PDF(Pubmed)
Abstract：
Amine modification through nucleophilic attack of the amine functionality is a very common chemical transformation. Under biorelevant conditions using acidic-to-neutral pH buffer, however, the nucleophilic reaction of alkyl amines (pKa ≈ 10) is not facile due to the generation of ammonium ions lacking nucleophilicity. Here, we disclose a unique molecular transformation system, catalysis driven by amyloid-substrate complex (CASL), that promotes amine modifications in acidic buffer. Ammonium ions attached to molecules with amyloid-binding capability were activated through deprotonation due to the close proximity to the amyloid catalyst formed by Ac-Asn-Phe-Gly-Ala-Ile-Leu-NH2 (NL6), derived from islet amyloid polypeptide (IAPP). Under the CASL conditions, alkyl amines underwent various modifications, i.e., acylation, arylation, cyclization, and alkylation, in acidic buffer. Crystallographic analysis and chemical modification studies of the amyloid catalysts suggested that the carbonyl oxygen of the Phe-Gly amide bond of NL6 plays a key role in activating the substrate amine by forming a hydrogen bond. Using CASL, selective conversion of substrates possessing equivalently reactive amine functionalities was achieved in catalytic reactions using amyloids. CASL provides a unique method for applying nucleophilic conversion reactions of amines in diverse fields of chemistry and biology.
摘要：
通过胺官能团的亲核攻击的胺修饰是非常常见的化学转化。在使用酸性至中性pH缓冲液的生物相关条件下，然而,由于缺乏亲核性的铵离子的产生，烷基胺（pKa≈10）的亲核反应不容易。这里,我们公开了一个独特的分子转化系统，由淀粉样蛋白-底物复合物（CASL）驱动的催化，促进酸性缓冲液中的胺修饰。由于与Ac-Asn-Phe-Gly-Ala-Ile-Leu-NH2（NL6）形成的淀粉样蛋白催化剂非常接近，因此通过去质子化激活了与具有淀粉样蛋白结合能力的分子相连的铵离子，来源于胰岛淀粉样多肽(IAPP)。在CASL条件下,烷基胺进行了各种修饰，即，酰化,芳基化,环化,和烷基化，在酸性缓冲液中。淀粉样蛋白催化剂的晶体学分析和化学修饰研究表明，NL6的Phe-Gly酰胺键的羰基氧在通过形成氢键活化底物胺中起关键作用。使用CASL，在使用淀粉样蛋白的催化反应中实现了具有等效反应性胺官能团的底物的选择性转化。CASL提供了在化学和生物学的不同领域中应用胺的亲核转化反应的独特方法。
