Devesh Kumar

Iron-containing enzymes : versatile catalysts of hydroxylation reactions in nature

Nonheme iron(IV)-oxo oxidants in enzymes: Spectroscopic properties and reactivity patterns Heme iron(IV)-oxo oxidants in enzymes: Spectroscopic properties and reactivity patterns Mechanism and function of taurine/ -ketoglutarate dioxygenase enzymes, an update Mechanism and function of cysteine dioxygenase enzymes Mechanism and function of heme peroxidase enzymes Mechanism and function of cytochrome P450 enzymes Biomimetic studies of mononuclear nonheme iron containing oxidants Biomimetic studies of mononuclear porphyrin containing oxidants Density functional calibration studies on iron-containing systems Density functional theory studies on isomerisation reactions catalyzed by cytochrome P450 enzymes Quantum mechanics/molecular mechanics studies of peroxidase enzymes Theoretical modelling of nonheme iron containing oxidants

One oxidant, many pathways: A theoretical perspective of monooxygenation mechanisms by cytochrome P450 enzymes

Density functional theoretical studies of monooxygenation reactivity of the high-valent oxoiron(IV) porphyrin cation-radical compound of cytochrome P450, the so-called Compound I, and of its precursor, the ferric(III)-hydroperoxide species, are described. The degeneracy of the spin states of Compound I, its electron deficiency, and dense orbital manifold lead to two-state and multi-state reactivity scenarios and may thereby create reactivity patterns as though belonging to two or more different oxidants. Most of the controversies in the experimental data are reconciled using Compound I as the sole competent oxidant. Theory finds ferric(III)-hydroperoxide to be a very sluggish oxidant, noncompetitive with Compound I. If and when Compound I is absent, P450 oxidation will logically proceed by another form, but this has to be more reactive than ferric(III)-hydroperoxide. Theoretical studies are conducted to pinpoint such an oxidant for P450.

Reactivity patterns of cytochrome P450 enzymes: multifunctionality of the active species, and the two states–two oxidants conundrum

Covering: up to 2006 but not exhaustively n This focused review discusses mechanisms of oxygenation of organic compounds by cytochrome P450, based on density functional theory (DFT) and hybrid DFT and molecular mechanics (DFT/MM). The reactivity of the active species, Compound I, generally involves two-state reactivity (TSR) and sometimes multi-state reactivity (MSR). The reactivity of the ferric-hydroperoxide species (Compound 0) is reviewed too. According to DFT calculations, Compound 0 must be silent in the presence of Compound I. Much of the experimental mechanistic data is shown to be accounted for by the TSR/MSR concept.

Effect of the Axial Ligand on Substrate Sulfoxidation Mediated by Iron(IV)–Oxo Porphyrin Cation Radical Oxidants

Cytochromes P450 catalyze a range of different oxygen-transfer processes including aliphatic and aromatic hydroxylation, epoxidation, and sulfoxidation reactions. Herein, we have investigated substrate sulfoxidation mediated by models of P450 enzymes as well as by biomimetic oxidants using density functional-theory methods and we have rationalized the sulfoxidation reaction barriers and rate constants. We carried out two sets of calculations: first, we calculated the sulfoxidation by an iron(IV)-oxo porphyrin cation radical oxidant [Fe(IV)=O(Por(+.))SH] that mimics the active site of cytochrome P450 enzymes with a range of different substrates, and second, we studied one substrate (dimethyl sulfide) with a selection of different iron(IV)-oxo porphyrin cation radical oxidants [Fe(IV)=O(Por(+.))L] with varying axial ligands L. The study presented herein shows that the barrier height for substrate sulfoxidation correlates linearly with the ionization potential of the substrate, thus reflecting the electron-transfer processes in the rate-determining step of the reaction. Furthermore, the axial ligand of the oxidant influences the pK(a) value of the iron(IV)-oxo group, and, as a consequence, the bond dissociation energy (BDE(OH) value correlates with the barrier height for the reverse sulfoxidation reaction. These studies have generalized substrate-sulfoxidation reactions and have shown how they fundamentally compare with substrate hydroxylation and epoxidation reactions.

The intrinsic axial ligand effect on propene oxidation by horseradish peroxidase versus cytochrome P450 enzymes.

The axial ligand effect on reactivity of heme enzymes is explored by means of density functional theoretical calculations of the oxidation reactions of propene by a model compound I species of horseradish peroxidase (HRP). The results are assessed vis-à-vis those of cytochrome P450 compound I. It is shown that the two enzymatic species perform C=C epoxidation and C–H hydroxylation in a multistate reactivity scenario with FeIII and FeIV electromeric situations and two different spin states, doublet and quartet. However, while the HRP species preferentially keeps the iron in a low oxidation state (FeIII), the cytochromexa0P450 species prefers the higher oxidation state (FeIV). It is found that HRP compound I has somewhat lower barriers than those obtained by the cytochromexa0P450 species. Furthermore, in agreement with experimental observations and studies on model systems, HRP prefers C=C epoxidation, whereas cytochromexa0P450 prefers C–H hydroxylation. Thus, had the compound I species of HRP been by itself, it would have been an epoxidizing agent, and at least as reactive as cytochromexa0P450. In the enzyme, HRP is much less reactive than cytochromexa0P450, presumably because HRP reactivity is limited by the access of the substrate to compound I.

Electronic properties of pentacoordinated heme complexes in cytochrome P450 enzymes: search for an Fe(I) oxidation state

The cytochrome P450s are versatile enzymes that catalyze a range of monoxygenation reactions. Their catalytic cycle includes molecular oxygen binding and two reduction and protonation steps to create the active species, Compound I. In an anaerobic environment, however, only two reduction steps starting from the resting state can take place. Currently, very little information is known on this doubly-reduced species; therefore, we have performed a detailed density functional theory (DFT) and combined quantum mechanics/molecular mechanics (QM/MM) study on this complex. In principle, the doubly-reduced pentacoordinated heme can exist in two possible electronic configurations, namely an Fe(I) with closed-shell heme or an Fe(II) coupled to a heme anion radical [Fe(II) Por(-*)]. Our calculations show that there are several close-lying spin states with a [Fe(II) Por(-*)] configuration and these states are much lower in energy than the alternative [Fe(I) Por(0)] situation. We have calculated spectroscopic parameters of the lowest lying sextet spin state, including IR spectra and EPR parameters.