Cao Jingyu, Lu Jingyuan, Cao Yuanxin, de Visser Sam P
Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom.
Department of Chemical Engineering, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom.
Chemistry. 2025 Mar 17;31(16):e202404250. doi: 10.1002/chem.202404250. Epub 2025 Jan 23.
The natural product synthesis of brevione J undergoes a cascade of reactions including an oxidative desaturation and a ring-expansion. The C-C desaturation of brevione B is catalyzed by the nonheme iron dioxygenase BrvJ using one molecule of O and α-ketoglutarate (αKG). However, whether the subsequent oxidative ring expansion reaction is also catalyzed by the same enzyme is unknown and remains controversial. To gain insight into the mechanism of brevione J biosynthesis a computational study is reported here using molecular dynamics and density functional theory approaches. The work predicts that both cycles can proceed in the same protein structure on an iron center with O and αKG for each cycle. The rate-determining step is a hydrogen atom abstraction step in both reaction cycles. Interestingly, the OH rebound barriers are high in energy in cycle 1 due to stereochemical interactions and substrate positioning that enable an efficient desaturation reaction.
短叶酮J的天然产物合成经历了一系列反应，包括氧化去饱和反应和扩环反应。短叶酮B的碳-碳去饱和反应由非血红素铁双加氧酶BrvJ催化，该反应消耗一分子氧气和α-酮戊二酸（αKG）。然而，后续的氧化扩环反应是否也由同一酶催化尚不清楚，仍存在争议。为深入了解短叶酮J的生物合成机制，本文报道了一项使用分子动力学和密度泛函理论方法的计算研究。该研究预测，两个反应循环均可在同一蛋白质结构中的铁中心上进行，每个循环均消耗氧气和α-酮戊二酸。两个反应循环的速率决定步骤均为氢原子提取步骤。有趣的是，由于立体化学相互作用和底物定位使得去饱和反应高效进行，循环1中的羟基回弹能垒在能量上较高。
