Second‐Coordination Sphere Effects on Selectivity and Specificity of Heme and Nonheme Iron Enzymes

Visser, Sam P. de

doi:10.1002/chem.201905119

Cited by 82 publications

(123 citation statements)

References 234 publications

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“…These predictions are in agreement with the observation that the Zn 2 + -induced inhibition of CYP3A4a ctivity is not relatedt ot he rate-determining step butt oi nteractions with cytochrome b 5 (a CYP450reductant). [17] Figure 3s hows as catterp lot of the driving force (DE8)f or the model A1 perturbed systemsd iscussed (Table 2) versus log k e and E act .B oth curves show an icely quadratic correlation between DE8 and the electron-transfer activation energy (E act ), which is not surprising as both E act and log k e [see Eqns. (2) and(3) in the Experimental Section] are quadratically connected to DE8.M oreover,t he plot shows that dramatic changes in the electron-transfer rate constant (log k e )c an be expectedd ue to minor externalp erturbations, such as the addition of solvent molecules or alkali ions in the second-coordination sphere of the heme.…”

Section: Resultsmentioning

confidence: 92%

“…[14] Often, the second-coordination sphere in heme andn onheme iron enzymes plays ac rucial role in determining the selectivity and activity of enzymes through either substrate and oxidant positioning or long-range electrostatic perturbations. [17] As the substrate-binding pocket in CYP450 isozymes is often tight, astraightforward Hammett analysis with analogous substrates is challenging. In particular,a ctive-site interactions and dynamicsm ay alter the binding affinity and/or reorientation of as ubstrate, thus modulating the site that is oxidizedb y compound I.T his argumenti so ften invoked to explain the experimentally observedp roduct ratios, which cannot be accounted for by calculated CÀHa ctivation barriers only.N evertheless, it has been established in many cases that amino acids far from the actives ite do influence the substrate binding and selectivity in CYP450 reactions.…”

Section: Introductionmentioning

confidence: 99%

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How Do Metal Ions Modulate the Rate‐Determining Electron‐Transfer Step in Cytochrome P450 Reactions?

Dixit

Warwicker

Visser

2020

Chemistry A European J

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Cytochrome P450 (CYP450)e nzymes play important roles in maintaining human health andt heir reaction rates are dependento nt he first electron transfer from the reduction partner.I nterestingly,e xperimental work has shown that this step is highly influenced by the addition of metal ions. To understand the effect of externalp erturbations on the CYP450 first reduction step, we have performed ac omputational studyw ith model complexes in the presence of metal and organic ions, solvent molecules, and an electricf ield. The results show that these medium-rangei nteractions affect the driving force as well as electron-transfer rates dramatically.Based on the location, distance, and direction of the ions/electric field, the catalytic reaction rates are enhanced or impaired. Calculations on al arge crystal structure with bonded alkali metal ions indicated inhibition patterns of the ions. Therefore, we predict that the activef orms of the naturalC YP450i sozymes will not have more than one alkali metal ion bound in the second-coordination sphere. As such, this study provides an insighti nto the activity of CYP450 enzymes and the effects of ions and electric field perturbations on their activity.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

How Do Metal Ions Modulate the Rate‐Determining Electron‐Transfer Step in Cytochrome P450 Reactions?

Dixit

Warwicker

Visser

2020

Chemistry A European J

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“…It has been shown that residues in the first and second coordination sphere contribute the most to this electric field. [4][5][6][7] Hence, the protein scaffold needs to be folded in a specific way such that these residues are in the correct spatial position and orientation to optimize the effect of the electric field on the active site.…”

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confidence: 99%

Direct Look at the Electric Field in Ketosteroid Isomerase and Its Variants

Hennefarth

Alexandrova

2020

ACS Catal.

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Enzymes catalyze a number of reactions with high efficiency and stereoselectivity. It is thought that strong, direct, and permanent electric fields within the active site of the enzyme contribute to the superb catalytic efficiency of enzymes. This effect is called electrostatic preorganization. Most often, electrostatic preorganization is analyzed by evaluating the local electric field at discrete points, such as a bond center, using, for example, vibrational Stark spectroscopy. However, the protein macromolecule creates a significantly more complicated heterogeneous electric field that affects the entire active site, whose total change density thus gets perturbed, with the implications for the catalytic mechanism. We present a global distribution of streamlines method to analyze the topology of the heterogeneous electric fields in within an enzyme active site. We focus on ketosteroid isomerase (KSI), an enzyme known to produce a field on the order of 100 MV/cm along the critical carbonyl bond in the steroid substrate. We investigate how mutations known to cause activity changes, as well as applied small external electric fields perturb the electric fields in the KSI active site. Where classical single-point analysis failed, using our method allowed us to properly correlate global changes in the electric field to changes in the reaction barrier. We were able to show that topologically similar local electric fields had similar reaction barriers.

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“…In general, the epoxidation barriers are also higher in energy for models B / D than those of models A / C shown above. Previously these differences were explained as originating from the axial ligand hydrogen bonding network that affects the redox potential of Cpd I and raises those in C c P [ 39 , 73 ].…”

Section: Resultsmentioning

confidence: 99%

“…Several attempts have been reported in the literature on the engineering of peroxidases with the aim to change their chemical properties and reactivity patterns [ 37 , 38 ]. In particular, first- and second-coordination sphere effects around the heme co-factor can lead to dramatic changes in the electronic properties of the metal center and consequently its conversion of substrates into products [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

Lee

Mubarak

Green

et al. 2020

IJMS

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Heme peroxidases have important functions in nature related to the detoxification of H2O2. They generally undergo a catalytic cycle where, in the first stage, the iron(III)–heme–H2O2 complex is converted into an iron(IV)–oxo–heme cation radical species called Compound I. Cytochrome c peroxidase Compound I has a unique electronic configuration among heme enzymes where a metal-based biradical is coupled to a protein radical on a nearby Trp residue. Recent work using the engineered Nδ-methyl histidine-ligated cytochrome c peroxidase highlighted changes in spectroscopic and catalytic properties upon axial ligand substitution. To understand the axial ligand effect on structure and reactivity of peroxidases and their axially Nδ-methyl histidine engineered forms, we did a computational study. We created active site cluster models of various sizes as mimics of horseradish peroxidase and cytochrome c peroxidase Compound I. Subsequently, we performed density functional theory studies on the structure and reactivity of these complexes with a model substrate (styrene). Thus, the work shows that the Nδ-methyl histidine group has little effect on the electronic configuration and structure of Compound I and little changes in bond lengths and the same orbital occupation is obtained. However, the Nδ-methyl histidine modification impacts electron transfer processes due to a change in the reduction potential and thereby influences reactivity patterns for oxygen atom transfer. As such, the substitution of the axial histidine by Nδ-methyl histidine in peroxidases slows down oxygen atom transfer to substrates and makes Compound I a weaker oxidant. These studies are in line with experimental work on Nδ-methyl histidine-ligated cytochrome c peroxidases and highlight how the hydrogen bonding network in the second coordination sphere has a major impact on the function and properties of the enzyme.

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Second‐Coordination Sphere Effects on Selectivity and Specificity of Heme and Nonheme Iron Enzymes

Cited by 82 publications

References 234 publications

How Do Metal Ions Modulate the Rate‐Determining Electron‐Transfer Step in Cytochrome P450 Reactions?

How Do Metal Ions Modulate the Rate‐Determining Electron‐Transfer Step in Cytochrome P450 Reactions?

Direct Look at the Electric Field in Ketosteroid Isomerase and Its Variants

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

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