Acceleration of Mechanistic Investigation of Plant Secondary Metabolism Based on Computational Chemistry

Abstract

This review describes the application of computational chemistry to plant secondary metabolism, focusing on the biosynthetic mechanisms of terpene/terpenoid, alkaloid, flavonoid, and lignin as representative examples. Through these biosynthetic studies, we exhibit several computational methods, including density functional theory (DFT) calculations, theozyme calculation, docking simulation, molecular dynamics (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) calculation. This review demonstrates how modern computational chemistry can be employed as an effective tool for revealing biosynthetic mechanisms and the potential of computational chemistry—for example, elucidating how enzymes regulate regio- and stereoselectivity, finding the key catalytic residue of an enzyme, and assessing the viability of hypothetical pathways. Furthermore, insights for the next research objective involving application of computational chemistry to plant secondary metabolism are provided herein. This review will be helpful for plant scientists who are not well versed with computational chemistry.

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

“…Computational chemistry is now widely applied to modeling reactions of biosynthetic relevance . Detailed descriptions of computational methods can be found elsewhere, but it is important that practitioners generating and interpreting results, along with nonpractitioners who consume, interpret, and synthesize those results, keep the following distinctions in mind.…”

DFT Study on the Biosynthesis of Asperterpenol and Preasperterpenoid Sesterterpenoids: Exclusion of Secondary Carbocation Intermediates and Origin of Structural Diversification

“…Subsequently, 1,2-H shift takes place almost barrierlessly to migrate the cation center from C3 to C2, affording a cyclopropyl-carbinyl cation ( IM7 ), in which the highly distorted cyclopropane C–C bonds effectively stabilize the adjacent carbocation. In general, cyclopropylcarbinyl cations are in equilibrium with the corresponding homoallyl cations. , The position of the equilibrium depends on environmental factors . Thus, another 1,2-H shift can occur via the homoallyl cation ( IM8 ) to form an allyl cation intermediate IM9a .…”

“…Terpene/terpenoids are biosynthesized via multistep reaction sequences catalyzed by terpene cyclases (TCs) . Recently, the combination of computational and experimental chemistry has clarified the reaction pathways/mechanisms of terpene cyclizations, including remarkable skeletal rearrangement reactions, long-range hydrogen-shifts, and cation migrations . These carbocation cascade reactions usually proceed via stable cation intermediates, such as tertiary (3°) carbocations, allyl cations, and cyclopropyl carbinyl cations, but some have been proposed to involve more unstable/reactive intermediates, such as secondary (2°) carbocations and even primary (1°) carbocations.…”

“… However, their putative reaction pathway includes several questionable 2° carbocation intermediates, B , D , and I . In biosynthetic carbocation cascades, the overall energy profile generally descends as the reactions proceed and the overall exothermicity is usually huge. ,, In contrast, their putative final intermediate I (2° carbocation) appears energetically unfavorable. Moreover, hydration of the 2° carbocation ( I ) at the C1 position should give racemic products, and therefore would not explain the stereochemistry of the natural products, asperterpenol A and B.…”

Analysis of Genetic Diversity in the Traditional Chinese Medicine Plant ‘Kushen’ (Sophora flavescens Ait.)

“…CAO seems to be a peroxisomal protein, indicating a need for intermediates in the QA pathway to be shuffled between subcellular compartments ( Yang et al, 2017 ). The conversion of 5-aminopentanal to Δ 1 -piperideine is thought to occur spontaneously ( Sato et al, 2018 , 2019 ). The remaining steps in the QA pathway remain unknown.…”