John C. Hackett

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The mechanisms of cytochrome P450 (CYP) catalyzed C-C bond cleavage have been strongly debated and difficult to unravel. Herein, deformylation mechanisms of the sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis are elucidated using molecular dynamics simulation, density functional theory, and hybrid quantum mechanics/molecular mechanics(More)
B3LYP density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization is explored and determined to be unlikely. However, proton-assisted homolysis of the peroxo hemiacetal intermediate to produce P450(More)
Resolution of the identity PBE (RI-PBE) and B3LYP density functional theory calculations are used to understand the cytochrome P450-catalyzed, Compound I-mediated oxidation of perchlorobenzenes, perfluorobenzenes, their phenols, and mixed chlorofluorobenzenes to form benzoquinones. Addition of Compound I to the chlorine-bearing carbon of perchlorobenzenes(More)
Small molecule host-guest complexes have traditionally provided model systems for biological ligand recognition. Nonetheless, direct extrapolation of these results is precluded by the comparative simplicity of these supramolecular assemblies. If energetic behavior analogous to small molecule host-guest chemistry exists, it is unclear how this would manifest(More)
Aromatase (CYP19) catalyzes the terminal step in estrogen biosynthesis, which requires three separate oxidation reactions, culminating in an enigmatic aromatization that converts an androgen to an estrogen. A stable ferric peroxo (Fe(3+)O(2)(2-)) intermediate is seen by electron paramagnetic resonance, but its role in this complex reaction remains(More)
A mitochondrial carrier family (MCF) of transport proteins facilitates the transfer of charged small molecules across the inner mitochondrial membrane. The human genome has ∼50 genes corresponding to members of this family. All MCF proteins contain three repeats of a characteristic and conserved PX(D/E)XX(K/R) motif thought to be central to the mechanism of(More)
Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. As a result, a number of synthetic steroidal or nonsteroidal aromatase inhibitors have been successfully developed. In addition, there are several(More)
The synthesis and biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference(More)
The cytochromes P450 constitute a ubiquitous family of metalloenzymes, catalyzing manifold reactions of biological and synthetic importance via a thiolate-ligated iron-oxo (IV) porphyrin radical species denoted compound I (Cpd I). Experimental investigations have implicated this intermediate in a broad spectrum of biophysically interesting phenomena,(More)
The CYP51 lanosterol 14alpha-demethylases are evolutionarily ancient enzymes ubiquitously distributed throughout the biological domains. The experimental X-ray crystal structure of Mycobacterium tuberculosis (Mtb) CYP51 is the first of an enzyme capable of catalyzing inert C-C bond cleavage. Amino acid sequence comparisons of CYP51 family members with other(More)