Coordination dynamics of iron center enables the C–H bond activation: QM/MM insight into the catalysis of hydroxyglutarate synthase (HglS)

Fu, Yuzhuang; Wang, Binju; Cao, Zexing

doi:10.1016/j.jcat.2023.115149

Cited by 6 publications

(5 citation statements)

References 123 publications

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“…The mechanism of oxygen activation and formation of Fe(IV)-oxo species have been extensively studied before. ,,,− In this study, we revisited 2OG-assisted O 2 activation in BesD with QM/MM calculations. As depicted in Figure , our calculations are focused on the quintet state, which has been identified as the most reactive state for O 2 activation across previous studies. ,− , In line with previous computational studies, the reaction is initiated by the attack of Fe(III)-superoxo species onto the 2OG, which is coupled to the C–C cleavage, affording a fresh CO 2 molecule and an Fe(II)-peracid intermediate in IC1.…”

Section: Resultsmentioning

confidence: 99%

Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

Zhang,

Li,

Yuan

et al. 2024

ACS Catal.

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Despite extensive studies, how carrier-protein-independent BesD dictates the reaction toward thermodynamically unfavored halogenation is still elusive. Here, we investigated the chlorination versus hydroxylation selectivity in both carrier-protein-independent halogenase BesD and hydroxylase-evolved halogenase Chi-14, employing extensive MD simulations and QM/MM calculations. In BesD, our calculations have shown that 2OGassisted O 2 activation affords the axial Fe(IV)-oxo species that is responsible for the substrate C−H activation. To facilitate the following Cl-rebound reaction, the nascent axial Fe(III)−OH species has to undergo conformational isomerization to the equatorial one. This can remove the steric effects between the axial Fe(III)−OH and the substrate radical, thereby enhancing the migration of the substrate radical toward the Cl − ligand during the Clrebound. Notably, the hydrogen-bond interactions with second-sphere residue Asn are vital to maintain the unsaturated five-coordination shell of the Fe center. This maintenance is essential for enabling the conformational transition of Fe(III)−OH from an axial to an equatorial orientation. Our results are in concordance with existing experimental findings, underscoring the pivotal influence of iron coordination dynamics in governing the catalytic processes of nonheme enzymes.

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Section: Resultsmentioning

confidence: 99%

Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

Zhang,

Li,

Yuan

et al. 2024

ACS Catal.

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“…All optimization and scans were performed using the DL-find optimizer implemented in the ChemShell package . Optimizations were performed using a def2-SVP basis set and labeled as B1. , The choice of the basis set was made in alignment with previous computational studies on other KDMs − ,, and many similar nonheme enzymes. ,− Energies were recalculated for better accuracy using a higher basis set def2-TZVP (B2 level of energy) . Zero-point energy calculations were performed for all optimizations and labeled as B3 (QM(B2 + ZPE)/MM).…”

Section: Methodsmentioning

confidence: 99%

“…As with some, but not all, other Fe(II)/2OG oxygenases, ,− experimental studies have illustrated that in KDM2A, a transition from off-line (with KDM2A, this involves coordination of 2OG C1 carboxylate trans to H284) binding mode to an in-line (with KDM2A, coordination of 2OG trans to H212) binding mode is necessary for the demethylation reaction (Figure S2). The importance of such a transition from off-line to in-line 2OG coordination mode for effective catalysis has been demonstrated in PHF8 (KDM7B), showing 40% sequence similarity with KDM2A- and DNA-modifying enzymes AlkB and ALKBH2. , The importance of the off-line/in-line 2OG coordination modes has also been demonstrated in the catalysis of other Fe(II)/2OG enzymes such as halogenases , and EFE. ,, A recent study on another Fe-dependent enzyme, HgIS, highlights the importance of active site conformation and the rearrangement of the iron center for the C–H bond activation . Therefore, understanding such conformational changes in the active site and Fe center rearrangements might have implications on the catalytic mechanism of other nonheme Fe(II) enzymes.…”

Section: Introductionmentioning

confidence: 98%

“…39,45,46 A recent study on another Fedependent enzyme, HgIS, highlights the importance of active site conformation and the rearrangement of the iron center for the C−H bond activation. 47 Therefore, understanding such conformational changes in the active site and Fe center rearrangements might have implications on the catalytic mechanism of other nonheme Fe(II) enzymes.…”

Section: Introductionmentioning

confidence: 99%

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The Unique Role of the Second Coordination Sphere to Unlock and Control Catalysis in Nonheme Fe(II)/2-Oxoglutarate Histone Demethylase KDM2A

Thomas,

Jaber Sathik Rifayee,

Chaturvedi

et al. 2024

Inorg. Chem.

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Nonheme Fe(II) and 2-oxoglutarate (2OG)-dependent histone lysine demethylases 2A (KDM2A) catalyze the demethylation of the mono- or dimethylated lysine 36 residue in the histone H3 peptide (H3K36me1/me2), which plays a crucial role in epigenetic regulation and can be involved in many cancers. Although the overall catalytic mechanism of KDMs has been studied, how KDM2 catalysis takes place in contrast to other KDMs remains unknown. Understanding such differences is vital for enzyme redesign and can help in enzyme-selective drug design. Herein, we employed molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) to explore the complete catalytic mechanism of KDM2A, including dioxygen diffusion and binding, dioxygen activation, and substrate oxidation. Our study demonstrates that the catalysis of KDM2A is controlled by the conformational change of the second coordination sphere (SCS), specifically by a change in the orientation of Y222, which unlocks the 2OG rearrangement from off-line to in-line mode. The study demonstrates that the variant Y222A makes the 2OG rearrangement more favorable. Furthermore, the study reveals that it is the size of H3K36me3 that prevents the 2OG rearrangement, thus rendering the enzyme inactivity with trimethylated lysine. Calculations show that the SCS and long-range interacting residues that stabilize the HAT transition state in KDM2A differ from those in KDM4A, KDM7B, and KDM6A, thus providing the basics for the enzyme-selective redesign and modulation of KDM2A without influencing other KDMs.

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“…Furthermore, the same QM regions were considered in QM/MM calculations and QM/MM MD simulations, as shown in Figure S5. The B3LYP treatment of the QM region has been demonstrated to be reliable in our previous studies. − Here, two basis sets were adopted in our calculations. The all-electron basis set Def2-SVP (labeled as B1) , was utilized in the geometry optimization by DL-FIND, and a relatively large basis set, Def2-TZVP (labeled as B2), was applied to determine relative energies.…”

Section: Computational Detailsmentioning

confidence: 99%

Elucidating the Enzymatic Mechanism of Dihydrocoumarin Degradation: Insight into the Functional Evolution of Methyl-Parathion Hydrolase from QM/MM and MM MD Simulations

Fu,

Yu,

Fan

et al. 2024

J. Phys. Chem. B

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Methyl-parathion hydrolase (MPH), which evolved from dihydrocoumarin hydrolase, offers one of the most efficient enzymes for the hydrolysis of methyl-parathion. Interestingly, the substrate preference of MPH shifts from the methyl-parathion to the lactone dihydrocoumarin (DHC) after its mutation of five specific residues (R72L, L273F, L258H, T271I, and S193Δ, m5-MPH). Here, extensive QM/MM calculations and MM MD simulations have been used to delve into the structure−function relationship of MPH enzymes and plausible mechanisms for the chemical and nonchemical steps, including the transportation and binding of the substrate DHC to the active site, the hydrolysis reaction, and the product release. The results reveal that the five mutations remodel the active pocket and reposition DHC within the active site, leading to stronger enzyme−substrate interactions. The MM/GBSA-estimated binding free energies are about −20.7 kcal/mol for m5-MPH and −17.1 kcal/mol for wild-type MPH. Furthermore, this conformational adjustment of the protein may facilitate the chemical step of DHC hydrolysis and the product release, although there is a certain influence on the substrate transport. The hydrolytic reaction begins with the nucleophilic attack of the bridging OH − with the energy barriers of 22.0 and 18.0 kcal/mol for the wild-type and m5-MPH enzymes, respectively, which is rate-determining for the entire process. Unraveling these mechanistic intricacies may help in the understanding of the natural evolution of enzymes for diverse substrates and establish the enzyme structure−function relationship.

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Coordination dynamics of iron center enables the C–H bond activation: QM/MM insight into the catalysis of hydroxyglutarate synthase (HglS)

Cited by 6 publications

References 123 publications

Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

The Unique Role of the Second Coordination Sphere to Unlock and Control Catalysis in Nonheme Fe(II)/2-Oxoglutarate Histone Demethylase KDM2A

Elucidating the Enzymatic Mechanism of Dihydrocoumarin Degradation: Insight into the Functional Evolution of Methyl-Parathion Hydrolase from QM/MM and MM MD Simulations

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