Can a Mononuclear Iron(III)‐Superoxo Active Site Catalyze the Decarboxylation of Dodecanoic Acid in UndA to Produce Biofuels?

Lin, Yen-Ting; Stańczak, Agnieszka; Manchev, Yulian; Straganz, Grit Daniela; Visser, Sam P. de

doi:10.1002/chem.201903783

Cited by 30 publications

(26 citation statements)

References 112 publications

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“…The large spin-state separation energies may originate from the strong polarity of the chemical model and the large dipole moment of the cluster. These energy gaps are large in comparison to other nonheme iron complexes as, for instance, in cysteine dioxygenase an open-shell singlet spin iron(III)-superoxo complex as ground state was found, while for the undecanoic acid-activating enzyme, a mononuclear iron model predicted the septet and triplet to be close in energy . Nevertheless, the computational results match experimental studies that characterized the iron(IV)-oxo species of VioC using UV–vis absorption and Mössbauer spectroscopic studies as a quintet spin ground state …”

Section: Resultssupporting

confidence: 61%

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

et al. 2021

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The viomycin biosynthesis enzyme VioC is a nonheme iron and α-ketoglutarate-dependent dioxygenase involved in the selective hydroxylation of L-arginine at the C 3position for antibiotics biosynthesis. Interestingly, experimental studies showed that using the substrate analogue, namely, L-homoarginine, a mixture of products was obtained originating from C 3hydroxylation, C 4 -hydroxylation, and C 3 −C 4 -desaturation. To understand how the addition of one CH 2 group to a substrate can lead to such a dramatic change in selectivity and activity, we decided to perform a computational study using quantum mechanical (QM) cluster models. We set up a large active-site cluster model of 245 atoms that includes the oxidant with its firstand second-coordination sphere influences as well as the substrate binding pocket. The model was validated against experimental work from the literature on related enzymes and previous computational studies. Thereafter, possible pathways leading to products and byproducts were investigated for a model containing L-Arg and one for L-homo-Arg as substrate. The calculated free energies of activation predict product distributions that match the experimental observation and give a low-energy C 3 -hydroxylation pathway for L-Arg, while for L-homo-Arg, several barriers are found to be close in energy leading to a mixture of products. We then analyzed the origins of the differences in product distributions using thermochemical, valence bond, and electrostatic models. Our studies show that the C 3 −H and C 4 −H bond strengths of L-Arg and Lhomo-Arg are similar; however, external perturbations from an induced electric field of the protein affect the relative C−H bond strengths of L-Arg dramatically and make the C 3 −H bond the weakest and guide the reaction to a selective C 3 -hydroxylation channel. Therefore, the charge distribution in the protein and the induced electric dipole field of the active site of VioC guides the L-Arg substrate activation to C 3 -hydroxylation and disfavors the C 4 -hydroxylation pathway, while this does not occur for L-homo-Arg. Tight substrate positioning and electrostatic perturbations from the second-coordination sphere residues in VioC also result in a slower overall reaction for L-Arg; however, they enable a high substrate selectivity. Our studies highlight the importance of the second-coordination sphere in proteins that position the substrate and oxidant, perturb charge distributions, and enable substrate selectivity.

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Section: Resultssupporting

confidence: 61%

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

et al. 2021

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“…MPnS belongs to the vast superfamily of mononuclear non‐heme iron (MNHFe) enzymes which catalyze various meaningful biochemical reactions . One of MNHFe classes also involving the activation of O 2 and the release of CO 2 is α‐ketoacid‐dependent oxygenases (αKAOs), like taurine dioxygenase (TauD), prolyl‐4‐hydroxylase (P4H), fumitremorgin B endoperoxidase, and other α‐ketoglutarate dioxygenases .…”

Section: Resultsmentioning

confidence: 99%

“…The present procedure has been developed into an important tool for the understanding of reaction mechanisms and various properties of enzymes . Indeed, it has been successfully applied to a large variety of enzymes by different research groups, including a lot of mononuclear non‐heme iron enzymes …”

Section: Methodsmentioning

confidence: 99%

How To Produce Methane Precursor in the Upper Ocean by An Untypical Non‐Heme Fe‐Dependent Methylphosphonate Synthase?

Yan

Chen

2020

ChemPhysChem

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A new methane formation pathway, which uses methylphosphonate (MPn) as the methane precursor, has been discovered in the upper ocean. Methylphosphonate synthase (MPnS) is a key piece in this pathway to produce MPn from 2‐hydroxyethylphosphonate (2‐HEP), using an untypical 2‐His‐1‐Gln non‐heme iron architecture. Herein, the MPnS reaction mechanism was demonstrated by the density functional calculations to mainly include the substrate hydroxyl deprotonation, the formation of a MPn radical and a formate, and the hydrogen abstraction of formate by MPn radical. The second‐shell Lys28’ may serve as a proton reservoir activating 2‐HEP and regenerating the Fe site. The Fe‐bound superoxide radical is a bifunctional species to deprotonate the substrate hydroxyl and abstract the substrate methylene hydrogen. Several alternative mechanisms have been ruled out. Furthermore, the catalytic activity of MPnS was found to be inactivated/reduced by the mutation of Gln152E/Gln152H/Gln152D, rendering a significant evolutionary advantage with an uncommon 2‐His‐1‐Gln triad introduced to the ferrous coordination sphere.

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“…In the next stage of the project, QM/MM structures were set up based on the 4L40 protein data bank structure [31], using procedures reported previously [65,[86][87][88]. The wild-type structure was converted from an iron(III)-heme with ligated water molecule into an iron(IV)-oxo(heme+•) species by removing the water protons and changing the Fe-O distance to 1.63Å.…”

Section: Enzyme Set-upmentioning

confidence: 99%

Bioengineering of Cytochrome P450 OleTJE: How Does Substrate Positioning Affect the Product Distributions?

et al. 2020

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The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleTJE isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, β-hydroxylation and decarboxylation of the substrate. The latter produces hydrocarbon products and hence can be used as biofuels. The origin of these product distributions is unclear, and, as such, we decided to investigate substrate positioning in the active site and find out what the effect is on the chemoselectivity of the reaction. In this work we present a detailed computational study on the wild-type and engineered structures of P450 OleTJE using a combination of density functional theory and quantum mechanics/molecular mechanics methods. We initially explore the wild-type structure with a variety of methods and models and show that various substrate activation transition states are close in energy and hence small perturbations as through the protein may affect product distributions. We then engineered the protein by generating an in silico model of the double mutant Asn242Arg/Arg245Asn that moves the position of an active site Arg residue in the substrate-binding pocket that is known to form a salt-bridge with the substrate. The substrate activation by the iron(IV)-oxo heme cation radical species (Compound I) was again studied using quantum mechanics/molecular mechanics (QM/MM) methods. Dramatic differences in reactivity patterns, barrier heights and structure are seen, which shows the importance of correct substrate positioning in the protein and the effect of the second-coordination sphere on the selectivity and activity of enzymes.

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Can a Mononuclear Iron(III)‐Superoxo Active Site Catalyze the Decarboxylation of Dodecanoic Acid in UndA to Produce Biofuels?

Cited by 30 publications

References 112 publications

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

How Do Electrostatic Perturbations of the Protein Affect the Bifurcation Pathways of Substrate Hydroxylation versus Desaturation in the Nonheme Iron-Dependent Viomycin Biosynthesis Enzyme?

How To Produce Methane Precursor in the Upper Ocean by An Untypical Non‐Heme Fe‐Dependent Methylphosphonate Synthase?

Bioengineering of Cytochrome P450 OleTJE: How Does Substrate Positioning Affect the Product Distributions?

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