Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

Walsh, Agnes A.; Szklarz, Grazyna D.; Scott, Emily E.

doi:10.1074/jbc.m113.452953

Cited by 245 publications

(254 citation statements)

References 61 publications

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“…Of these six P450s, 1A2 exhibits the smallest and narrowest active site (Sansen et al, 2007). This architecture is conserved in structures of P450s 1A1 (Walsh et al, 2013) and 1B1 (Wang et al, 2011), and the narrow hydrophobic cavity is consistent with the roles of these enzymes in metabolism of polycyclic aromatic hydrocarbons. This narrow cavity is reinforced by the passage of helix F below helix G, and this redirection of the F helix is associated with a distortion of the F helix as it passes over the active site cavity (Fig.…”

Section: Introductionmentioning

confidence: 65%

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

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This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drugmetabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b 5 . Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b 5 and P450 surfaces, showing that b 5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b 5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

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Section: Introductionmentioning

confidence: 65%

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

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“…The resulting trajectory was analyzed to find the best substrate orientation, and the enzymesubstrate complex was minimized for another 1000 steps, as described earlier. This optimal substrate orientation was used as a starting point for automated docking with the Affinity module of Insight II using default parameters, as described earlier (Ericksen and Szklarz, 2005;Tu et al, 2008;Huang and Szklarz, 2010;Walsh et al, 2013). Residues within 10 Å from the initial substrate position comprised the flexible region of the protein during all docking runs.…”

Section: Structural Computational and Functional Analysis Of Cyp2b3mentioning

confidence: 99%

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism

et al. 2016

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Crystal structures of CYP2B35 and CYP2B37 from the desert woodrat were solved in complex with 4-(4-chlorophenyl)imidazole (4-CPI). The closed conformation of CYP2B35 contained two molecules of 4-CPI within the active site, whereas the CYP2B37 structure demonstrated an open conformation with three 4-CPI molecules, one within the active site and the other two in the substrate access channel. To probe structurefunction relationships of CYP2B35, CYP2B37, and the related CYP2B36, we tested the O-dealkylation of three series of related substrates-namely, 7-alkoxycoumarins, 7-alkoxy-4-(trifluoromethyl)coumarins, and 7-alkoxy-4-methylcoumarinswith a C1-C7 side chain. CYP2B35 showed the highest catalytic efficiency (k cat /K M ) with 7-heptoxycoumarin as a substrate, followed by 7-hexoxycoumarin. In contrast, CYP2B37 showed the highest catalytic efficiency with 7-ethoxy-4-(trifluoromethyl) coumarin (7-EFC), followed by 7-methoxy-4-(trifluoromethyl) coumarin (7-MFC). CYP2B35 had no dealkylation activity with 7-MFC or 7-EFC. Furthermore, the new CYP2B-4-CPI-bound structures were used as templates for docking the 7-substituted coumarin derivatives, which revealed orientations consistent with the functional studies. In addition, the observation of multiple -Cl and -NH-p interactions of 4-CPI with the aromatic side chains in the CYP2B35 and CYP2B37 structures provides insight into the influence of such functional groups on CYP2B ligand binding affinity and specificity. To conclude, structural, computational, and functional analysis revealed striking differences between the active sites of CYP2B35 and CYP2B37 that will aid in the elucidation of new structure-activity relationships.

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“…Shimada et al also reported that the oxidative metabolites formations of acenaphthene and acenaphthylene with P450 1B1 were more rapid than those with 1A2 (Shimada et al, 2015). The active site of the P450 1A1 enzyme has been reported to share a closer similarity to that of P450 1B1 than that of 1A2 (Walsh et al, 2013). It has also been reported that P450 1B1 is able to catalyze the activation of both polycyclic aromatic hydrocarbons and aryl amines (Shimada et al, 1996).…”

Section: Metabolism Of Clpyr By P450 Enzymesmentioning

confidence: 87%

“…This result is consistent with differences in the structures of the P450 1A1, 1A2, and 1B1 enzymes in regions associated with substrate access/egress, and regio-and stereo-selective substrate binding. The structure of the P450 1A1 enzyme was reported to prefer polycyclic aromatic hydrocarbons and other planar molecules, while 1A2 displayed a preference for aromatic amines and heterocyclic compounds (Zanger and Schwab, 2013;Walsh et al, 2013). Therefore, the planar structure of ClPyr may better fit the P450 1A1 active site.…”

Section: Metabolism Of Clpyr By P450 Enzymesmentioning

confidence: 99%

Dechlorane Plus and decabromodiphenyl ether in atmospheric particles of northeast Asian cities

Kakimoto

Nagayoshi

Akutsu

et al. 2014

Environ Sci Pollut Res

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Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

Cited by 245 publications

References 61 publications

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism

Dechlorane Plus and decabromodiphenyl ether in atmospheric particles of northeast Asian cities

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