手性牛心果碱的应用价值和生物合成研究进展

Recent advances in the application value and biosynthesis of chiral reticuline

摘要:

手性牛心果碱是苄基异喹啉生物碱生物合成途径中的核心骨架分子，其高效、高选择性的生物合成是突破天然提取瓶颈和实现苄基异喹啉生物碱规模化生产的关键。近年来，合成生物学与代谢工程的发展使得微生物宿主异源合成手性牛心果碱和苄基异喹啉生物碱取得重要突破。然而，R-型牛心果碱的生物合成仍受限于关键酶的立体选择性，需通过酶工程和途径重构等策略加以解决。莲植物研究中揭示的R-立体化学偏好性为R-型苄基异喹啉生物碱的合成提供了新路径。本文系统综述了手性牛心果碱作为苄基异喹啉生物碱重要骨架的应用价值、合成途径和最新研究进展，剖析当前挑战并据此提出未来研究方向，旨在为下一代高效、高选择性苄基异喹啉生物碱药物的开发与应用提供理论支撑与实践指导。

Abstract:

Chiral reticuline serves as the core skeleton molecule in the biosynthetic pathway of benzylisoquinoline alkaloids (BIAs). Its efficient and highly selective biosynthesis is crucial for overcoming the limitations of natural extraction and enabling the large-scale production of BIAs. Recent advances in synthetic biology and metabolic engineering have led to significant breakthroughs in the heterologous production of chiral reticuline and BIAs in microbial hosts. However, the biosynthesis of (R)-reticuline remains constrained by the stereoselectivity of key enzymes, necessitating resolution through strategies such as enzyme engineering and pathway reconstitution. Studies on Nelumbo nucifera revealing an (R)-stereochemical preference offer novel pathways for synthesizing (R)-configured BIAs. This review systematically summarizes the application value of chiral reticuline as a key scaffold of BIAs, its synthetic pathways, and the latest research progress. We critically analyze current challenges and propose future research directions, aiming to provide both theoretical support and practical guidance for developing next-generation high-efficiency, high-selectivity BIAs.