Awakawa Takayoshi, Mori Takahiro, Ushimaru Richiro, Abe Ikuro
Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Collaborative Research Institute for Innovative Microbiology, the University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
Nat Prod Rep. 2023 Jan 25;40(1):46-61. doi: 10.1039/d2np00014h.
Non-heme iron- and α-ketoglutarate-dependent oxygenases (αKG OXs) are key enzymes that play a major role in diversifying the structure of fungal meroterpenoids. They activate a specific C-H bond of the substrate to first generate radical species, which is usually followed by oxygen rebound to produce cannonical hydroxylated products. However, in some cases remarkable chemistry induces dramatic structural changes in the molecular scaffolds, depending on the stereoelectronic characters of the substrate/intermediates and the resulting conformational changes/movements of the active site of the enzyme. Their molecular bases have been extensively investigated by crystallographic structural analyses and structure-based mutagenesis, which revealed intimate structural details of the enzyme reactions. This information facilitates the manipulation of the enzyme reactions to create unnatural, novel molecules for drug discovery. This review summarizes recent progress in the structure-based engineering of αKG OX enzymes, involved in the biosynthesis of polyketide-derived fungal meroterpenoids. The literature published from 2016 through February 2022 is reviewed.
非血红素铁和α-酮戊二酸依赖性加氧酶（αKG OXs）是关键酶，在真菌聚酮衍生的meroterpenoids结构多样化中起主要作用。它们激活底物的特定C-H键以首先生成自由基物种，随后通常是氧反弹以产生典型的羟基化产物。然而，在某些情况下，根据底物/中间体的立体电子特征以及酶活性位点随之产生的构象变化/移动，显著的化学反应会导致分子支架发生剧烈的结构变化。通过晶体学结构分析和基于结构的诱变对其分子基础进行了广泛研究，揭示了酶反应的详细结构细节。这些信息有助于操纵酶反应以创造用于药物发现的非天然新分子。本综述总结了参与聚酮衍生的真菌meroterpenoids生物合成的αKG OX酶基于结构的工程改造的最新进展。回顾了2016年至2022年2月发表的文献。
