Mechanistic Insights into a Stibene Cleavage Oxygenase NOV1 from Quantum Mechanical/Molecular Mechanical Calculations

Lu, Jiarui; Lai, Wenzhen

doi:10.1002/open.201800259

Cited by 11 publications

(7 citation statements)

References 62 publications

(131 reference statements)

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“…However, the end-on structure in the quintet state, which is the reactive state for the BTG13-catalyzed reaction, is 3.5 kcal/mol lower than that of the side-on structure. The former mode is thus proven to be more energetically favorable, which is consistent with the findings in other dioxygenases. ,− Therefore, in this work, the end-on mode was considered as the starting point of the catalytic reaction.…”

Section: Resultssupporting

confidence: 83%

Mechanistic Investigation on C–C Bond Cleavage of Anthraquinone Catalyzed by an Atypical Nonheme Iron-Dependent Dioxygenase BTG13

Deng,

Su,

Hou

et al. 2024

ACS Catal.

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An atypical nonheme iron-dependent dioxygenase BTG13 with a rare iron coordination of four histidine residues and a carboxylated-lysine (Kcx) was recently reported to catalyze the C 4a −C 10 bond cleavage of anthraquinone. However, the reaction mechanism of BTG13 remains elusive. Herein, the detailed mechanism of BTG13 is studied using molecular dynamics simulations and density functional theory calculations. The comprehensive mechanistic study shows that the most favorable pathway for the C−C bond cleavage of anthraquinone involves two unusual steps: (1) a hydrogen atom abstraction (HAA) from an sp 3 -hybridized carbon of the substrate by Fe III −O 2•− and (2) an oxygen rebound to the substrate radical via homolytic O−O bond cleavage, which activates Fe III −OOH to form Fe IV �O species. Furthermore, our results reveal that Kcx could increase the electron-donating ability of the ferrous iron, thereby boosting the activation of dioxygen to form Fe III −O 2•− species and facilitating the following HAA and O−O bond cleavage processes. This study advances the current knowledge of reactions catalyzed by iron-dependent oxygenases.

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Section: Resultssupporting

confidence: 83%

Mechanistic Investigation on C–C Bond Cleavage of Anthraquinone Catalyzed by an Atypical Nonheme Iron-Dependent Dioxygenase BTG13

Deng,

Su,

Hou

et al. 2024

ACS Catal.

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“…A separate QM/MM study proposed that the oxidizing species was a side-on Fe(II) superoxo radical. 194 However, both computational works were based on a problematic crystal structure; thus, the precise mechanism is still unknown. 195 As we further our understanding of the reaction mechanism of CCOs, we propose that a +2 charge will remain constant throughout the catalytic cycle.…”

Section: Nonheme Iron Oxygenases With a 4-hismentioning

confidence: 99%

“…There is still debate surrounding the mechanism of CCOs. A separate QM/MM study proposed that the oxidizing species was a side-on Fe(II) superoxo radical . However, both computational works were based on a problematic crystal structure; thus, the precise mechanism is still unknown .…”

Section: Nonheme Iron Oxygenases With a 4-his Ligand Scaffoldmentioning

confidence: 99%

Charge Maintenance during Catalysis in Nonheme Iron Oxygenases

Traore

Liu

2022

ACS Catal.

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Here, the choice of the first coordination shell of the metal center is analyzed from the perspective of charge maintenance in a binary enzyme–substrate complex and an O2-bound ternary complex in the nonheme iron oxygenases. Comparing homogentisate 1,2-dioxygenase and gentisate dioxygenase highlights the significance of charge maintenance after substrate binding as an important factor that drives the reaction coordinate. We then extend the charge analysis to several common types of nonheme iron oxygenases containing either a 2-His-1-carboxylate facial triad or a 3-His or 4-His ligand motif, including extradiol and intradiol ring-cleavage dioxygenases, thiol dioxygenases, α-ketoglutarate-dependent oxygenases, and carotenoid cleavage oxygenases. After forming the productive enzyme–substrate complex, the overall charge of the iron complex at the 0, +1, or +2 state is maintained in the remaining catalytic steps. Hence, maintaining a constant charge is crucial to promote the reaction of the iron center beginning from the formation of the Michaelis or ternary complex. The charge compensation to the iron ion is tuned not only by protein-derived carboxylate ligands but also by substrates. Overall, these analyses indicate that charge maintenance at the iron center is significant when all the necessary components form a productive complex. This charge maintenance concept may apply to most oxygen-activating metalloenzymes systems that do not draw electrons and protons step-by-step from a separate reactant, such as NADH, via a reductase. The charge maintenance perception may also be useful in proposing catalytic pathways or designing prototypical reactions using artificial or engineered enzymes for biotechnological applications.

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“…The protonation states of Lys134 and 4'-hydroxyl minimally affected the transition state energies suggesting that the interaction between these two groups is strictly for proper substrate positioning rather than to enable proton shuttling. The study by Lu, et al found the initial reactive state to be a side-on Fe II -O 2 − complex with partial electron transfer from resveratrol to the iron-oxy complex [78]. For the quintet spin state, the unpaired electrons on O 2 and resveratrol have anti-parallel spins suitable for peroxo bridge formation between O 2 and the α-carbon of resveratrol.…”

Section: Computational Studiesmentioning

confidence: 99%