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Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode.

Porubsky PR, Battaile KP, Scott EE
J Biol Chem 285 22282-90 (2010)
Related entries: 3gph, 3lc4

Cited: 52 times
EuropePMC logo PMID: 20463018

Abstract

Human microsomal cytochrome P450 (CYP) 2E1 is widely known for its ability to oxidize >70 different, mostly compact, low molecular weight drugs and other xenobiotic compounds. In addition CYP2E1 oxidizes much larger C9-C20 fatty acids that can serve as endogenous signaling molecules. Previously structures of CYP2E1 with small molecules revealed a small, compact CYP2E1 active site, which would be insufficient to accommodate medium and long chain fatty acids without conformational changes in the protein. In the current work we have determined how CYP2E1 can accommodate a series of fatty acid analogs by cocrystallizing CYP2E1 with omega-imidazolyl-octanoic fatty acid, omega-imidazolyl-decanoic fatty acid, and omega-imidazolyl-dodecanoic fatty acid. In each structure direct coordination of the imidazole nitrogen to the heme iron mimics the position required for native fatty acid substrates to yield the omega-1 hydroxylated metabolites that predominate experimentally. In each case rotation of a single Phe(298) side chain merges the active site with an adjacent void, significantly altering the active site size and topology to accommodate fatty acids. The binding of these fatty acid ligands is directly opposite the channel to the protein surface and the binding observed for fatty acids in the bacterial cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium. Instead of the BM3-like binding mode in the CYP2E1 channel, these structures reveal interactions between the fatty acid carboxylates and several residues in the F, G, and B' helices at successive distances from the active site.

Articles - 3koh mentioned but not cited (6)

  1. Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode. Porubsky PR, Battaile KP, Scott EE. J Biol Chem 285 22282-22290 (2010)
  2. 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)
  3. 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)
  4. Kinetic characterizations of diallyl sulfide analogs for their novel role as CYP2E1 enzyme inhibitors. Rahman MA, Midde NM, Wu X, Li W, Kumar S. Pharmacol Res Perspect 5 (2017)
  5. 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)
  6. Xanthates As Useful Probes for Testing the Active Sites of Cytochromes P450 4A11 and 2E1. Stoyanova T, Lessigiarska I, Mikov M, Pajeva I, Yanev S. Front Pharmacol 8 672 (2017)


Reviews citing this publication (15)

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  8. Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1. Rao PS, Midde NM, Miller DD, Chauhan S, Kumar A, Kumar S. Curr Drug Metab 16 486-503 (2015)
  9. Roles of Cytochrome P450 in Metabolism of Ethanol and Carcinogens. Peter Guengerich F, Avadhani NG. Adv Exp Med Biol 1032 15-35 (2018)
  10. Cytochrome P450 research and The Journal of Biological Chemistry. Guengerich FP. J Biol Chem 294 1671-1680 (2019)
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  14. Hepatic cytochrome P450 ubiquitination: conformational phosphodegrons for E2/E3 recognition? Correia MA, Wang Y, Kim SM, Guan S. IUBMB Life 66 78-88 (2014)
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Articles citing this publication (31)

  1. Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. Walsh AA, Szklarz GD, Scott EE. J Biol Chem 288 12932-12943 (2013)
  2. Rethinking biological activation of methane and conversion to liquid fuels. Haynes CA, Gonzalez R. Nat Chem Biol 10 331-339 (2014)
  3. Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site. Berka K, Hendrychová T, Anzenbacher P, Otyepka M. J Phys Chem A 115 11248-11255 (2011)
  4. 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)
  5. Structural differences between soluble and membrane bound cytochrome P450s. Denisov IG, Shih AY, Sligar SG. J Inorg Biochem 108 150-158 (2012)
  6. Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance. Zong H, Armoni M, Harel C, Karnieli E, Pessin JE. Am J Physiol Endocrinol Metab 302 E532-9 (2012)
  7. 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)
  8. Molecular probes of the mechanism of cytochrome P450. Oxygen traps a substrate radical intermediate. Cooper HL, Groves JT. Arch Biochem Biophys 507 111-118 (2011)
  9. Impaired sperm chromatin integrity in obese mice. Duale N, Steffensen IL, Andersen J, Brevik A, Brunborg G, Lindeman B. Andrology 2 234-243 (2014)
  10. Human cytochrome P450 enzymes bind drugs and other substrates mainly through conformational-selection modes. Guengerich FP, Wilkey CJ, Phan TTN. J Biol Chem 294 10928-10941 (2019)
  11. Structural and dynamic basis of human cytochrome P450 7B1: a survey of substrate selectivity and major active site access channels. Cui YL, Zhang JL, Zheng QC, Niu RJ, Xu Y, Zhang HX, Sun CC. Chemistry 19 549-557 (2013)
  12. ChannelsDB: database of biomacromolecular tunnels and pores. Pravda L, Sehnal D, Svobodová Vareková R, Navrátilová V, Toušek D, Berka K, Otyepka M, Koca J. Nucleic Acids Res 46 D399-D405 (2018)
  13. Human liver cytochrome P450 3A4 ubiquitination: molecular recognition by UBC7-gp78 autocrine motility factor receptor and UbcH5a-CHIP-Hsc70-Hsp40 E2-E3 ubiquitin ligase complexes. Wang Y, Kim SM, Trnka MJ, Liu Y, Burlingame AL, Correia MA. J Biol Chem 290 3308-3332 (2015)
  14. Investigation of indazole unbinding pathways in CYP2E1 by molecular dynamics simulations. Shen Z, Cheng F, Cheng F, Xu Y, Fu J, Xiao W, Shen J, Liu G, Li W, Tang Y. PLoS One 7 e33500 (2012)
  15. Structure of pyrazole derivatives impact their affinity, stoichiometry, and cooperative interactions for CYP2E1 complexes. Hartman JH, Bradley AM, Laddusaw RM, Perry MD, Miller GP. Arch Biochem Biophys 537 12-20 (2013)
  16. 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)
  17. 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)
  18. Understanding a substrate's product regioselectivity in a family of enzymes: a case study of acetaminophen binding in cytochrome P450s. Yang Y, Wong SE, Lightstone FC. PLoS One 9 e87058 (2014)
  19. SUMOylation regulates cytochrome P450 2E1 expression and activity in alcoholic liver disease. Tomasi ML, Ramani K, Ryoo M, Cossu C, Floris A, Murray BJ, Iglesias-Ara A, Spissu Y, Mavila N. FASEB J 32 3278-3288 (2018)
  20. Covalent modification and time-dependent inhibition of human CYP2E1 by the meta-isomer of acetaminophen. Harrelson JP, Stamper BD, Chapman JD, Goodlett DR, Nelson SD. Drug Metab Dispos 40 1460-1465 (2012)
  21. Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future. Guengerich FP. Adv Pharmacol 95 1-47 (2022)
  22. Type II ligands as chemical auxiliaries to favor enzymatic transformations by P450 2E1. Ménard A, Fabra C, Huang Y, Auclair K. Chembiochem 13 2527-2536 (2012)
  23. Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone. Gong EC, Chea S, Balupuri A, Kang NS, Chin YW, Choi YH. Molecules 23 E555 (2018)
  24. Metabolic Activation and Carcinogenesis of Tobacco-Specific Nitrosamine N'-Nitrosonornicotine (NNN): A Density Function Theory and Molecular Docking Study. Fan T, Sun G, Zhao L, Cui X, Zhong R. Int J Environ Res Public Health 16 E178 (2019)
  25. 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)
  26. The Polyphenolic Profile and Antioxidant Activity of Five Vegetal Extracts with Hepatoprotective Potential. Costea L, Chițescu CL, Boscencu R, Ghica M, Lupuliasa D, Mihai DP, Deculescu-Ioniță T, Duțu LE, Popescu ML, Luță EA, Nițulescu GM, Olaru OT, Gîrd CE. Plants (Basel) 11 1680 (2022)
  27. Camelus dromedarius putative cytochrome P450 enzyme CYP2E1: complete coding sequence and phylogenetic tree. Alanazi MS, Saeed HM, Abduljaleel ZA. Biochem Genet 50 285-297 (2012)
  28. Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity. Zhang Y, Yan T, Wang T, Liu X, Hamada K, Sun D, Sun Y, Yang Y, Wang J, Takahashi S, Wang Q, Krausz KW, Jiang C, Xie C, Yang X, Gonzalez FJ. Acta Pharm Sin B 12 2224-2238 (2022)
  29. 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)
  30. CREB-Regulated Transcriptional Coactivator 2 Proteome Landscape is Modulated by SREBF1. Lim JM, Anwar MA, Han HS, Koo SH, Kim KP. Mol Cell Proteomics 22 100637 (2023)
  31. Transcriptome Analysis to Elucidate the Effects of Milk Replacer Feeding Level on Intestinal Function and Development of Early Lambs. Wang G, Zhang Q, Chen Z, Huang Y, Wang W, Zhang X, Jia J, Gao Q, Xu H, Li C. Animals (Basel) 13 1733 (2023)


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