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. 2012 Dec 5;134(48):19839-50.
doi: 10.1021/ja309082k. Epub 2012 Nov 26.

Gas-phase studies of substrates for the DNA mismatch repair enzyme MutY

Anna Zhachkina Michelson  1 , Aleksandr Rozenberg, Yuan Tian, Xuejun Sun, Julianne Davis, Anthony W Francis, Valerie L O'Shea, Mohan Halasyam, Amelia H Manlove, Sheila S David, Jeehiun K Lee
Affiliations

Gas-phase studies of substrates for the DNA mismatch repair enzyme MutY

Anna Zhachkina Michelson et al. J Am Chem Soc. .

Abstract

The gas-phase thermochemical properties (tautomeric energies, acidity, and proton affinity) have been measured and calculated for adenine and six adenine analogues that were designed to test features of the catalytic mechanism used by the adenine glycosylase MutY. The gas-phase intrinsic properties are correlated to possible excision mechanisms and MutY excision rates to gain insight into the MutY mechanism. The data support a mechanism involving protonation at N7 and hydrogen bonding to N3 of adenine. We also explored the acid-catalyzed (non-enzymatic) depurination of these substrates, which appears to follow a different mechanism than that employed by MutY, which we elucidate using calculations.

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Figures

Figure 1
Figure 1
Adenine removal from DNA catalyzed by the MutY glycosylase.
Figure 2
Figure 2
Adenine and synthetic analogs studied herein.
Figure 3
Figure 3
The eight possible tautomeric structures of 7-deazaadenine (Z). Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 4
Figure 4
The seven possible tautomeric structures of 3-deazaadenine (Z3). Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 5
Figure 5
The seven possible tautomeric structures of 1-deazaadenine (Z1). Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 6
Figure 6
The three possible tautomeric structures of Q. Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 7
Figure 7
The two possible tautomeric structures of M. Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 8
Figure 8
The two possible tautomeric structures of B. Gas phase acidities are in red; gas phase proton affinities are in blue. Relative stabilities are in parentheses. Calculations were conducted at B3LYP/6-31+G(d); reported values are ΔH at 298 K.
Figure 9
Figure 9
Structures of 4a, 4b, 4aH+ and 4bH+ and calculated proton affinities. Relative stabilities of the two neutral tautomers are shown in parentheses. Calculations were conducted at B3LYP/6-31+G(d) [ΔH at 298 K in kcal mol−1].
Figure 10
Figure 10
Structure of deprotonated 4a and 4b and calculated acidities. Calculations were conducted at B3LYP/6-31+G(d) [ΔH at 298 K in kcal mol−1].
Figure 11
Figure 11
Structures of 4a and 4b and calculated acidity of the most acidic site. Relative stabilities of the two neutral tautomers are shown in parentheses. Calculations were conducted at B3LYP/6-31+G(d) [ΔH at 298 K in kcal mol−1].
Figure 12
Figure 12
Reaction coordinate for the base-catalyzed tautomerization of 4b to 4a. “A–” represents deprotonated reference acid. Values in red are B3LYP/6-31+G(d) calculated ΔHacid values (298 K).
Figure 13
Figure 13
Calculated (B3LYP/6-31+G(d)) gas phase acidities (ΔH, kcal mol−1) of the N9-H for neutral adenine analogs. Substrates are ordered in decreasing acidity (increasing ΔHacid value).
Figure 14
Figure 14
Calculated (B3LYP/6-31+G(d)) gas phase acidities (kcal mol−1) of the N9-H for N7-protonated nucleobase analogs. (Z and M have no N7 to protonate; acidities are shown for comparison). Substrates are ordered in decreasing acidity (increasing ΔHacid values).
Figure 15
Figure 15
Calculated (B3LYP/6-31+G(d)) gas phase acidities (kcal mol−1) of the N9-H for N7-protonated, N3-hydrogen-bonded adenine analogs. Substrates are ordered in decreasing acidity (increasing ΔHacid values).
Figure 16
Figure 16
Calculated (B3LYP/6-31+G(d)) gas phase PAs (ΔH, kcal mol−1) of the N7 for adenine and analogs. Substrates are ordered in increasing PA.
Figure 17
Figure 17
Aqueous N9-H acidities (kcal mol−1) of nucleobase analogs with the most basic site protonated.
Figure 18
Figure 18
Calculated (B3LYP/6-31+G(d)) gas phase acidities (ΔH, kcal mol−1) of the N9-H for N7-protonated nucleobase analog Z13.
Scheme 1
Scheme 1
See this image and copyright information in PMC

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