Hou Yaning, Chen Jingyun, Liu Weizhe, Zhu Gaohua, Yang Qianying, Wang Xin
Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng 475004, China.
Molecules. 2024 Nov 22;29(23):5518. doi: 10.3390/molecules29235518.
Post-transition state bifurcation (PTSB) is a fundamental process in which a single transition state leads to multiple products. This phenomenon is important in both biological and chemical contexts and offers valuable insights into reaction mechanisms and their applications. The theozyme model, which focuses on key residues within enzymes, offers a computationally efficient method for studying these processes while preserving the enzyme's catalytic properties. This approach enhances our understanding of how enzymes stabilize and direct the transition state, thereby influencing product distribution and selectivity. In this study, we investigate the dynamics and regulatory mechanisms of the PTSB reaction catalyzed by the enzyme NgnD. The enzyme NgnD facilitates a cycloaddition reaction that produces both [6 + 4] and [4 + 2] adducts, with a preference for the [6 + 4] adduct. By analyzing the potential energy surface, bond length distribution, and interactions between the theozyme and the ambimodal transition state, we elucidate the role of the enzyme's active site residues in determining product selectivity. We illustrate how these key residues contribute to the formation of different adducts, providing insights from various perspectives. Using theozyme models, we propose how the four most influential active residues collectively might control the direction of adduct formation through their cumulative effects.
过渡态后分叉（PTSB）是一个基本过程，其中单一的过渡态会产生多种产物。这种现象在生物学和化学环境中都很重要，并且为反应机制及其应用提供了有价值的见解。专注于酶内关键残基的理论酶模型提供了一种计算效率高的方法来研究这些过程，同时保留酶的催化特性。这种方法增强了我们对酶如何稳定和引导过渡态从而影响产物分布和选择性的理解。在本研究中，我们研究了由NgnD酶催化的PTSB反应的动力学和调控机制。NgnD酶促进了一种环加成反应，该反应产生[6 + 4]和[4 + 2]加合物，且更倾向于[6 + 4]加合物。通过分析势能面、键长分布以及理论酶与双峰过渡态之间的相互作用，我们阐明了酶活性位点残基在决定产物选择性方面的作用。我们展示了这些关键残基如何有助于形成不同的加合物，从多个角度提供了见解。使用理论酶模型，我们提出了四个最具影响力的活性残基如何通过它们的累积效应共同控制加合物形成的方向。
