Soluble epoxide hydrolase

M. Sandberg, J. Meijer, Structural Characterization of the Human Soluble Epoxide Hydrolase Gene (EPHX2) , Biochem. Biophys. Res. Commun. 1996, 221, 333 - 339. 

B. Borhan, A. D. Jones, F. Knot, D. F. Grant, M. J. Kurth, B. D. Hammock, Mechanism of Soluble Epoxide Hydrolase. Formation of an a-Hydroxy Ester-Enzyme Intermediate through Asp-333 , J. Biol. Chem. 1995, 270, 26923 - 26930. 

C. Morisseau, G. Du, J. W. Newman, B. D. Hammock, Mechanism of Mammalian Soluble Epoxide Hydrolase by Chalcone Oxide Derivatives , Arch. Biochem. Biophys. 1998, 356, 214 - 228 C. Morisseau, M. H. Goodrow, D. Dowdy, J. Zheng, J. F. Greene, J. R. Sanborn, B. D. Hammock, Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases , Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8849 - 8854. 

M. Arandt, F. Muller, A. Mecky, W. Hinz, P. Urban, D. Pompon, R. Kellner, F. Oesch, Catalytic Triad of Microsomal Epoxide Hydrolase Replacement of Glu404 with Asp Leads to a Strongly Increased Turnover Rate , Biochem. J. 1999, 337, 37 - 43 M. Arandt, H. Wagner, F. Oesch, Asp333, Asp495, and His523 form the Catalytic Triad of Rat Soluble Epoxide Hydrolase , J. Biol. Chem. 1996, 271, 4223 - 4229. 

G. M. Lacourciere, R. N. Armstrong, Microsomal and Soluble Epoxide Hydrolases are Members of the Same Family of C-X Bond Hydrolase Enzymes , Chem. Res. Toxicol. 1994, 7, 121 - 124. 

J. F. Greene, J. W. Newman, K. C. Williamson, B. D. Hammock, Toxicity of Epoxy Fatty Acids and Related Compounds to Cells Expressing Human Soluble Epoxide Hydrolase , Chem. Res. Toxicol. 2000, 13, 217 - 226. 

Figure 2.16 The mechanism of soluble epoxide hydrolase starts with a...

Over the past year, racemic 1,2-dialkyl epoxides were resolved enzymatically using soluble epoxide hydrolase (sEH), although the outcome of the reaction is characteristically substrate-dependent. In an example of the best enantioselection exhibited, epoxide 65 afforded the (Ji ,4i )-diol 66 upon treatment with sEH at pH 7.4. The course of these reactions is different from those in which the same substrates were treated with microsomal epoxide hydrolase <99T11589>. 

Srivastava PK, Sharma VK, Kalonia DS, Grant DF (2004) Polymorphisms in human soluble epoxide hydrolase effects on enzyme activity, enzyme stability, and quaternary structure. Arch Biochem Biophys 427 164-169... 

Chiappe, C., Leandri, E., Lucchesi, S., Pieraccini, D., Hammock, B.D., and Morisseau, C. 2004. Biocatalysis in ionic liquids The stereoconvergent hydrolysis of trans- -methylstyrene oxide catalyzed by soluble epoxide hydrolase. Journal of Molecular Catalysis B Enzymatic, 27 243 8. 

Nakagawa Y, Wheelock CE, Morisseau C, Goodrow MH, Hammock BG, Hammock BD. 3D-QSAR analysis of inhibition of murine soluble epoxide hydrolase (MsEH) by benzoylureas, arylureas, and their analogues. Bioorg Med Chem 2000 8 2663-73. 

Mouse soluble epoxide hydrolase log IC50 data for 484 molecules ... 

Morisseau C, Du G, Newman JW, Hammock BD. Mechanism of mammalian soluble epoxide hydrolase inhibition by chalcone oxide derivatives. Arch Biochem Biophys 1998 356 214-28. 

EC 3.3.2 Ether hydrolases EC 3.3.2.9 Microsomal epoxide hydrolase [EPHXI] mEH EC 3.3.2.10 Soluble epoxide hydrolase [EPHX2) sEH... 

McElroy, N.R. and Jurs, P.C. (2003) QSAR and classification of murine and human soluble epoxide hydrolase inhibition by urea-like compounds. J. Med. Chem., 46, 1066-1080. 

The enzyme exists in multiple forms with different substrate specificities. It is found mainly in the endoplasmic reticulum in close proximity to cytochromes P-450, and like the latter is also present in greater amounts in the centrilobular areas of the liver. Epoxide hydrolase is therefore well placed to carry out its important role in detoxifying the chemically unstable and often toxic epoxide intermediates produced by cytochromes P-450 mediated hydroxylation. Soluble epoxide hydrolases have also been described and the enzyme has been detected in the nuclear membrane. 

Several membrane-bound and soluble epoxide hydrolases from mammalian origin have been purified and (at least partially) sequenced. Some of them have also been cloned and overexpressed, which is the case for the soluble EH from rat liver which has been overexpressed in Escherichia cob 54, 55. This enzyme (as well as its microsomal analog) was shown to share an amino acid sequence similarity to a region around the active center of a bacterial haloalkane dehalogenase 56, an enzyme with known three-dimensional structure that belongs to the a/(3-hydrolase fold-family 571. Rat soluble EH forms a dimer from two complete structural monomeric units, both possessing a distinct active site. The EH activity is known to be located close to the C-terminal unit, while the function of the N-terminal unit remains unknown 581. 

Computational approaches to evaluate different mechanistic proposals for an enzyme have made great strides in the past 10 years. The chapter by Hopmann and Himo describe one such approach and its application to three different enzymatic reactions involving the transformation of an epoxide. The procedures and parameters to make a model of the active site are presented first and are followed by discussions of limonene epoxide hydrolase, soluble epoxide hydrolases, and haloalcohol dehalogenase. The results generally support the currently accepted mechanism for each enzyme but provide new insights into their regioselectivities. 

In this chapter, we will provide an overview of the employed methodology. To illustrate the various aspects of the methodology and to give the reader a feeling about the state of the art of the field, three very recent applications will be discussed in detail. All three enzymes are concerned with epoxide-transforming reactions, namely limonene epoxide hydrolase (LEH), soluble epoxide hydrolase (sEH), " and haloalcohol dehalo-genase C (HheC). First, however, a brief presentation of DFT and its accuracy will be given. 

Figure 1 Building an active site model of the human soluble epoxide hydrolase, (a) X-ray crystal structure with the active site highlighted (PDB 1VJ5) (b) Important active site residues, a water molecule, and the CIU inhibitor, are extracted from the PDB file (c) Final quantum chemical model of the sEH active site. Residues are truncated so that in principle only important side chains and backbone parts were included in the model. The substrate MSO is modeled instead of the inhibitor. Asterisks indicate atoms that were kept fixed to their crystallographically observed positions.

Scheme 6 Epoxide hydrolysis mechanism of soluble epoxide hydrolase (residue numbering as in human sEH). Step A is referred to as the alkylation half-reaction while steps B and C comprise the hydrolytic half-reaction.

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