Understanding the Catalytic Mechanism of Xanthosine Methyltransferase in Caffeine Biosynthesis from QM/MM Molecular Dynamics and Free Energy Simulations

Qian, Ping; Guo, Haobo; Yue, Yufei; Wang, Liang; Yang, Xiaohan; Guo, Hong

doi:10.1021/acs.jcim.6b00153

Cited by 12 publications

(5 citation statements)

References 28 publications

(70 reference statements)

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“…Therefore, it is necessary to clarify the above fundamental questions of SnoK and SnoN. Herein, a series of QM/MM calculations have been performed, which has been widely and successfully applied for simulating the enzymatic reactions. − …”

Section: Introductionmentioning

confidence: 99%

Mechanism of Uncoupled Carbocyclization and Epimerization Catalyzed by Two Non-Heme Iron/α-Ketoglutarate Dependent Enzymes

Zhu

Liu

2019

J. Chem. Inf. Model.

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The non-heme iron/α-ketoglutarate dependent enzymes SnoK and SnoN from Streptomyces nogalater are involved in the biosynthesis of anthracycline nogalamycin. Although they have similar active sites, SnoK is responsible for carbocyclization whereas SnoN solely catalyzes the hydroxyl epimerization. Herein, we performed docking, molecular simulations, and a series of combined quantum mechanics and molecular mechanics (QM/MM) calculations to illuminate the mechanisms of two enzymes. The catalytic reactions of two enzymes occur on the quintet state surface. For SnoK, the whole reaction includes two separated hydrogen-abstraction steps and one radical addition, and the latter step is calculated to be rate limiting with an energy barrier of 21.7 kcal/mol. Residue D106 is confirmed to participate in the construction of the hydrogen bond network, which plays a crucial role in positioning the bulky substrate in a specific orientation. Moreover, it is found that SnoN is only responsible for the hydrogen abstraction of the intermediate, and no residue was suggested to be suitable for donating a hydrogen atom to the substrate radical, which further confirms the suggestion based on experiments that either a cellular reductant or another enzyme protein could donate a hydrogen atom to the substrate. Our docking results coincide with the previous structural study that the different roles of two enzymes are achieved by minor changes in the alignment of the substrates in front of the reactive ferryl-oxo species. This work highlights the reaction mechanisms catalyzed by SnoK and SnoN, which is helpful for engineering the enzymes for the biosynthesis of anthracycline nogalamycin.

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Section: Introductionmentioning

confidence: 99%

Mechanism of Uncoupled Carbocyclization and Epimerization Catalyzed by Two Non-Heme Iron/α-Ketoglutarate Dependent Enzymes

Zhu

Liu

2019

J. Chem. Inf. Model.

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“…This observation was evidenced in a two-dimensional free energy landscape for these DA reactions, and a one-dimensional reaction coordinate for these reactions would lead to potential artifacts and uncertainty in the locations of transition states, which in the end leads to an ambiguous reaction mechanism [ 6 , 7 ]. Although semi-empirical (SE) QM/MM calculations have been widely used [ 12 , 24 , 25 , 26 , 27 , 28 , 29 ], unfortunately, these semi-empirical methods may lead to large errors in the results due to the approximations adopted. Thus, high-level quantum mechanical methods at ab initio levels are necessary for a reliable depiction of electron redistribution during the reaction, which can be critical to the energetics such as activation and reaction free energies.…”

Section: Introductionmentioning

confidence: 99%

Efficient Computation of Free Energy Surfaces of Diels–Alder Reactions in Explicit Solvent at Ab Initio QM/MM Level

Liu

Jia

et al. 2018

Molecules

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For Diels–Alder (DA) reactions in solution, an accurate and converged free energy (FE) surface at ab initio (ai) quantum mechanical/molecular mechanical (QM/MM) level is imperative for the understanding of reaction mechanism. However, this computation is still far too expensive. In a previous work, we proposed a new method termed MBAR+wTP, with which the computation of the ai FE profile can be accelerated by several orders of magnitude via a three-step procedure: (I) an umbrella sampling (US) using a semi-empirical (SE) QM/MM Hamiltonian is performed; (II) the FE profile is generated using the Multistate Bennett Acceptance Ratio (MBAR) analysis; and (III) a weighted Thermodynamic Perturbation (wTP) from the SE Hamiltonian to the ai Hamiltonian is performed to obtain the ai QM/MM FE profile using weight factors from the MBAR analysis. In this work, this method is extended to the calculations of two-dimensional FE surfaces of two Diels–Alder reactions of cyclopentadiene with either acrylonitrile or 1-4-naphthoquinone at ai QM/MM level. The accurate activation free energies at the ai QM/MM level, which are much closer to the experimental measurements than those calculated by other methods, indicate that this MBAR+wTP method can be applied in the studies of complex reactions in condensed phase with much-enhanced efficiency.

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“…Caffeine biosynthesis involves the conversion of xanthosine into Cf [19]. The final step in this biosynthetic pathway is the conversion of Tb to Cf, which involves three successive methylation reactions catalyzed by Cf synthase [21]. The N1, N3, and N7 positiocons of Tb are then methylated, resulting in the formation of Cf [20] [21] [22].…”

Section: Possible Allelochemicals In Coffee Necmentioning

confidence: 99%

Cellular Growth Dynamics Affects Allelopathic Activity in Coffee Cell Culture

Asrori¹,

Ogita²

2023

AJPS

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Cellular growth dynamics and allelopathic activity in coffee cell cultures were examined as follows: First, we compared allelopathic activity of seven woody plant calli, Coffea canephora, Derris indica, Ficus carica L., Juniperus conferta, Prunus persica, Punica granatum, and Sonneratia ovata, using a modified "sandwich method bioassay" and found that coffee callus showed the strongest growth inhibition to lettuce seedling nearly 90% of hypocotyl and 96% of root. This coffee callus actively proliferated, with a 21-fold increase during five weeks of subculture, with a growth curve comprising two typical phases: a lag phase of 0 -2 weeks of culture and an exponential phase of 3 -5 weeks of culture. Allelopathic activity varied depending on the growth phase of the coffee callus. The strongest allelopathic activity was detected in 1 -2-week-old callus showing nearly 100% inhibitory effect on lettuce seedling growth. As the allelopathic activity of coffee calli is extremely high, beyond the natural level in coffee leaves and green beans, we focused on analyzing the allelopathic activity of its aqueous extracts using high-performance liquid chromatography. Several prominent peaks, including two reference alkaloids, theobromine and caffeine, which are known allelochemicals in coffee plants, and three distinct unknown peaks were identified at 270 nm in coffee calli during the lag phase (1 -2 weeks of culture). The higher value of the total phenolic content in the lag phase also suggested a key biosynthetic pathway in relation to the allelopathic activity of coffee callus will be activated in the lag phase.

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Understanding the Catalytic Mechanism of Xanthosine Methyltransferase in Caffeine Biosynthesis from QM/MM Molecular Dynamics and Free Energy Simulations

Cited by 12 publications

References 28 publications

Mechanism of Uncoupled Carbocyclization and Epimerization Catalyzed by Two Non-Heme Iron/α-Ketoglutarate Dependent Enzymes

Mechanism of Uncoupled Carbocyclization and Epimerization Catalyzed by Two Non-Heme Iron/α-Ketoglutarate Dependent Enzymes

Efficient Computation of Free Energy Surfaces of Diels–Alder Reactions in Explicit Solvent at Ab Initio QM/MM Level

Cellular Growth Dynamics Affects Allelopathic Activity in Coffee Cell Culture

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