MECHANISM OF ALKALINE-HYDROLYSIS OF S-ADENOSYL-L-METHIONINE AND RELATED SULFONIUM NUCLEOSIDES
MECHANISM OF ALKALINE-HYDROLYSIS OF S-ADENOSYL-L-METHIONINE AND RELATED SULFONIUM NUCLEOSIDES
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DOI：
10.1021/ja00496a032
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发表时间：
1979-01-01
影响因子：
15
通讯作者：
BORCHARDT, RT
中科院分区：
文献类型：
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作者：
BORCHARDT, RT
锍核苷如S-腺苷甲硫氨酸（SAM）和5“-脱氧-5”-二甲基硫代腺苷（DMTA）对温和的碱性条件非常不稳定，导致糖苷键断裂。这种糖苷裂解是由消除反应引起的，其中质子夺取发生在与锍中心相邻的C原子（5“位）处，随后消除形成4”，5“双键。糖苷键的裂解可以被设想为消除反应的协同部分或通过形成快速分解的半缩醛中间体。SAM（DMTA）的糖苷裂解速率与OH-浓度不呈线性关系.这种非线性是由于两种反应物种的存在造成的。SAM-（或DMTA-）具有电离的2“-（或3”-）羟基（pKa = 12.1），其水解速率（k1 = 0.0363 M-1 s-1）远低于非电离物质（k1 = 0.790 M-1 s-1）。在所研究的pH范围内不具有酸性官能团的3“-脱氧-SAM的水解表现出对OH-浓度的线性依赖性（k1 = 0.488 M-1 s-1）。在NaOD/D2 O中使用DMTA的NMR实验显示，在水解期间，仅单个H原子在5“位与氘交换。小的初级氘同位素效应（kH/kD = apx. 1.4)观察到的DMTA和DMTA的水解-建议这些质子抽象的不对称过渡态。对于非离子化的DMTA的水解，观察到一个显着的溶剂同位素效应（K1（H2O）/K1（D2 O）= 0.524），表明过渡态与大量的键使H受体。对于DMTA的水解-缺乏溶剂同位素效应（k2（H2O）/k2（D2 O）= 1.02），表明反应物中具有很少的键断裂的过渡态。
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 C 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 not linearly dependent on OH- concentration. This nonlinearity resulted because of the existence of 2 reacting species. SAM- (or DMTA-), which has the 2''- (or 3''-) 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 OH- concentration (k1 = 0.488 M-1 s-1). NMR experiments using DMTA in NaOD/D2O revealed that during the hydrolysis only a single H atom was exchanged with deuterium at the 5'' position. The small primary deuterium isotope effects (kH/kD = .apprx. 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(H2O)/k1(D2O) = 0.524) suggesting a transition state with substantial bond making to the H acceptor. For the hydrolysis of DMTA- the lack of a solvent isotope effect (k2(H2O)/k2(D2O) = 1.02) suggested a transition state with little bond breaking in the reactant.