Catalysis driven by an amyloid-substrate complex

• 成果类型: Article
• 署名作者: Sawazaki, Taka; Sasaki, Daisuke; Sohma, Youhei
• 署名单位: Wakayama Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13050
• DOI: 10.1073/pnas.2314704121
• 发表日期: 2024-05-07
• 关键词: hydrogen-bond; peptides; thioamide; proteins; fibrils

摘要

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 approximate to 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 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.