You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Toxin, Toxin Target Database.
NameBifunctional epoxide hydrolase 2
Synonyms
  • 3.3.2.10
  • CEH
Gene NameEPHX2
OrganismHuman
Amino acid sequence
>lcl|BSEQ0001892|Bifunctional epoxide hydrolase 2
MTLRAAVFDLDGVLALPAVFGVLGRTEEALALPRGLLNDAFQKGGPEGATTRLMKGEITL
SQWIPLMEENCRKCSETAKVCLPKNFSIKEIFDKAISARKINRPMLQAALMLRKKGFTTA
ILTNTWLDDRAERDGLAQLMCELKMHFDFLIESCQVGMVKPEPQIYKFLLDTLKASPSEV
VFLDDIGANLKPARDLGMVTILVQDTDTALKELEKVTGIQLLNTPAPLPTSCNPSDMSHG
YVTVKPRVRLHFVELGSGPAVCLCHGFPESWYSWRYQIPALAQAGYRVLAMDMKGYGESS
APPEIEEYCMEVLCKEMVTFLDKLGLSQAVFIGHDWGGMLVWYMALFYPERVRAVASLNT
PFIPANPNMSPLESIKANPVFDYQLYFQEPGVAEAELEQNLSRTFKSLFRASDESVLSMH
KVCEAGGLFVNSPEEPSLSRMVTEEEIQFYVQQFKKSGFRGPLNWYRNMERNWKWACKSL
GRKILIPALMVTAEKDFVLVPQMSQHMEDWIPHLKRGHIEDCGHWTQMDKPTEVNQILIK
WLDSDARNPPVVSKM
Number of residues555
Molecular Weight62615.22
Theoretical pI6.21
GO Classification
Functions
  • magnesium ion binding
  • toxic substance binding
  • 10-hydroxy-9-(phosphonooxy)octadecanoate phosphatase activity
  • epoxide hydrolase activity
  • lipid phosphatase activity
  • phosphatase activity
  • protein homodimerization activity
  • receptor binding
Processes
  • inflammatory response
  • positive regulation of vasodilation
  • dephosphorylation
  • reactive oxygen species metabolic process
  • small molecule metabolic process
  • epoxygenase P450 pathway
  • phospholipid dephosphorylation
  • response to toxic substance
  • regulation of cholesterol metabolic process
  • cholesterol homeostasis
  • stilbene catabolic process
  • xenobiotic metabolic process
  • cellular calcium ion homeostasis
  • arachidonic acid metabolic process
  • positive regulation of gene expression
  • drug metabolic process
  • regulation of blood pressure
Components
  • peroxisome
  • cytosol
  • extracellular exosome
  • cytoplasm
General FunctionToxic substance binding
Specific FunctionBifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID181395
UniProtKB IDP34913
UniProtKB Entry NameHYES_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0010668|Bifunctional epoxide hydrolase 2 (EPHX2)
ATGAAAGGAGAGATCACACTTTCCCAGTGGATACCACTCATGGAAGAAAACTGCAGGAAG
TGCTCCGAGACCGCTAAAGTCTGCCTCCCCAAGAATTTCTCCATAAAAGAAATCTTTGAC
AAGGCGATTTCAGCCAGAAAGATCAACCGCCCCATGCTCCAGGCAGCTCTCATGCTCAGG
AAGAAAGGATTCACTACTGCCATCCTCACCAACACCTGGCTGGACGACCGTGCTGAGAGA
GATGGCCTGGCCCAGCTGATGTGTGAGCTGAAGATGCACTTTGACTTCCTGATAGAGTCG
TGTCAGGTGGGAATGGTCAAACCTGAACCTCAGATCTACAAGTTTCTGCTGGACACCCTG
AAGGCCAGCCCCAGTGAGGTCGTTTTTTTGGATGACATCGGGGCTAATCTGAAGCCAGCC
CGTGACTTGGGAATGGTCACCATCCTGGTCCAGGACACTGACACGGCCCTGAAAGAACTG
GAGAAAGTGACCGGAATCCAGCTTCTCAATACCCCGGCCCCTCTGCCGACCTCTTGCAAT
CCAAGTGACATGAGCCATGGGTACGTGACAGTAAAGCCCAGGGTCCGTCTGCATTTTGTG
GAGCTGGGCTCCGGCCCTGCTGTGTGCCTCTGCCATGGATTTCCCGAGAGTTGGTATTCT
TGGAGGTACCAGATCCCTGCTCTGGCCCAGGCAGGTTACCGGGTCCTAGCTATGGACATG
AAAGGCTATGGAGAGTCATCTGCTCCTCCCGAAATAGAAGAATATTGCATGGAAGTGTTA
TGTAAGGAGATGGTAACCTTCCTGGATAAACTGGGCCTCTCTCAAGCAGTGTTCATTGGC
CATGACTGGGGTGGCATGCTGGTGTGGTACATGGCTCTCTTCTACCCCGAGAGAGTGAGG
GCGGTGGCCAGTTTGAATACTCCCTTCATACCAGCAAATCCCAACATGTCCCCTTTGGAG
AGTATCAAAGCCAACCCAGTATTTGATTACCAGCTCTACTTCCAAGAACCAGGAGTGGCT
GAGGCTGAACTGGAACAGAACCTGAGTCGGACTTTCAAAAGCCTCTTCAGAGCAAGCGAT
GAGAGTGTTTTATCCATGCATAAAGTCTGTGAAGCGGGAGGACTTTTTGTAAATAGCCCA
GAAGAGCCCAGCCTCAGCAGGATGGTCACTGAGGAGGAAATCCAGTTCTATGTGCAGCAG
TTCAAGAAGTCTGGTTTCAGAGGTCCTCTAAACTGGTACCGAAACATGGAAAGGAACTGG
AAGTGGGCTTGCAAAAGCTTGGGACGGAAGATCCTGATTCCGGCCCTGATGGTCACGGCG
GAGAAGGACTTCGTGCTCGTTCCTCAGATGTCCCAGCACATGGAGGACTGGATTCCCCAC
CTGAAAAGGGGACACATTGAGGACTGTGGGCACTGGACACAGATGGACAAGCCAACCGAG
GTGAATCAGATCCTCATTAAGTGGCTGGATTCTGATGCCCGGAACCCACCGGTGGTCTCA
AAGATGTAG
GenBank Gene IDL05779
GeneCard IDNot Available
GenAtlas IDEPHX2
HGNC IDHGNC:3402
Chromosome Location8
Locus8p21-p12
References
  1. Beetham JK, Tian T, Hammock BD: cDNA cloning and expression of a soluble epoxide hydrolase from human liver. Arch Biochem Biophys. 1993 Aug 15;305(1):197-201. 8342951
  2. Sandberg M, Meijer J: Structural characterization of the human soluble epoxide hydrolase gene (EPHX2). Biochem Biophys Res Commun. 1996 Apr 16;221(2):333-9. 8619856
  3. Sandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ: Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. J Biol Chem. 2000 Sep 15;275(37):28873-81. 10862610
  4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  5. Nusbaum C, Mikkelsen TS, Zody MC, Asakawa S, Taudien S, Garber M, Kodira CD, Schueler MG, Shimizu A, Whittaker CA, Chang JL, Cuomo CA, Dewar K, FitzGerald MG, Yang X, Allen NR, Anderson S, Asakawa T, Blechschmidt K, Bloom T, Borowsky ML, Butler J, Cook A, Corum B, DeArellano K, DeCaprio D, Dooley KT, Dorris L 3rd, Engels R, Glockner G, Hafez N, Hagopian DS, Hall JL, Ishikawa SK, Jaffe DB, Kamat A, Kudoh J, Lehmann R, Lokitsang T, Macdonald P, Major JE, Matthews CD, Mauceli E, Menzel U, Mihalev AH, Minoshima S, Murayama Y, Naylor JW, Nicol R, Nguyen C, O'Leary SB, O'Neill K, Parker SC, Polley A, Raymond CK, Reichwald K, Rodriguez J, Sasaki T, Schilhabel M, Siddiqui R, Smith CL, Sneddon TP, Talamas JA, Tenzin P, Topham K, Venkataraman V, Wen G, Yamazaki S, Young SK, Zeng Q, Zimmer AR, Rosenthal A, Birren BW, Platzer M, Shimizu N, Lander ES: DNA sequence and analysis of human chromosome 8. Nature. 2006 Jan 19;439(7074):331-5. 16421571
  6. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  7. Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, Bradbury JA, Enayetallah AE, Zeldin DC, Grant DF: Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol. 2003 Aug;64(2):482-90. 12869654
  8. Cronin A, Mowbray S, Durk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M: The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1552-7. Epub 2003 Feb 6. 12574508
  9. Newman JW, Morisseau C, Harris TR, Hammock BD: The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1558-63. Epub 2003 Feb 6. 12574510
  10. Srivastava PK, Sharma VK, Kalonia DS, Grant DF: Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity, enzyme stability, and quaternary structure. Arch Biochem Biophys. 2004 Jul 15;427(2):164-9. 15196990
  11. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. 19608861
  12. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  13. Charles RL, Burgoyne JR, Mayr M, Weldon SM, Hubner N, Dong H, Morisseau C, Hammock BD, Landar A, Eaton P: Redox regulation of soluble epoxide hydrolase by 15-deoxy-delta-prostaglandin J2 controls coronary hypoxic vasodilation. Circ Res. 2011 Feb 4;108(3):324-34. doi: 10.1161/CIRCRESAHA.110.235879. Epub 2010 Dec 16. 21164107
  14. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  15. Gomez GA, Morisseau C, Hammock BD, Christianson DW: Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis. Biochemistry. 2004 Apr 27;43(16):4716-23. 15096040
  16. Gomez GA, Morisseau C, Hammock BD, Christianson DW: Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. Protein Sci. 2006 Jan;15(1):58-64. Epub 2005 Dec 1. 16322563
  17. Eldrup AB, Soleymanzadeh F, Taylor SJ, Muegge I, Farrow NA, Joseph D, McKellop K, Man CC, Kukulka A, De Lombaert S: Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase. J Med Chem. 2009 Oct 8;52(19):5880-95. doi: 10.1021/jm9005302. 19746975
  18. Eldrup AB, Soleymanzadeh F, Farrow NA, Kukulka A, De Lombaert S: Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2010 Jan 15;20(2):571-5. doi: 10.1016/j.bmcl.2009.11.091. Epub 2009 Nov 22. 19969453
  19. Lo HY, Man CC, Fleck RW, Farrow NA, Ingraham RH, Kukulka A, Proudfoot JR, Betageri R, Kirrane T, Patel U, Sharma R, Hoermann MA, Kabcenell A, Lombaert SD: Substituted pyrazoles as novel sEH antagonist: investigation of key binding interactions within the catalytic domain. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6379-83. doi: 10.1016/j.bmcl.2010.09.095. Epub 2010 Sep 19. 20934334