5 and C6 carbon atoms is diagnostic of the stereochemistry of the initial cyclobutane adduct. Thus, the 5S,6R isomer of d(TpA)* shown in Figure 1 will be derived from the cis–syn adduct (1) in which both the thymidine and 2′-deoxyadenosine moieties are in the anti conformation about their glycosidic bonds. Conversely, the 5R,6S isomer will be formed from the originally proposed trans–syn cyclobutane adduct (14) where thymidine is in the syn orientation.Figure 1.


High-resolution crystal structure of the intramolecular d(TpA) thymine-adenine photoadduct and its mechanistic implications.

Davies RJ, Malone JF, Gan Y, Cardin CJ, Lee MP, Neidle S - Nucleic Acids Res. (2007)

Structure of d(TpA)* and the precursor cyclobutane photoadduct (1).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851629&req=5

Figure 1: Structure of d(TpA)* and the precursor cyclobutane photoadduct (1).
Mentions: Initial characterization of d(TpA)* suggested that it was a cyclobutane derivative (of uncertain stereochemistry) generated by [2 + 2] photoaddition of the 5,6-double bond of thymine across the C6 and C5 positions of adenine (11,15). A subsequent investigation of its solution structure by multi-dimensional 1H NMR and molecular modelling methods (14) led to the conclusion that it was a trans–syn cyclobutane adduct akin to structure (1) in Figure 1 (which is drawn with cis–syn stereochemistry). However, this assignment was later shown to be incompatible with the 13C NMR spectrum by Zhao et al. (16) who deduced that d(TpA)* results from strain-relieving ring expansion of the precursor cyclobutane adduct to give the more stable valence isomer incorporating an 8-membered heterocyclic ring that is depicted in Figure 1. In this structure, the configuration at the original thymine C5 and C6 carbon atoms is diagnostic of the stereochemistry of the initial cyclobutane adduct. Thus, the 5S,6R isomer of d(TpA)* shown in Figure 1 will be derived from the cis–syn adduct (1) in which both the thymidine and 2′-deoxyadenosine moieties are in the anti conformation about their glycosidic bonds. Conversely, the 5R,6S isomer will be formed from the originally proposed trans–syn cyclobutane adduct (14) where thymidine is in the syn orientation.Figure 1.

Bottom Line: This is consistent with d(TpA)* arising by valence isomerization of a precursor cyclobutane photoproduct with cis-syn stereochemistry that is generated by [2 + 2] photoaddition of the thymine 5,6-double bond across the C6 and C5 positions of adenine.This mode of photoaddition should be favoured by the stacked conformation of adjacent T and A bases in B-form DNA.It is probable that the primary photoreaction is mechanistically analogous to pyrimidine dimerization despite having a much lower quantum yield.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, School of Chemistry and Chemical Engineering, Queen's University, Belfast BT7 1NN, UK. j.davies@qub.ac.uk

ABSTRACT
A high-resolution crystal structure is reported for d(TpA)*, the intramolecular thymine-adenine photoadduct that is produced by direct ultraviolet excitation of the dinucleoside monophosphate d(TpA). It confirms the presence of a central 1,3-diazacyclooctatriene ring linking the remnants of the T and A bases, as previously deduced from heteronuclear NMR measurements by Zhao et al. (The structure of d(TpA)*, the major photoproduct of thymidylyl-(3'-5')-deoxyadenosine. Nucleic Acids Res., 1996, 24, 1554-1560). Within the crystal, the d(TpA)* molecules exist as zwitterions with a protonated amidine fragment of the eight-membered ring neutralizing the charge of the internucleotide phosphate monoanion. The absolute configuration at the original thymine C5 and C6 atoms is determined as 5S,6R. This is consistent with d(TpA)* arising by valence isomerization of a precursor cyclobutane photoproduct with cis-syn stereochemistry that is generated by [2 + 2] photoaddition of the thymine 5,6-double bond across the C6 and C5 positions of adenine. This mode of photoaddition should be favoured by the stacked conformation of adjacent T and A bases in B-form DNA. It is probable that the primary photoreaction is mechanistically analogous to pyrimidine dimerization despite having a much lower quantum yield.

Show MeSH