<br>Leloir 糖基转移酶、糖苷磷酸化酶和转糖苷酶催化糖苷键形成时的侧链构象限制,ACS Catalysis

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Leloir 糖基转移酶、糖苷磷酸化酶和转糖苷酶催化糖苷键形成时的侧链构象限制
ACS Catalysis ( IF 11.3 ) Pub Date : 2021-04-13 , DOI: 10.1021/acscatal.1c00896
Jonathan C K Quirke _{1,

2,

3} , David Crich _{1,

2,

3}

Affiliation

碳水化合物侧链构象是控制异头中心反应性的重要因素，即糖苷键的形成和断裂，无论是通过化学方法还是通过糖苷水解酶进行水解。在自然界中，糖苷键的形成是由糖基转移酶（GT）、糖苷磷酸化酶和转糖苷酶催化的。通过分析糖核苷酸依赖性 (Leloir) GT 的 118 个晶体结构、糖苷磷酸化酶的 136 个晶体结构和与吡喃己糖苷或其类似物在供体位点（-1 位点）结合的转糖苷酶的 54 个晶体结构，我们确定大多数酶催化糖苷合成的酶，无论是 GT、糖苷磷酸化酶还是转糖苷酶，都将其底物侧链限制为最具反应性的高斯、高斯( gg ) 构象，以实现糖基转移的氧碳鎓离子样过渡态的最大稳定性。半乳糖系列偏离了这一趋势，α-半乳糖基转移酶优先将其底物限制为反应性第二高的反式( gt ) 构象，而 β-半乳糖基转移酶则倾向于反应性最低的反式( tg ) 构象。这一见解将有助于促进利用这些固有侧链偏好的改进的构象限制性 GT 抑制剂的设计和开发。

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Side Chain Conformation Restriction in the Catalysis of Glycosidic Bond Formation by Leloir Glycosyltransferases, Glycoside Phosphorylases, and Transglycosidases

Carbohydrate side chain conformation is an important factor in the control of reactivity at the anomeric center, i.e. in the making and breaking of glycosidic bonds, whether by chemical means or, for hydrolysis, by glycoside hydrolases. In nature glycosidic bond formation is catalyzed out by glycosyltransferases (GTs), glycoside phosphorylases, and transglycosidases. By an analysis of 118 crystal structures of sugar nucleotide dependent (Leloir) GTs, 136 crystal structures of glycoside phosphorylases, and 54 crystal structures of transglycosidases bound to hexopyranosides or their analogues at the donor site (−1 site), we determined that most enzymes that catalyze glycoside synthesis, be they GTs, glycoside phosphorylases, or transglycosidases, restrict their substrate side chains to the most reactive gauche,gauche (gg) conformation to achieve maximum stabilization of the oxocarbenium ion-like transition state for glycosyl transfer. The galactose series deviates from this trend, with α-galactosyltransferases preferentially restricting their substrates to the secondmost reactive gauche,trans (gt) conformation and β-galactosyltransferases favoring the least reactive trans,gauche (tg) conformation. This insight will help promote the design and development of improved, conformationally restricted GT inhibitors that take advantage of these inherent side chain preferences.

更新日期：2021-05-07

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