Enhancing the proline effect:: Pseudo-prolines for tailoring cis/trans isomerization
Enhancing the proline effect:: Pseudo-prolines for tailoring cis/trans isomerization
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DOI：
10.1021/ja973966s
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发表时间：
1998-04-01
影响因子：
15
通讯作者：
Mutter, M
中科院分区：
文献类型：
--
作者：
Keller, M;Sager, C;Mutter, M
顺反异构化的脯氨酸样恶唑烷和噻唑烷，表示伪脯氨酸，研究了与胰凝乳蛋白酶偶联测定和H-1 NMR。制备了一系列在Psi Pro的2-C位携带不同立体化学取代基的肽，用于评估与immersed键的异构化有关的动力学和热力学数据。Psi Pro显示出增强的脯氨酸效应，允许顺式含量沿着酰亚胺键被调整在5和约100%之间。这些Pro替代物可用作β-转角VI型模拟物，并可用于将特异性顺式酰亚胺键引入肽和蛋白质中。与Cys衍生的噻唑烷相比，来自Ser和Thr的Psi Pro显示出关于酰亚胺键的异构化速率的显著差异。与Pro本身一样，使用LiCl/TFE作为溶剂，可以将恶唑烷和噻唑烷的（S）差向异构体的顺式含量从约40-60%提高，从而允许更准确地测量异构化动力学。一般而言，含有Psi Pro的肽与其脯氨酸类似物相比，表现出增强的顺式/反式异构化的异构化速率常数，这取决于2-C Psi Pro位置处的立体化学和取代度。例如，与Pro相比，2-C二甲基化Psi Pro的异构化过程的热力学势垒降低了约2- 4千卡/摩尔。总之，Psi Pro代表了增强Pro的构象和结构效应的多功能Pro替代物，并在肽设计和工程中提供了广泛的应用。
Cis-trans isomerization of proline-like oxazolidines and thiazolidines, denoted pseudo-prolines, is investigated spectrophotometrically with a chymotrypsin coupled assay and by H-1 NMR. A series of peptides carrying substituents of varying stereochemistry at the 2-C position of Psi Pro was prepared for evaluating kinetic and thermodynamic data pertaining to the isomerization of the imidic bond. Psi Pro are shown to exhibit an enhanced proline effect, allowing the cis content along the imide bond to be tailored between 5 and about 100%. These Pro surrogates may serve as beta-turn type VI mimetics and can be used to introduce specifically cis-imide bonds into peptides and proteins. Psi Pro derived from Ser and Thr show a marked difference in the rate of isomerization about the imide bond compared to Cys derived thiazolidines. As with Pro itself, the cis content for the (S) epimers of oxazolidines and thiazolidines can be raised from about 40-60% using LiCl/TFE as a solvent, allowing more accurate measurements of the isomerization kinetics. In general, peptides containing Psi Pro exhibit enhanced isomerization rate constants for cis/trans isomerization compared to their proline analogues depending on stereochemistry and degree of substitution at the 2-C Psi Pro position. For example, the thermodynamic barrier of the isomerization process for 2-C dimethylated Psi Pro is decreased by about 2-4.kcal/mol in comparison to Pro. In summary, Psi Pro represent versatile Pro surrogates enhancing the conformational and structural effects of Pro and offer a wide range of applications in peptide design and engineering.