The Directive of the Protein: How Does Cytochrome P450 Select the Mechanism of Dopamine Formation?
ABSTRACT 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.
- Canadian Journal of Chemistry 08/2014; 92(8):750-757. DOI:10.1139/cjc-2014-0052 · 1.01 Impact Factor
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ABSTRACT: Terminally bound oxo complexes of late transition metals have been difficult to synthesize or isolate. Their scarcity is in part due to the electronic repulsion between oxo ligands and metal elements with highly occupied d orbitals. This study attempts to provide extra stability to such metal-oxo species. The prototypical metal-oxo trifluorophosphane complexes [(PF3)5CrO, (PF3)4FeO, and (PF3)3NiO] are studied here. The results are compared with the corresponding carbonyl counterparts [(CO)5CrO, (CO)4FeO, and (CO)3NiO]. Predicted bond dissociation energies are 90 (Cr-O), 83 (Fe-O), and 59 (Ni-O) kcal/mol, higher than those of their carbonyl counterparts by around 10 kcal/mol. Consistent with bonding considerations and population analyses, the metal-oxo bonds are strengthened from the carbonyl to the trifluorophosphine complexes. Although the improvement is modest, it proves clearly that strong electron-withdrawing frameworks help in stabilizing metal-oxo complexes. This general idea may be utilized in further studies to seek or even design elusive terminal metal-oxo species and to keep pushing the limits of this area. In addition, improved viabilities are also found for the dioxygen-metal complexes [(PF3)5CrO2, (PF3)4FeO2, and (PF3)3NiO2], compared with their carbonyl counterparts.Theoretical Chemistry Accounts 04/2015; 134(4). DOI:10.1007/s00214-015-1643-5 · 2.14 Impact Factor
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ABSTRACT: The present study was aimed to investigate the effects of the cytochrome P450 (CYP) 2D6*10 genetic polymorphism on postoperative patient-controlled morphine usage. A total of 114 patients were selected, and 102 patients completed the study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used to determine the CYP2D6*10 genotype, and patients were categorized into three groups according to CYP2D6 genotype: heterozygous (m/w), wild-type homozygous (w/w), and mutant homozygous (m/m). Total morphine usage and visual analogue score (VAS) were determined 72 hours after the operation and compared across the three genotype groups. Statistical methods used to analyze results were the χ(2) test, analysis of variance, and multiple linear regression analysis; P<0.05 was considered to be statistically significant. The cumulative use of morphine in the m/w group was significantly higher than that in the m/m group between T0.5 and T4h (P<0.05). There were no significant differences in the loading dose of morphine or VAS among the different genotypes within 72 hours of operation. Patients carrying the CYP2D6*10 m/w genotype required higher doses of morphine at T0.5~T4h compared to the m/m group, and therefore received a higher cumulative dose of morphine post-operation. This phenomenon may be due to a decreased ability to synthesize endogenous opioid peptide.International Journal of Clinical and Experimental Medicine 01/2015; 8(2):2760-5. · 1.42 Impact Factor