Molecular and Crystal Structure of O4-Methyluridine. Reaction Coordinates for an Incipient Nucleophilic Attack Seen by Short Intermolecular Sugar-Base Interactions

Base-alkylated nucleosides are mutagenic in that they are capable of inducing base mispairing. Here we report the first structure of an O-alkylated pyrimidine nucleoside, O⁴-methyluridine (C10H14O6N2). The compound crystallizes with two independent molecules per asymmetric unit in the orthorhombic space group D2⁴-P212121 with unit cell parameters a = 4.986 (1) Å,b= 19.463 (1) Å,c = 23.453 (1) Å, V- 2275 ų, 2 = 8, Dc = 1.507 g cm⁻³, Dm = 1.51 g cm⁻³. The structure was solved by direct methods and refined by full-matrix least-squares technique to a final R index of 0.028 (Rw = 0.035) using 1916 intensities with I > 1.5σ(I). Molecules A and B exhibit the favored ribofuranosyl and glycosyl conformations: the ³T2 sugar pucker {PA = 7.6 (3)°, τmA = 37.5 (2)°, PB= 11.4 (3)°, τmB = 42.0 (2)°) and the anti conformation about the glycosyl bond C(l′)-N(l) (XA = 9.4 (3)° and XB = 10.9 (3)°). The conformations about the exocyclic C(4′)-C(5′) bond are gauche⁺ (ψA = 56.1 (3)° and ψB = 52.7 (3)°). Methylation profoundly affects the geometric and electronic properties of the pyrimidine ring such that they more closely resemble those of cytosine than diketo uracil. The close approach of the 0(4′) oxygen atom of a neighboring sugar to the base of molecule A represents the reaction coordinates for an incipient nucleophilic attack by 0(4′) on the base C(2) atom, which results in pyramidization at the C(2) atom and distortion of the pyrimidine ring to a twist boat conformation. Further significant changes are induced in the bond orders about the C(7)-0(4)-C(4)-C(5)-C(6) fragment. Methylation precludes base-base hydrogen bonds, and only base-sugar and sugar-sugar hydrogen bonds are found. In both molecules the keto O(2) atoms are involved in hydrogen bonding. The hydrogen bond preferences exhibited by O⁴-methyluridine suggest that only certain pairing schemes with guanosine are possible. For the O⁴-methyluridine to engage in these pairings, the C(7) methyl group has to be rotated about 80 from the observed syn-periplanar orientation. © 1983, American Chemical Society. All rights reserved.

Duke Scholars

Author Richard Gerald Brennan Biochemistry