The Directive of the Protein: How Does Cytochrome P450 Select the Mechanism of Dopamine Formation?
Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.Journal of the American Chemical Society (Impact Factor: 12.11). 05/2011; 133(20):7977-84. DOI: 10.1021/ja201665x
Dopamine can be generated from tyramine via arene hydroxylation catalyzed by a cytochrome P450 enzyme (CYP2D6). Our quantum mechanical/molecular mechanical (QM/MM) results reveal the decisive impact of the protein in selecting the 'best' reaction mechanism. Instead of the traditional Meisenheimer-complex mechanism, the study reveals a mechanism involving an initial hydrogen atom transfer from the phenolic hydroxyl group of the tyramine to the iron-oxo of the compound I (Cpd I), followed by a ring-π radical rebound that eventually leads to dopamine by keto-enol rearrangement. This mechanism is not viable in the gas phase since the O-H bond activation by Cpd I is endothermic and the process does not form a stable intermediate. By contrast, the in-protein reaction has a low barrier and is exothermic. It is shown that the local electric field of the protein environment serves as a template that stabilizes the intermediate of the H-abstraction step and thereby mediates the catalysis of dopamine formation at a lower energy cost. Furthermore, it is shown that external electric fields can either catalyze or inhibit the process depending on their directionality.
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- "In contrast to the mechanism responsible for oxidation (hydroxylation) reactions catalyzed by CYP enzymes that has been partially explained (Schyman et al. 2011), information on the mechanism of nitroreduction catalyzed by these enzymes is still lacking. Therefore , this feature is the aim of the present study. "
ABSTRACT: Objectives: The herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. Methods: Molecular modeling capable of evaluating interactions of AAI with the active site of human CYP1A1, 1A2 and 1B1 under the reductive conditions was used. In silico docking, employing soft-soft (flexible) docking procedure was used to study the interactions of AAI with the active sites of these human enzymes. Results: The predicted binding free energies and distances between an AAI ligand and a heme cofactor are similar for all CYPs evaluated. AAI also binds to the active sites of CYP1A1, 1A2 and 1B1 in similar orientations. The carboxylic group of AAI is in the binding position situated directly above heme iron. This ligand orientation is in CYP1A1/1A2 further stabilized by two hydrogen bonds; one between an oxygen atom of the AAI nitro-group and the hydroxyl group of Ser122/Thr124; and the second bond between an oxygen atom of dioxolane ring of AAI and the hydroxyl group of Thr497/Thr498. For the CYP1B1:AAI complex, however, any hydrogen bonding of the nitro-group of AAI is prevented as Ser122/Thr124 residues are in CYP1B1 protein replaced by hydrophobic residue Ala133. Conclusion: The experimental observations indicate that CYP1B1 is more than 10× less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å.Neuro endocrinology letters 12/2012; 33(Suppl3):25-32. · 0.80 Impact Factor
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ABSTRACT: Dicobalt octacarbonyl is known to react with diolefins to give substitution products of the types (diene)Co2(CO)6 and (diene)2Co2(CO)4. The butadiene derivatives (C4H6)Co2(CO)n (n = 6, 5, 4, 3, 2) have been investigated by density functional theory using the B3LYP and BP86 methods. The lowest energy (C4H6)Co2(CO)n (n = 6, 5, 4) structures have bridging CO groups and terminal butadiene ligands. For the (C4H6)Co2(CO)6 and (C4H6)Co2(CO)5 structures the CoCo distances of ∼2.5 Å suggest formal single bonds. However, for the lowest energy (C4H6)Co2(CO)4 structure the significantly shorter CoCo distance of ∼2.3 Å suggests the formal triple bond required to give the cobalt atom the favored 18-electron configuration. Bridging butadiene ligands are also found in (C4H6)Co2(CO)n structures including all of the lowest energy (C4H6)Co2(CO)3 and (C4H6)Co2(CO)2 structures. Both the B3LYP and BP86 methods predict butadiene dissociation from (C4H6)2Co2(CO)4 to be energetically favored over CO dissociation by ∼8 kcal/mol. For (C4H6)2Co2(CO)n (n = 3, 2) the BP86 method predicts CO dissociation to be favored energetically over butadiene dissociation by ∼8 kcal/mol. However, the B3LYP method predicts essentially equal CO and butadiene dissociation energies within ∼1 kcal/mol from (C4H6)2Co2(CO)n (n = 3, 2).Computational and Theoretical Chemistry 11/2012; 999:129–137. DOI:10.1016/j.comptc.2012.08.026 · 1.55 Impact Factor
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ABSTRACT: The computational analysis of the rhodium-catalyzed Pauson-Khand reaction indicates that the key transition state is highly charge-polarized, wherein different diastereoisomers have distinctively different charge polarization patterns. Experimental studies demonstrate that chloro-enynes provide the optimal σ-electron-withdrawing group to promote polarization and thereby reduce the activation barrier to provide a highly diastereoselective reaction at room temperature.Journal of the American Chemical Society 05/2011; 133(20):7621-3. DOI:10.1021/ja107895g · 12.11 Impact Factor
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