QM/MM study of the stereospecific proton exchange of glutathiohydroxyacetone by glyoxalase I

Jafari, Sonia; Ryde, Ulf; Irani, Mehdi

doi:10.1016/j.rechem.2019.100011

Cited by 6 publications

(30 citation statements)

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“…This confirms the higher basicity of Glu-172 compared to Glu-99, as was previously proposed. [23][24][25][26] The big-QM energies of the four states are compared in Table 1, showing that the S1, S2 and R2 states are almost degenerate, whereas the R1 state is ~4 kcal/mol less stable than the others. In the latter, both protons (H1 and H2) point toward Glu-99, which may destabilize it by steric effects.…”

Section: Resultsmentioning

confidence: 99%

“…In summary, the three studies indicated that the higher basicity and flexibility of Glu-172 may explain the special stereospecificity of GlxI. Despite all previous studies, [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] there is not any computationally or experimentally confirmed mechanism for the reaction of the R enantiomer of the normal substrate of GlxI. Moreover, there are two opposing mechanisms for the S substrate and they are based on either a rather primitive ab initio method (HF/4-31G) or a small model of the active site with no constraints on the residues during optimization processes.…”

Section: Introductionmentioning

confidence: 83%

“…23 Recently, we confirmed the higher basicity of this residue by quantum mechanical cluster (QM-cluster) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. [24][25][26] In addition, we showed through molecular dynamics (MD) simulations that Glu-172 has a higher flexibility than Glu-99 and this flexibility causes its displacement form the Zn ion and its higher basicity. 25 However, Hartree-Fock and density functional theory (DFT) calculations using relatively small models and symmetric glutamates could not explain the unusual specificity of GlxI.…”

Section: Introductionmentioning

confidence: 98%

“…[26][27][28] In the last two decades, different aspects of the catalytic mechanism of GlxI have been studied. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Two mechanisms were proposed for the reaction of the S substrate with GlxI in 2001. [27][28][29] Richter and Krauss (RK), 28 used Hartree-Fock calculations, coupled with a frozen effective fragment potential, 38,39 whereas Creighton and Hamilton (CH), 29 summarizing experimental aspects of the catalytic mechanism of GlxI up to that date, suggested independently the same three-step mechanism shown in Scheme 2.…”

Section: Introductionmentioning

confidence: 99%

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Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

et al. 2020

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Glyoxalase I (GlxI) is a member of the glyoxalase system, which is important in cell detoxification and converts hemithioacetals of methylglyoxal (a cytotoxic byproduct of sugar metabolism that may react with DNA or proteins and introduce nucleic acid strand breaks, elevated mutation frequencies and structural or functional changes of the proteins) and glutathione into Dlactate. GlxI accepts both the S and R enantiomers of hemithioacetal, but converts them to only the S-D enantiomer of lactoylglutathione. Interestingly, the enzyme shows this unusual specificity with a rather symmetric active site (a Zn ion coordinated to two glutamate residues; Glu-99 and Glu-172), making the investigation of its reaction mechanism challenging. Herein, we have performed a series of combined quantum mechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-D enantiomer of the product. In addition, the results do not show any low-energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

et al. 2020

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“…Information about which alternative is more stable can be obtained by studying the root-mean-square deviation (RMSD) values of various atoms from the positions observed in the crystal structure. A similar method has been used to determine preferred protonation states of the active-site glutamates of glyoxalase I, 35 , 36 His residues in three proteins, 37 and for homocitrate and its nearby residues in nitrogenase. 38 The MD simulations showed almost the same RMSDs for the A and B conformations of Ser-309 and Val-342 but a much lower average RMSD for the B conformation of Ser-344 (0.17 vs 0.63 Å).…”

Section: Methodsmentioning

confidence: 99%

QM/MM Study of the Catalytic Reaction of Myrosinase; Importance of Assigning Proper Protonation States of Active-Site Residues

Jafari

Ryde

Irani

2021

J. Chem. Theory Comput.

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Myrosinase from Sinapis alba hydrolyzes glycosidic bonds of β- d - S -glucosides. The enzyme shows an enhanced activity in the presence of l -ascorbic acid. In this work, we employed combined quantum mechanical and molecular mechanical (QM/MM) calculations and molecular dynamics simulations to study the catalytic reaction of wild-type myrosinase and its E464A, Q187A, and Q187E mutants. Test calculations show that a proper QM region to study the myrosinase reaction must contain the whole substrate, models of Gln-187, Glu-409, Gln-39, His-141, Asn-186, Tyr-330, Glu-464, Arg-259, and a water molecule. Furthermore, to make the deglycosylation step possible, Arg-259 must be charged, Glu-464 must be protonated on OE2, and His-141 must be protonated on the NE2 atom. The results indicate that assigning proper protonation states of the residues is more important than the size of the model QM system. Our model reproduces the anomeric retaining characteristic of myrosinase and also reproduces the experimental fact that ascorbate increases the rate of the reaction. A water molecule in the active site, positioned by Gln-187, helps the aglycon moiety of the substrate to stabilize the buildup of negative charge during the glycosylation reaction and this in turn makes the moiety a better leaving group. The water molecule also lowers the glycosylation barrier by ∼9 kcal/mol. The results indicate that the Q187E and E464A mutants but not the Q187A mutant can perform the glycosylation step. However, the energy profiles for the deglycosylation step of the mutants are not similar to that of the wild-type enzyme. The Glu-464 residue lowers the barriers of the glycosylation and deglycosylation steps. The ascorbate ion can act as a general base in the reaction of the wild-type enzyme only if the Glu-464 and His-141 residues are properly protonated.

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Can a quantum mechanical cluster model explain the special stereospecificity of glyoxalase I?

Parvaneh

Parsa

Irani

2020

Computational and Theoretical Chemistry

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QM/MM study of the stereospecific proton exchange of glutathiohydroxyacetone by glyoxalase I

Cited by 6 publications

References 84 publications

Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

QM/MM Study of the Catalytic Reaction of Myrosinase; Importance of Assigning Proper Protonation States of Active-Site Residues

Can a quantum mechanical cluster model explain the special stereospecificity of glyoxalase I?

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