What Factors Determine the Brevione B Desaturation Mechanism in the Nonheme Iron Dioxygenase BrvJ?

The natural product synthesis of brevione J undergoes a cascade of reactions including an oxidative desaturation and a ring-expansion. The C1-C2 desaturation of brevione B is catalyzed by the nonheme iron dioxygenase BrvJ using one molecule of O2 and a-ketoglutarate (aKG). However, whether the subsequent oxidative ring expansion reaction is also catalyzed by the same enzyme is unknown and remains controversial.

Energy-entropy method using multiscale cell correlation to calculate binding free energies in the SAMPL8 host-guest challenge.

Free energy drives a wide range of molecular processes such as solvation, binding, chemical reactions and conformational change. Given the central importance of binding, a wide range of methods exist to calculate it, whether based on scoring functions, machine-learning, classical or electronic structure methods, alchemy, or explicit evaluation of energy and entropy. Here we present a new energy-entropy (EE) method to calculate the host-guest binding free energy directly from molecular dynamics (MD) simulation.

Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase.

The report uses density functional theory to address the mechanism of heme degradation by the enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap heme molecules and degrade them to maintain iron homeostasis in the biosystem. The degradation is initiated by complexation of the heme, then formation of the iron-hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin by hydroxylation, thereby enabling eventually the cleavage of the porphyrin ring.

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.

Oxygen economy of cytochrome P450: what is the origin of the mixed functionality as a dehydrogenase-oxidase enzyme compared with its normal function?

The economy of dioxygen consumption by enzymes constitutes a fundamental problem in enzymatic chemistry (ref 1). Sometimes, the enzyme converts ALL the oxygen into water, without affecting the organic substrate, thereby acting as an "oxidase" (ref 1). Other times, the enzyme converts all the oxygen into water and causes desaturation in the substrate, thus exhibiting a mixed function as both "oxidase" and "dehydrogenase" (refs 2-5).

Radical clock substrates, their C-H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does theory reveal about the clocks' behavior?

There is an ongoing and tantalizing controversy regarding the mechanism of a key process in nature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D.

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.

Electrophilic aromatic chlorination and haloperoxidation of chloride catalyzed by polyfluorinated alcohols: a new manifestation of template catalysis.

We have demonstrated that a polyfluorinated alcohol, 2,2,2-trifluoroethanol, solvent enables haloperoxidase type activity and the oxychlorination of arenes (benzene and its alkylated derivatives) without a metal catalyst. The polyfluorinated alcohol has a dual function; it catalyzes electrophilic chlorination of less reactive arenes by several orders of magnitude and oxidation of chloride at lower H+ concentrations. DFT calculations show that a complementary charge template in the transition state explains the catalysis of the electrophilic chlorination.

Can a single oxidant with two spin states masquerade as two different oxidants? A study of the sulfoxidation mechanism by cytochrome p450.

Density functional calculations were performed on the sulfoxidation reaction by a model compound I (Cpd I) of cytochrome P450. By contrast to previous alkane hydroxylation studies, which exhibit a dominant low-spin (LS) pathway, the sulfoxidation follows a dominant high-spin (HS) reaction. Thus, competing hydroxylation and sulfoxidation processes as observed for instance by Jones et al.

Fluorinated alcohols enable olefin epoxidation by H2O2: template catalysis.

Experimental observations show that direct olefin epoxidation by H(2)O(2), which is extremely sluggish otherwise, occurs in fluorinated alcohol (R(f)OH) solutions under mild conditions requiring no additional catalysts. Theoretical calculations of ethene and propene epoxidation by H(2)O(2) in the gas phase and in the presence of methanol and of two fluorinated alcohols, presented in this paper, show that the fluoro alcohol itself acts as a catalyst for the reaction by providing a template that stabilizes specifically the transition state (TS) of the reaction. Thus, much like an enzyme, the fluoro alcohol provides a complementary charge template that leads to the reduction of the barrier by 5-8 kcal mol(-)(1).

Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory.

Recent computational studies of alkane hydroxylation and alkene epoxidation by a model active species of the enzyme cytochrome P-450 reveal a two-state reactivity (TSR) scenario in which the information content of the product distribution is determined jointly by two states. TSR is used to reconcile the dilemma of the consensus 'rebound mechanism' of alkane hydroxylation, which emerged from experimental studies of ultra-fast radical clocks. The dilemma, stated succinctly as 'radicals are both present and absent and the rebound mechanism is both right and wrong', is simply understood once one is cognizant that the mechanism operates by two states, one low-spin (LS) the other high-spin (HS).

The 'push' effect of the thiolate ligand in cytochrome P450: a theoretical gauging.

The 'push' effect of the thiolate ligand in cytochrome P450 is investigated using density functional calculations. Theory supports Dawson's postulate that the 'push' effect is crucial for the heterolytic O-O bond cleavage of ferric-peroxide, as well as for controlling the Fe(III)/Fe(II) redox process and gating the catalytic cycle. Two energetic factors that contribute to the 'push' effect are revealed.

Chameleon States: High-Valent Metal-Oxo Species of Cytochrome P450 and Its Ruthenium Analogue.

Chameleon states: the ruthenium and iron metalloporphyrin analogues of compound I of cytochrome P450 (1; L = thiolate) possess low-lying states that change their electronic structure with solvent polarization. The ground state of the ruthenium complex is a low-spin electrophilic state, whereas the ground state of the iron complex is triradicaloid.