Fe(II)/α-酮戊二酸依赖型卤化酶作为生物催化剂的最新研究进展

Recent advances of Fe(II)/α-ketoglutarate-dependent halogenase as biocatalysts

关键词:  Fe(II)/α-酮戊二酸依赖型卤化酶  生物催化剂  卤化反应  生物合成

Key words:  Fe(II)/α-ketoglutarate-dependent halogenase  Biocatalyst  Halogenation reaction  biosynthesis

摘要:

摘要：生物催化C-H键活化在药物和精细化学品合成中具有关键作用，其中碳-卤键的高选择性构建是重要研究方向。尽管该领域取得显著进展，但未活化C(sp3)-H键的选择性卤化仍面临化学惰性突破、区域及立体控制等多重挑战。Fe(II)/α-酮戊二酸依赖型（Fe(II)/α-KG）卤化酶通过独特的自由基反应机制，能在温和条件下实现未活化sp3碳中心的精准卤化，展现出优异的区域、化学和立体选择性，为药物合成提供了创新工具。Fe(II)/α-KG卤化酶包括载体蛋白型和独立型两类，其在生物碱、氨基酸和核苷酸等天然产物生物合成中的卤化反应备受关注。本文综述了Fe(II)/α-KG卤化酶的催化机理及应用研究进展，并探讨了利用基因挖掘等生物信息学方法发掘新型Fe(II)/α-KG卤化酶的潜力，旨在为探索Fe(II)/α-KG卤化酶作为生物催化剂在新型卤化物合成途径等方面的研究提供有价值的参考。

Abstract:

In the field of biocatalysis, where C-H bond activation plays a pivotal role in the synthesis of pharmaceuticals and fine chemicals, with the highly selective construction of carbon-halogen bonds represents a critical research frontier. Despite remarkable advancements in this domain, selective halogenation of unactivated sp3 C-H bonds remains challenging due to inherent chemical inertness, difficulties in regioselectivity control, and precise stereochemical configuration regulation. Fe(II)/α-ketoglutarate-dependent halogenases (Fe(II)/α-KG halogenases) address these challenges through a unique radical-based mechanism, enabling precise halogenation of unactivated sp3 carbon centers under mild conditions. These enzymes exhibit exceptional regioselectivity, chemoselectivity, and stereoselectivity, thereby serving as innovative tools for pharmaceutical synthesis. Based on their distinct mechanisms of action, Fe(II)/α-KG halogenases are categorized into two major classes: carrier protein-dependent and independent types. Their halogenation reactions in the biosynthesis of natural products, including alkaloids, amino acids, and nucleotides, have garnered significant attention. This article systematically reviews recent advances in the catalytic mechanisms and applications of Fe(II)/α-KG halogenases, while exploring the potential of bioinformatics approaches such as gene mining for discovering novel variants. This review aims to provide a theoretical foundation for the development of these enzymes as biocatalysts in synthesizing innovative halogenated compounds.