Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
J Am Chem Soc. 2012 Nov 28;134(47):19454-62. doi: 10.1021/ja308295p. Epub 2012 Nov 15.
Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of more than 60,000 known natural products. This abundance of compounds is generated using a very limited pool of substrates based on linear isoprenoids. The astounding chemodiversity obtained by terpene cyclases suggests a tremendous catalytic challenge to these often promiscuous enzymes. In the current study we present a detailed mechanistic view of the biosynthesis of the monoterpene bornyl diphosphate (BPP) from geranyl diphosphate by BPP synthase using state of the art simulation methods. We identify the bornyl cation as an enzyme-induced bifurcation point on the multidimensional free energy surface, connecting between the product BPP and the side product camphene. Chemical dynamics simulations suggest that the active site diphosphate moiety steers reaction trajectories toward product formation. Nonetheless, chemical dynamics is not precise enough for exclusive product formation, providing a rationale for the lack of fidelity in this promiscuous terpene cyclase.
萜烯合酶负责在超过 60000 种已知天然产物的多步合成中进行初始环化级联反应。这些化合物的丰富度是基于线性异戊二烯利用非常有限的底物池生成的。萜烯合酶获得的惊人的化学多样性表明，这些通常是混杂的酶面临着巨大的催化挑战。在目前的研究中，我们使用最先进的模拟方法，对单萜烯莰烯二磷酸（BPP）从香叶基二磷酸到 BPP 合酶的生物合成提出了详细的机制观点。我们确定了莰烯阳离子作为酶诱导的分岔点，连接产物 BPP 和副产物莰烯。化学动力学模拟表明，活性位点的二磷酸部分引导反应轨迹向产物形成。尽管如此，化学动力学的精确性还不足以实现排他性的产物形成，这为这种混杂的萜烯合酶缺乏保真度提供了依据。
