Catalysis of tRNA Aminoacylation: Single Turnover to Steady-State Kinetics of tRNA Synthetases

Santra, Mantu; Bagchi, Biman

doi:10.1021/jp305045w

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…In addition, we only addressed four possible criteria, but other characteristic properties may also be optimized to support the functionality of biological systems. It would also be interesting to apply the mathematical formalism and the ranking method to other enzymatic systems that display high fidelity (i.e., low error rates) due to the presence of the KPR mechanism, e.g., aminoacyl-tRNA synthetase. ,, …”

Section: Discussionmentioning

confidence: 99%

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Trade-Offs between Error, Speed, Noise, and Energy Dissipation in Biological Processes with Proofreading

2019

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High accuracy of major biological processes relies on the ability of the participating enzymatic molecules to preferentially select the correct substrate from a pool of chemically similar substrates by activating the so-called proofreading mechanisms. While the importance of such mechanisms is widely accepted, it is still unclear how evolution has optimized the biological systems with respect to certain characteristic properties. Here, using a discrete-state stochastic framework with a first-passage analysis, we theoretically investigate trade-offs between four characteristic properties of enzymatic systems, namely, error, speed, noise, and energy dissipation. Specifically, two fundamental biological processes are examined, i.e., DNA replication in the T7 bacteriophage and tRNA selection during protein translation in Escherichia coli. Notably, all of the characteristic properties cannot be completely optimized at the same time due to trade-offs between them. To understand the relative importance of the computed quantities to the enzymatic functionality, we introduce a new quantitative metric to rank the properties. The results demonstrate that the reaction speed is the principal characteristic property that evolution optimizes in both enzymatic systems and that the energy dissipation comes in second. In addition, the error and the noise are always ranked third and fourth, respectively, regardless of the system considered. Physicochemical arguments to explain these observations are presented.

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Section: Discussionmentioning

confidence: 99%

“…It would also be interesting to apply the mathematical formalism and the ranking method to other enzymatic systems that display high fidelity (i.e., low error rates) due to the presence of the KPR mechanism, e.g., aminoacyl-tRNA synthetase. 22,36,37 ■ ASSOCIATED CONTENT * S Supporting Information…”

Section: ■ Conclusionmentioning

confidence: 99%

Trade-Offs between Error, Speed, Noise, and Energy Dissipation in Biological Processes with Proofreading

2019

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“…We presented an augmented kinetic scheme that included the role of water and employed the versatile technique of first passage time distribution to obtain time-dependent rate. The theory explained discrepancy between single turn over and steady state rate for both class I and class II enzymes [10].…”

Section: Introductionmentioning

confidence: 93%

“…In a previous study, we investigated the catalytic process of aminoacylation of tRNA. We showed that for class I synthetases, the steady state and single molecular events provide somewhat different kinetics [10]. We presented an augmented kinetic scheme that included the role of water and employed the versatile technique of first passage time distribution to obtain time-dependent rate.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Proofreading at Single Molecular Level: Aminoacylation of tRNAIle and the Role of Water as an Editor

Santra

Bagchi

2013

PLoS ONE

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Proofreading/editing in protein synthesis is essential for accurate translation of information from the genetic code. In this article we present a theoretical investigation of efficiency of a kinetic proofreading mechanism that employs hydrolysis of the wrong substrate as the discriminatory step in enzyme catalytic reactions. We consider aminoacylation of tRNAIle which is a crucial step in protein synthesis and for which experimental results are now available. We present an augmented kinetic scheme and then employ methods of stochastic simulation algorithm to obtain time dependent concentrations of different substances involved in the reaction and their rates of formation. We obtain the rates of product formation and ATP hydrolysis for both correct and wrong substrates (isoleucine and valine in our case, respectively), in single molecular enzyme as well as ensemble enzyme kinetics. The present theoretical scheme correctly reproduces (i) the amplitude of the discrimination factor in the overall rates between isoleucine and valine which is obtained as (1.8×102).(4.33×102) = 7.8×104, (ii) the rates of ATP hydrolysis for both Ile and Val at different substrate concentrations in the aminoacylation of tRNAIle. The present study shows a non-michaelis type dependence of rate of reaction on tRNAIle concentration in case of valine. The overall editing in steady state is found to be independent of amino acid concentration. Interestingly, the computed ATP hydrolysis rate for valine at high substrate concentration is same as the rate of formation of Ile-tRNAIle whereas at intermediate substrate concentration the ATP hydrolysis rate is relatively low. We find that the presence of additional editing domain in class I editing enzyme makes the kinetic proofreading more efficient through enhanced hydrolysis of wrong product at the editing CP1 domain.

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“…Finally, master equations involved in all such problems are solved by employing the method of mean first passage time [32,36,37], Gillespie algorithm or straight forward numerical integration. We adopt both the deterministic approach by solving differential equations numerically and stochastic simulation by employing Gillespie algorithm [38,39].…”

Section: In the Scheme The Primary Events Are The Following: (1) Thementioning

confidence: 99%

A Stochastic Chemical Dynamic Approach to Correlate Autoimmunity and Optimal Vitamin-D Range

2014

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Motivated by several recent experimental observations that vitamin-D could interact with antigen presenting cells (APCs) and T-lymphocyte cells (T-cells) to promote and to regulate different stages of immune response, we developed a coarse grained but general kinetic model in an attempt to capture the role of vitamin-D in immunomodulatory responses. Our kinetic model, developed using the ideas of chemical network theory, leads to a system of nine coupled equations that we solve both by direct and by stochastic (Gillespie) methods. Both the analyses consistently provide detail information on the dependence of immune response to the variation of critical rate parameters. We find that although vitamin-D plays a negligible role in the initial immune response, it exerts a profound influence in the long term, especially in helping the system to achieve a new, stable steady state. The study explores the role of vitamin-D in preserving an observed bistability in the phase diagram (spanned by system parameters) of immune regulation, thus allowing the response to tolerate a wide range of pathogenic stimulation which could help in resisting autoimmune diseases. We also study how vitamin-D affects the time dependent population of dendritic cells that connect between innate and adaptive immune responses. Variations in dose dependent response of anti-inflammatory and pro-inflammatory T-cell populations to vitamin-D correlate well with recent experimental results. Our kinetic model allows for an estimation of the range of optimum level of vitamin-D required for smooth functioning of the immune system and for control of both hyper-regulation and inflammation. Most importantly, the present study reveals that an overdose or toxic level of vitamin-D or any steroid analogue could give rise to too large a tolerant response, leading to an inefficacy in adaptive immune function.

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Catalysis of tRNA Aminoacylation: Single Turnover to Steady-State Kinetics of tRNA Synthetases

Cited by 9 publications

References 34 publications

Trade-Offs between Error, Speed, Noise, and Energy Dissipation in Biological Processes with Proofreading

Trade-Offs between Error, Speed, Noise, and Energy Dissipation in Biological Processes with Proofreading

Kinetic Proofreading at Single Molecular Level: Aminoacylation of tRNAIle and the Role of Water as an Editor

A Stochastic Chemical Dynamic Approach to Correlate Autoimmunity and Optimal Vitamin-D Range

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