Mechanism of a Soluble Fumarate Reductase from<i>Shewanella frigidimarina</i>:  A Theoretical Study

Lucas, Fátima; Ramos, María J.

doi:10.1021/jp057456t

Cited by 5 publications

(8 citation statements)

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“…For small models, typically with less than 150 atoms, ,,– our preferred choice of methodology has been density functional theory (DFT) . We have used it in several catalytic and inhibition mechanisms of various enzymes, having obtained very good values in agreement with experiment.…”

Section: Resultsmentioning

confidence: 99%

“…A creative mind together with adequate computational resources and a talent for "traveling" through a PES can do the trick! For small models, typically with less than 150 atoms, 7,12,[36][37][38] our preferred choice of methodology has been density functional theory (DFT). 39 We have used it in several catalytic and inhibition mechanisms of various enzymes, having obtained very good values in agreement with experiment.…”

Section: Resultsmentioning

confidence: 99%

“…Computational enzymatic catalysis is our favorite field of research, and rather than briefly introducing several of those mechanisms in which we have been involved lately, for example, PFL, , COX2, uroporphyrinogen III decarboxylase, fumarate reductase, thiol/disulfide exchange, thioredoxin, and DsbA, , we chose to present in greater detail two cases that we have studied at length, ribonucleotide reductase ,,,– and farnesyltransferase. ,,– , We have chosen them not only because they are very different systems but also for the simple reason that we have had to apply a large spectrum of different methodologies to unravel their respective catalytic and inhibition mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Computational Enzymatic Catalysis

2008

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Computational methodologies are playing increasingly important roles in elucidating and presenting the complete and detailed mechanisms of enzymatic reactions because of their capacity to determine and characterize intermediates and transition states from both structural and energetics points of view, independent of their reduced lifetimes and without interfering with the natural reactional flux. These features are turning the field into an active and interesting area of research, involving a diverse range of studies, mostly directed at understanding the ways in which enzymes function under certain circumstances and predicting how they will behave under others. The accuracy of the computational data obtained for a given mechanistic hypothesis depends essentially on three mutually exclusive factors: the accuracy of the Hamiltonian of the reaction mechanism, consideration of the modulating aspect of the enzyme's structure in the energetics of the active center, and consideration of the enzyme's conformational fluctuations and dynamics. Although, unfortunately, it is impossible at present to optimize these crucial factors simultaneously, the success of any enzymatic mechanistic study depends on the level of equilibrium achieved among them. Different authors adopt different solutions, and this Account summarizes the most favored, with emphasis placed on our own preferences. Another crucial aspect in computational enzymatic catalysis is the model used in the calculations. Our aim is to build the simplest model that captures the essence of the catalytic power of an enzyme, allowing us to apply the highest possible theoretical level and minimize accidental errors. The choice is, however, far from obvious, ranging from simple models containing tens of atoms up to models of full enzymes plus solvent. Many factors underlie the choice of an appropriate model; here, examples are presented of very different modeling strategies that have been employed to obtain meaningful results. One particular case study, that of enzyme ribonucleotide reductase (RNR), a radical enzyme that catalyzes the reduction of ribonucleotides into deoxyribonucleotides, is one of the examples illustrating how the successive increase of the system's size does not dramatically change the thermodynamics and kinetics of the reaction. The values obtained and presented speak for themselves in that the only ones that are distinctly different are those calculated using an exceedingly small model, which omitted the amino acids that establish hydrogen bonds with the reactive unit of the substrate. This Account also describes our computational analysis of the mechanism of farnesyltransferase, a heterodimeric zinc metalloenzyme that is currently one of the most fascinating targets in cancer research. We focus on the present methodologies that we have been using, our models and understanding of the problem, and the accuracy of results and associated problems within this area of research.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Computational Enzymatic Catalysis

2008

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“…This is consistent with the active site in respiratory complex II 38 that shields the negative charges in succinate carboxylates by hydrogen bonding with positively charged residues and with previous calculations on similar reactions. 40 These models had 45, 44, and 51 atoms, respectively.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Succinate had its carboxylates protonated into succinic acid for both E1 elimination from H 2 Suc (butanedioic acid) and E1cb elimination from H 2 Suc – [(E)-4-hydroxy-4-oxidobut-3-enoic acid]. This is consistent with the active site in respiratory complex II that shields the negative charges in succinate carboxylates by hydrogen bonding with positively charged residues and with previous calculations on similar reactions . These models had 45, 44, and 51 atoms, respectively.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms for Flavin-Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

Curtolo

Arantes

2020

J. Chem. Inf. Model.

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Flavins are versatile biological cofactors which catalyze proton-coupled electron transfers (PCET) with varying number and coupling of electrons. Flavin mediated oxidation of nicotinamide adenine dinucleotide (NADH) and of succinate, initial redox reactions in cellular respiration, were examined here with multiconfigurational quantum chemical calculations and a simple analysis of the wave-function proposed to quantify electron transfer along the proton reaction coordinate. The mechanism of NADH oxidation is a prototypical hydride transfer, with two electrons moving concerted with the proton to the same acceptor group. However, succinate oxidation depends on the elimination step and can proceed through the transfer of hydride or hydrogen-atom, with proton and electrons moving to different groups in both cases. These results help to determine the mechanism of fundamental but still debated biochemical reactions, and illustrate a new diagnostic tool for electron transfer that can be useful to characterize a broad class of PCET processes.

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