A water-mediated and substrate-assisted aminoacylation mechanism in the discriminating aminoacyl-tRNA synthetase GlnRS and non-discriminating GluRS

Aboelnga, Mohamed M.; Hayward, John; Gauld, James W.

doi:10.1039/c7cp02969a

Cited by 12 publications

(11 citation statements)

References 41 publications

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“…We further suggested that the ribozymal mechanism that we discovered is common in the editing reaction of various aaRS systems beyond the classes ( Table 1) [63]. In fact, Thermus thermophilus IleRS (class Ia) [77], Pyrococcus abyssi ThrRS (class IIa) [72,74,75,78], and Enterococcus faecalis ProRS (class IIa) [71] showed the similar binding mode of the nucleophilic water in the catalytic site. Furthermore, Kumar et al also suggested that the editing reaction of the complex of prolyl-tRNA synthetase (ProRS) and alanyl-tRNA Pro exhibited a similar mechanism, in which the 2 0 -OH group of A76 of tRNA Pro was involved in the substrate binding and the activation of the nucleophilic water [71].…”

Section: Ab Initio Qm/mm MD Simulation Of Editing Reactionmentioning

confidence: 67%

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Kang¹,

Sumi²,

Tateno³

2019

Panorama of Contemporary Quantum Mechanics - Concepts and Applications

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In this chapter, we present recent advances of theoretical analyses toward understandings of functional mechanisms of biological macromolecular systems, employing ab initio electronic structure calculations. Two distinct types of triggers to invoke dramatic rearrangements of electronic structures in the reaction centers are revealed by full ab initio quantum mechanics (QM) calculations (first example) and hybrid ab initio QM/molecular mechanics (MM) molecular dynamics (MD) calculations (second example). First, we demonstrate dramatic rearrangements of molecular orbitals (MOs) induced by binding of a hydroxyl ion (OH À) to the [4Fe-3S] cluster found in hydrogenases, which catalyzes both dissociation and production of dihydrogen (H 2). This induces the significant delocalization of the LUMO, resulting in formation of electron transfer pathways required for the catalysis. Thus, in organisms, just a tiny species (e.g. OH À ligand) can play a key role for the biological functions. Second, we indicate dynamical rearrangements of MOs occurring in the enzymatic reactions of RNA-protein complexes. As the catalysis proceeds, the reactive MOs, which do not belong to the frontier orbitals in the initial stages of the reaction, are dramatically reconstituted in the hybrid ab initio QM/MM MD simulations, resulting in the frontier orbitals, which is a feature characteristic to biological macromolecular systems.

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Section: Ab Initio Qm/mm MD Simulation Of Editing Reactionmentioning

confidence: 67%

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Kang¹,

Sumi²,

Tateno³

2019

Panorama of Contemporary Quantum Mechanics - Concepts and Applications

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“…In the porphyrin/chlorophyll category, GLUTAM-ATE-TRNA LIGASE (GluRS), MAGNESIUM-CHELAT ASE SUBUNIT CHLI (GUN4) and DIVINYL CHLORO-PHYLLIDE A 8-VINYL-REDUCTASE (DVR) genes showed upregulation under white light. These genes localize in the chloroplast and are involved in the biosynthesis of chlorophyll and heme molecules, essential for light-harvesting and energy transduction in photosynthesis and the cell growth [41][42][43][44]. The flavonoids are thought to participate in protecting the photosynthetic apparatus against photoinhibition under excessive light [45].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analyses of cacao flavonoids produced in photobioreactors

et al. 2021

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Background Theobroma cacao is a major source of flavonoids such as catechins and their monomers proanthocyanidins (PAs), widely studied for their potential benefits in cardiovascular diseases. Light has been shown to promote plant secondary metabolite production in vitro. In this study, cacao cells cultured in 7.5 L stirred tank photobioreactors (STPs) were exposed to a change of white to blue LED lights for 28 days (d). Results Transcriptomic analyses were performed in three time points comparing changing expression patterns, after cell exposure to white light (d0-VS-d14), after a shift from white to blue light (d14-VS-d15), and after an extended period of blue light for the following 15 days (d15-VS-d28). Under white light, there was enrichment in metabolic pathways associated with cell growth (carbon, glycolysis, and amino acid biosynthesis) accompanied by a significant increase in the PAs content. In the shift to blue light, further increase in PAs content was observed concomitantly with the significant expression of TWO-COMPONENT RESPONSE REGULATOR genes involved in the early stress responses via circadian clock and hormone pathways. Under blue light exposure, we observed a depletion of PAs content associated with ROS-mediated stress pathways. Conclusions Light effects on large-scale cell cultures in photobioreactors are complex and pleiotropic; however, we have been able to identify key regulatory players upstream cacao flavonoid biosynthesis in STPs, including TWO-COMPONENT SYSTEM and ROS-signaling genes. The crosstalk between flavonoid biosynthesis and regulatory networks led to understand the dynamics of flavonoid production and degradation in response to light-driven ROS signals. This can be used to optimize the time, and the yield of in vitro targeted metabolites in large-scale culture systems.

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“…Using MOE and the NAMD program, we submitted the resulting minimized model for unconstrained 10 ns MD simulation with a time step of 2 fs under constant pressure and temperature until the system reached equilibrium using a protocol we have successfully used in related studies. − It is noted that the default settings of MOE were used, which includes use of the PME method for calculating Coulombic interactions, cutoffs for nonbonded long-range interactions of between 8 and 10 Å, and tether ranges from 0 to 100 Å applied to all heavy atoms. Furthermore, the standard protocol that is encoded in MOE was used to parametrize any ligands using the Amber12 force field.…”

Section: Computational Methodsmentioning

confidence: 99%

Unraveling the Critical Role Played by _Ado762′OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase

2018

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Archaeal threonyl-tRNA synthetase (ThrRS) possesses an editing active site wherein tRNA that has been misaminoacylated with serine (i.e., Ser-tRNA) is hydrolytically cleaved to serine and tRNA. It has been suggested that the free ribose sugar hydroxyl of Ado76 of the tRNA (2'OH) is the mechanistic base, promoting hydrolysis by orienting a nucleophilic water near the scissile Ser-tRNA ester bond. We have performed a computational study, involving molecular dynamics (MD) and hybrid ONIOM quantum mechanics/molecular mechanics (QM/MM) methods, considering all possible editing mechanisms to gain an understanding of the role played by 2'OH group. More specifically, a range of concerted or stepwise mechanisms involving four-, six-, or eight-membered transition structures (total of seven mechanisms) were considered. In addition, these seven mechanisms were fully optimized using three different DFT functionals, namely, B3LYP, M06-2X, and M06-HF. The M06-HF functional gave the most feasible energy barriers followed by the M06-2X functional. The most favorable mechanism proceeds stepwise through two six-membered ring transition states in which the2'OH group participates, overall, as a shuttle for the proton transfer from the nucleophilic HO to the bridging oxygen (3'O) of the substrate. More specifically, in the first step, which has a barrier of 25.9 kcal/mol, the 2'-OH group accepts a proton from the attacking nucleophilic water while concomitantly transferring its proton onto the substrates C-O center. Then, in the second step, which also proceeds with a barrier of 25.9 kcal/mol, the 2'-OH group transfers its proton on the adjacent3'-oxygen, cleaving the scissile C-O3' bond, while concomitantly accepting a proton from the previously formed C-OH group.

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A water-mediated and substrate-assisted aminoacylation mechanism in the discriminating aminoacyl-tRNA synthetase GlnRS and non-discriminating GluRS

Cited by 12 publications

References 41 publications

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Transcriptomic analyses of cacao flavonoids produced in photobioreactors

Unraveling the Critical Role Played by _Ado762′OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase

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A water-mediated and substrate-assisted aminoacylation mechanism in the discriminating aminoacyl-tRNA synthetase GlnRS and non-discriminating GluRS

Cited by 12 publications

References 41 publications

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

Transcriptomic analyses of cacao flavonoids produced in photobioreactors

Unraveling the Critical Role Played by Ado762′OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase

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Unraveling the Critical Role Played by _Ado762′OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase