GH47 and Other Glycoside Hydrolases Catalyze Glycosidic Bond Cleavage with the Assistance of Substrate Super-arming at the Transition State.
GH47 and Other Glycoside Hydrolases Catalyze Glycosidic Bond Cleavage with the Assistance of Substrate Super-arming at the Transition State.
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DOI：
10.1021/acscatal.1c02750
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发表时间：
2021-08-20
期刊：
影响因子：
12.9
通讯作者：
Crich D
中科院分区：
文献类型：
--
作者：
Quirke JCK;Crich D
超臂糖基供体，其取代基主要处于假轴位置，通过显著稳定氧卡宾类过渡态，表现出强烈的糖基化反应活性。X-射线晶体结构分析表明，GH47糖苷水解酶家族已经进化到使其底物偏离基态构象而扭曲，从而在假轴位置上呈现多个C-O键，从而有利于其底物的构象超武装，从而增强催化作用。通过对文献突变研究的分析，我们发现在GHS 6和47中适当放置的芳香族残基在它们的底物上立体地加强了超臂构象。另一方面，GH家族45、81和134通过氢键而不是空间相互作用来维持更活跃的环构象，从而在其底物上施加构象超级武装。精选的生长激素家族对底物超级武装的认识提供了与合成碳水化合物化学和自然界进一步平行的方法，并为设计改进的糖苷酶抑制剂开辟了进一步的途径。
Super-armed glycosyl donors, whose substituents are predominantly held in pseudoaxial positions, exhibit strongly increased reactivity in glycosylation through significant stabilization of oxocarbenium-like transition states. Examination of X-ray crystal structures reveals that the GH47 family of glycoside hydrolases have evolved so as to distort their substrates away from the ground state conformation in such a manner as to present multiple C-O bonds in pseudoaxial positions and so benefit from conformational super-arming of their substrates, thereby enhancing catalysis. Through analysis of literature mutagenic studies, we show that a suitably placed aromatic residue in GHs 6 and 47 sterically enforces super-armed conformations on their substrates. GH families 45, 81, and 134 on the other hand impose conformational super-arming on their substrates, by maintaining the more active ring conformation through hydrogen bonding rather than steric interactions. The recognition of substrate super-arming by select GH families provides a further parallel with synthetic carbohydrate chemistry and nature and opens further avenues for the design of improved glycosidase inhibitors.
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影响因子：
62.1
作者：
Adero PO;Amarasekara H;Wen P;Bohé L;Crich D
通讯作者：
Crich D
影响因子：
15
作者：
Hudson KL;Bartlett GJ;Diehl RC;Agirre J;Gallagher T;Kiessling LL;Woolfson DN
通讯作者：
Woolfson DN
影响因子：
5.2
作者：
Jensen, HH;Bols, M
通讯作者：
Bols, M
影响因子：
3.2
作者：
Gloster TM;Davies GJ
通讯作者：
Davies GJ
影响因子：
6.6
作者：
Compain, Philippe
通讯作者：
Compain, Philippe