MECHANISM OF ALKALINE-HYDROLYSIS OF S-ADENOSYL-L-METHIONINE AND RELATED SULFONIUM NUCLEOSIDES

Sulfonium nucleosides such as S-adenosylmethionine (SAM) and 5’-deoxy-5’-dimethylthioadenosine (DMTA) are very labile to mild alkaline conditions resulting in the cleavage of the glycosidic bond. This glycoside cleavage results from an elimination reaction where proton abstraction occurs at the carbon atom (5’ position) adjacent to the sulfonium center with subsequent elimination to form a 4’,5’ double bond. Cleavage of the glycosidic bond can be envisioned as a concerted part of the elimination reaction or via the formation of a “hemiacetal” intermediate which rapidly breaks down. The rate of glycosidic cleavage of SAM (DMTA) was found not to be linearly dependent on hydroxide ion concentration. This nonlinearity resulted because of the existence of two reacting species. SAM- (or DMTA-), which has the 2’-(or 3’c-) hydroxyl group ionized (pka = 12.1), undergoes hydrolysis at a substantially slower rate (k1 = 0.0363 M-1 s-1) than the nonionized species (k1 = 0.790 M-1 s-1). The hydrolysis of 3’-deoxy-SAM, which does not have an acidic functionality in the pH range studied, exhibits a linear dependence on hydroxide ion concentration (k1 = 0.488 M-1 s-1)-NMR experiments using DMTA in Na0D/D20 revealed that during the hydrolysis only a single hydrogen atom was exchanged with deuterium at the 5’ position. The small primary deuterium isotope effects (kH/kD = ~1.4) observed for the hydrolysis of both DMTA and DMTA- suggest asymmetric transition states for these proton abstractions. For the hydrolysis of the nonionized DMTA a significant solvent isotope effect was observed (k1(H20)/k1(D20) = 0.524) suggesting a transition state with substantial bond making to the hydrogen acceptor. In contrast, for the hydrolysis of DMTA- the lack of a solvent isotope effect (k2(H20)/k2(D20) = 1.02) suggested a transition state with little bond breaking in the reactant. © 1979, American Chemical Society. All rights reserved.