Side Chain Conformation Restriction in the Catalysis of Glycosidic Bond Formation by Leloir Glycosyltransferases, Glycoside Phosphorylases, and Transglycosidases.
Side Chain Conformation Restriction in the Catalysis of Glycosidic Bond Formation by Leloir Glycosyltransferases, Glycoside Phosphorylases, and Transglycosidases.
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DOI：
10.1021/acscatal.1c00896
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发表时间：
2021-05-07
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
碳水化合物侧链构象是控制异头中心反应性的重要因素，即在糖苷键的形成和断裂中，无论是化学还是通过糖苷水解酶水解。在自然界中，糖苷键的形成由糖基转移酶（GT）、糖苷磷酸化酶和转糖苷酶催化。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个晶体结构和在供体位点（-1位点）与吡喃己糖苷或其类似物结合的转糖苷酶的54个晶体结构，我们确定了催化糖苷合成的大多数酶，无论是GT、糖苷磷酸化酶还是转糖苷酶，将它们的底物侧链限制为最具反应性的偏侧（gauche，gauche）构象，以实现用于糖基转移的氧碳正离子样过渡态的最大稳定化。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在第二大活性的反式（gt）构象，而β-半乳糖基转移酶则倾向于反应性最小的反式（tg）构象。这一见解将有助于利用这些固有的侧链偏好设计和开发改进的构象限制性GT抑制剂。
Carbohydrate side chain conformation is an important factor in the control of reactivity at the anomeric center, ie, in the making and breaking of glycosidic bonds, whether chemically or, for hydrolysis, by glycoside hydrolases. In nature glycosidic bond formation is catalyzed out by glycosyltransferases (GTs), glycoside phosphoryases, and transglycosidases. By 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 analogs 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 second-most reactive gauche,trans (gt) conformation, and β-galactosyltransferases favoring the least reactive trans,gauche (tg) conformation. This insight will help progress the design and development of improved, conformationally-restricted GT inhibitors that take advantage of these inherent side chain preferences.
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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：
18.2
作者：
Artola M;Wu L;Ferraz MJ;Kuo CL;Raich L;Breen IZ;Offen WA;Codée JDC;van der Marel GA;Rovira C;Aerts JMFG;Davies GJ;Overkleeft HS
通讯作者：
Overkleeft HS
影响因子：
4.8
作者：
Gagnon, Susannah M. L.;Meloncelli, Peter J.;Evans, Stephen V.
通讯作者：
Evans, Stephen V.
DOI：
10.1179/096805101101532828
发表时间：
2001-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
影响因子：
--
作者：
Gronow, S;Oertelt, C;Holst, O
通讯作者：
Holst, O
影响因子：
3.2
作者：
Gloster TM;Davies GJ
通讯作者：
Davies GJ