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Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.

DeVore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE
FEBS J 279 1621-31 (2012)
Related entries: 3t3q, 3t3r, 3t3s

Cited: 41 times
EuropePMC logo PMID: 22051186

Abstract

Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine.

Articles - 3t3z mentioned but not cited (10)

  1. Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. DeVore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE. FEBS J 279 1621-1631 (2012)
  2. Methionine Adenosyltransferase α1 Is Targeted to the Mitochondrial Matrix and Interacts with Cytochrome P450 2E1 to Lower Its Expression. Murray B, Peng H, Barbier-Torres L, Robinson AE, Li TWH, Fan W, Tomasi ML, Gottlieb RA, Van Eyk J, Lu Z, Martínez-Chantar ML, Liangpunsakul S, Skill NJ, Mato JM, Lu SC. Hepatology 70 2018-2034 (2019)
  3. Dynamics of CYP51: implications for function and inhibitor design. Yu X, Cojocaru V, Mustafa G, Salo-Ahen OM, Lepesheva GI, Wade RC. J Mol Recognit 28 59-73 (2015)
  4. Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis. Diesinger T, Buko V, Lautwein A, Dvorsky R, Belonovskaya E, Lukivskaya O, Naruta E, Kirko S, Andreev V, Buckert D, Bergler S, Renz C, Schneider E, Kuchenbauer F, Kumar M, Günes C, Büchele B, Simmet T, Müller-Enoch D, Wirth T, Haehner T. PLoS One 15 e0235990 (2020)
  5. An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation. Wang Y, Lin W, Wu N, He X, Wang J, Feng Z, Xie XQ. J Mol Model 24 243 (2018)
  6. The CYP71AZ P450 Subfamily: A Driving Factor for the Diversification of Coumarin Biosynthesis in Apiaceous Plants. Krieger C, Roselli S, Kellner-Thielmann S, Galati G, Schneider B, Grosjean J, Olry A, Ritchie D, Matern U, Bourgaud F, Hehn A. Front Plant Sci 9 820 (2018)
  7. Nonlinear molecular dynamics of quercetin in Gynocardia odorata and Diospyros malabarica fruits: Its mechanistic role in hepatoprotection. Ghosh A, Sarmah P, Patel H, Mukerjee N, Mishra R, Alkahtani S, Varma RS, Baishya D. PLoS One 17 e0263917 (2022)
  8. Inhibition of human cytochrome P450 2E1 and 2A6 by aldehydes: structure and activity relationships. Kandagatla SK, Mack T, Simpson S, Sollenberger J, Helton E, Raner GM. Chem Biol Interact 219 195-202 (2014)
  9. Study on incompatibility of traditional chinese medicine: evidence from formula network, chemical space, and metabolism room. Long W, Zhang XD, Wu HY, Jin J, Yu GY, He X, Wang H, Shen X, Zhou ZW, Liu PX, Fan SJ. Evid Based Complement Alternat Med 2013 352145 (2013)
  10. Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds. Hu K, Tu H, Xie J, Yang Z, Li Z, Chen Y, Liu Y. Toxics 11 495 (2023)


Reviews citing this publication (5)

  1. Structural diversity of eukaryotic membrane cytochrome p450s. Johnson EF, Stout CD. J Biol Chem 288 17082-17090 (2013)
  2. Conformational diversity and ligand tunnels of mammalian cytochrome P450s. Yu X, Cojocaru V, Wade RC. Biotechnol Appl Biochem 60 134-145 (2013)
  3. Cytochrome P450 2E1 and its roles in disease. Guengerich FP. Chem Biol Interact 322 109056 (2020)
  4. Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity. Shimada T. Toxicol Res 33 79-96 (2017)
  5. Coumarin-Based Profluorescent and Fluorescent Substrates for Determining Xenobiotic-Metabolizing Enzyme Activities In Vitro. Raunio H, Pentikäinen O, Juvonen RO. Int J Mol Sci 21 E4708 (2020)

Articles citing this publication (26)

  1. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes. DeVore NM, Scott EE. J Biol Chem 287 26576-26585 (2012)
  2. Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast. Scheler U, Brandt W, Porzel A, Rothe K, Manzano D, Božić D, Papaefthimiou D, Balcke GU, Henning A, Lohse S, Marillonnet S, Kanellis AK, Ferrer A, Tissier A. Nat Commun 7 12942 (2016)
  3. Structural and thermodynamic basis of (+)-α-pinene binding to human cytochrome P450 2B6. Wilderman PR, Shah MB, Jang HH, Stout CD, Halpert JR. J Am Chem Soc 135 10433-10440 (2013)
  4. Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition. Shimada T, Kim D, Murayama N, Tanaka K, Takenaka S, Nagy LD, Folkman LM, Foroozesh MK, Komori M, Yamazaki H, Guengerich FP. Chem Res Toxicol 26 517-528 (2013)
  5. Roles of Human CYP2A6 and Monkey CYP2A24 and 2A26 Cytochrome P450 Enzymes in the Oxidation of 2,5,2',5'-Tetrachlorobiphenyl. Shimada T, Kakimoto K, Takenaka S, Koga N, Uehara S, Murayama N, Yamazaki H, Kim D, Guengerich FP, Komori M. Drug Metab Dispos 44 1899-1909 (2016)
  6. Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen. Shahrokh K, Cheatham TE, Yost GS. Biochim Biophys Acta 1820 1605-1617 (2012)
  7. Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13. Shimada T, Takenaka S, Murayama N, Kramlinger VM, Kim JH, Kim D, Liu J, Foroozesh MK, Yamazaki H, Guengerich FP, Komori M. Xenobiotica 46 211-224 (2016)
  8. Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. Shimada T, Takenaka S, Kakimoto K, Murayama N, Lim YR, Kim D, Foroozesh MK, Yamazaki H, Guengerich FP, Komori M. Chem Res Toxicol 29 1029-1040 (2016)
  9. Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone. Kakimoto K, Murayama N, Takenaka S, Nagayoshi H, Lim YR, Kim V, Kim D, Yamazaki H, Komori M, Guengerich FP, Shimada T. Xenobiotica 49 131-142 (2019)
  10. Evaluation of inhibition selectivity for human cytochrome P450 2A enzymes. Stephens ES, Walsh AA, Scott EE. Drug Metab Dispos 40 1797-1802 (2012)
  11. Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel. Cui YL, Zheng QC, Zhang JL, Zhang HX. Biopolymers 103 53-66 (2015)
  12. Structural and biophysical characterization of human cytochromes P450 2B6 and 2A6 bound to volatile hydrocarbons: analysis and comparison. Shah MB, Wilderman PR, Liu J, Jang HH, Zhang Q, Stout CD, Halpert JR. Mol Pharmacol 87 649-659 (2015)
  13. Structural basis for cooperative binding of azoles to CYP2E1 as interpreted through guided molecular dynamics simulations. Levy JW, Hartman JH, Perry MD, Miller GP. J Mol Graph Model 56 43-52 (2015)
  14. Effects of protein flexibility on the site of metabolism prediction for CYP2A6 substrates. Sheng Y, Chen Y, Wang L, Liu G, Li W, Tang Y. J Mol Graph Model 54 90-99 (2014)
  15. Identification of novel natural inhibitors of Opisthorchis felineus cytochrome P450 using structure-based screening and molecular dynamic simulation. Shukla R, Chetri PB, Sonkar A, Pakharukova MY, Mordvinov VA, Tripathi T. J Biomol Struct Dyn 36 3541-3556 (2018)
  16. Exploring the structure characteristics and major channels of cytochrome P450 2A6, 2A13, and 2E1 with pilocarpine. Fan JR, Li H, Zhang HX, Zheng QC. Biopolymers 109 e23108 (2018)
  17. Nitrogen inversion barriers affect the N-oxidation of tertiary alkylamines by cytochromes P450. Rydberg P, Jørgensen MS, Jacobsen TA, Jacobsen AM, Madsen KG, Olsen L. Angew Chem Int Ed Engl 52 993-997 (2013)
  18. Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants. Shimada T, Murayama N, Kakimoto K, Takenaka S, Lim YR, Yeom S, Kim D, Yamazaki H, Guengerich FP, Komori M. Xenobiotica 48 565-575 (2018)
  19. Site-specific oxidation of flavanone and flavone by cytochrome P450 2A6 in human liver microsomes. Nagayoshi H, Murayama N, Kakimoto K, Takenaka S, Katahira J, Lim YR, Kim V, Kim D, Yamazaki H, Komori M, Guengerich FP, Shimada T. Xenobiotica 49 791-802 (2019)
  20. X-ray crystal structure of the cytochrome P450 2B4 active site mutant F297A in complex with clopidogrel: insights into compensatory rearrangements of the binding pocket. Shah MB, Jang HH, Zhang Q, David Stout C, Halpert JR. Arch Biochem Biophys 530 64-72 (2013)
  21. Nitric Oxide Mediated Degradation of CYP2A6 via the Ubiquitin-Proteasome Pathway in Human Hepatoma Cells. Cerrone J, Lee CM, Mi T, Morgan ET. Drug Metab Dispos 48 544-552 (2020)
  22. π-π Stacking mediated drug-drug interactions in human CYP2E1. Liu Y, Liu BY, Hao P, Li X, Li YX, Wang JF. Proteins 81 945-954 (2013)
  23. Functional characterization and tissue expression of marmoset cytochrome P450 2E1. Uehara S, Uno Y, Tomioka E, Inoue T, Sasaki E, Yamazaki H. Biopharm Drug Dispos 38 394-397 (2017)
  24. New amino acid-Schiff base derived from s-allyl cysteine and methionine alleviates carbon tetrachloride-induced liver dysfunction. Ratha P, Chitra L, Ancy I, Kumaradhas P, Palvannan T. Biochimie 138 70-81 (2017)
  25. A dual substrate kinetic model for cytochrome P450BM3-F87G catalysis: simultaneous binding of long chain aldehydes and 4-fluorophenol. Ledford C, McMahon M, Whitesell A, Khan G, Kandagatla SK, Hurst DP, Reggio PH, Raner GM. Biotechnol Lett 39 311-321 (2017)
  26. Design, Synthesis, and Biological Studies of Flavone-Based Esters and Acids as Potential P450 2A6 Inhibitors. Goyal N, Do C, Sridhar J, Shaik S, Thompson A, Perry T, Carter L, Foroozesh M. Chem Res Toxicol 36 1973-1979 (2023)


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