New features in the catalytic cycle of cytochrome P450 during the formation of compound I from compound 0

Density functional theory (DFT) is applied to the dark section of the catalytic cycle of the enzyme cytochrome P450, namely, the formation of the active species, Compound I (Cpd I), from the ferric-hydroperoxide species (Cpd 0) by a protonation-assisted mechanism. The chosen 96-atom model includes the key functionalities deduced from experiment: Asp(251), Thr(252), Glu(366), and the water channels that relay the protons. The DFT model calculations show that (a) Cpd I is not formed spontaneously from Cpd 0 by direct protonation, nor is the process very exothermic. The process is virtually thermoneutral and involves a significant barrier such that formation of Cpd I is not facile on this route. (b) Along the protonation pathway, there exists an intermediate, a protonated Cpd 0, which is a potent oxidant since it is a ferric complex of water oxide. Preliminary quantum mechanical/molecular mechanical calculations confirm that Cpd 0 and Cpd I are of similar energy for the chosen model and that protonated Cpd 0 may exist as an unstable intermediate. The paper also addresses the essential role of Thr(252) as a hydrogen-bond acceptor (in accord with mutation studies of the OH group to OMe).     

Active species of horseradish peroxidase (HRP) and cytochrome P450: two electronic chameleons

The active site of HRP Compound I (Cpd I) is modeled using hybrid density functional theory (UB3LYP). The effects of neighboring amino acids and of environmental polarity are included. The low-lying states have porphyrin radical cationic species (Por(*)(+)). However, since the Por(*)(+) species is a very good electron acceptor, other species, which can be either the ligand or side chain amino acid residues, may participate in electron donation to the Por(*)(+) moiety, thereby making Cpd I behave like a chemical chameleon. Thus, this behavior that was noted before for Cpd I of P450 is apparently much more wide ranging than initially appreciated. Since chemical chameleonic behavior property was found to be expressed not only in the properties of Cpd I itself, but also in its reactivity, the roots of this phenomenon are generalized. A comparative discussion of Cpd I species follows for the enzymes HRP, CcP, APX, CAT (catalase), and P450.     

How does product isotope effect prove the operation of a two-state "rebound" mechanism in C-H hydroxylation by cytochrome P450?

C-H hydroxylation is a fundamental process. In Nature it is catalyzed by the enzyme cytochrome P450, in a still-debated mechanism that poses a major intellectual challenge for both experiment and theory; currently, the opinions keep swaying between the original single-state rebound mechanism, a two-oxidant mechanism (where ferric peroxide participates as a second oxidant, in addition to the primary active species, the high-valent iron-oxo species), and two-state reactivity (TSR) mechanism (where two spin states are involved). Recent product isotope effect (PIE) measurements for the trans-2-phenyl-methyl cyclopropane probe (1), led Newcomb and co-workers (Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065) to rule out TSR in favor of the two-oxidant scenario, since the direction of the PIE was at odds with the one predicted from calculations on methane hydroxylation. The present report describes a density functional theoretical study of C-H hydroxylation of the Newcomb probe, 1, leading to rearranged (3) and unrearranged (2) products. Our study shows that the reaction occurs via TSR in which the high-spin pathway gives dominant rearranged products, whereas the low-spin pathway favors unrearranged products. The calculated PIE(2/3) values based on TSR are found to be in excellent agreement with the experimental data of Newcomb and co-workers. This match between experiment and theory makes a strong case that the reaction occurs via TSR mechanism.     

Recent strategy(ies) for the electrocatalytic reduction of CO2: Ni single-atom catalysts for the selective electrochemical formation of CO in aqueous electrolytes

To decrease the global carbon footprint concerns and to diminish the energy crisis, electrocatalytic reduction of CO₂ which results in the formulation of value-added chemicals is a potential solution. In this review, single-atom catalysts (SACs) which are rapidly growing and being developed as the stimulating catalytic materials for electrocatalytic reduction of CO₂ with improved selectivity, efficiency, and stability are considered. Various factors which are responsible for the efficient CO₂ reduction are discussed. The pyrolytic approach for the preparation of Ni-based SACs and the maximum atom utilization efficiency for the desirable production of CO from CO₂ are highlighted.     

Palladium-catalyzed convenient one-pot synthesis of multi-substituted 2-pyrones via transesterification and alkenylation of enynoates

An efficient one-pot protocol for the synthesis of multi-substituted 2-pyrone derivatives from internal alkynes and unactivated alkenes is reported. The methodology involves difunctionalization of internal alkynes by using Pd(II) as a catalyst alongwith X-Phos as ligand via 6-endo transesterification and subsequent alkenylation pathway. Notable features include simple and easily available starting materials, including a range of unactivated alkenes, reduced synthetic steps and mild reaction conditions with high efficiency.     

Steric factors override thermodynamic driving force in regioselectivity of proline hydroxylation by prolyl-4-hydroxylase enzymes

Prolyl-4-hydroxylase is an important nonheme iron-containing dioxygenase in humans involved in the regioselective hydroxylation of a proline residue in a peptide chain on the C(4) position. In biosystems this process is important to create collagen cross-linking and cellular responses to hypoxia. We have performed a series of density functional theory (DFT) studies into the origin of the regioselectivity of proline hydroxylation by P4H enzymes using a minimal active site model (where substrate is unhindered in the binding site) and a larger active site model that incorporates steric hindrance of the substrate by several secondary sphere aromatic residues. Our studies show that thermodynamically the most favorable hydrogen atom abstraction position of proline is from the C(5) position; hence, the small model gives a low reaction barrier and large exothermicity for this process. However, stereochemical repulsions of the substrate with aromatic residues of Tyr(140) and Trp(243) in the second coordination sphere prevent C(5) hydroxylation and make C(4) hydroxylation the dominant mechanism, despite a lesser driving force for the reaction. These studies explain the remarkable regioselectivity of proline hydroxylation by P4H enzymes and show that the regioselectivity is kinetically controlled but not thermodynamically. In addition, we calculated spectroscopic parameters and found good agreement with experimental data.     

Mass–yield distributions of fission products from photo-fission of natPb induced by 50–70 MeV bremsstrahlung

The mass–yield distributions of various fission products have been determined in the 50-, 60- and 70-MeV end point bremsstrahlung induced fission of ^natPb using off-line γ-ray spectrometric technique in the electron linac at Pohang Accelerator Laboratory, Korea. The mass–yield distributions are symmetric with average mass of 102.34, 102.25 and 102.03 and FWHM of 21, 22 and 23 mass unit, respectively. From the present data and literature data in the 50–85 MeV bremsstrahlung induced fission of ²⁰⁹Bi the following observations were obtained: (i) The average masses of the yield distributions in the 50–85 MeV bremsstrahlung induced fission of ^natPb and ²⁰⁹Bi are around 102.25 ± 0.25 and 103 ± 0.5, respectively. (ii) The FWHM of the mass–yield distributions increases from about 21 mass units at 50 MeV to 23 mass units at 70–85 MeV, which is explained from the point of increase in multi-chance fission probability with increasing excitation energy. (iii) Within the bremsstrahlung energy range of 50–85 MeV, the role of nuclear structure effect in the mass–yield distribution was observed in the photo-fission of ²⁰⁹Bi, whereas it was not seen in case of ^natPb. This may be due to the presence of so many isotopes in ^natPb unlike mono-isotopic ²⁰⁹Bi.