Epoxide hydrolases structure

Arand, M., Cronin, A., Adamska, M. and Oesch, F. (2005) Epoxide hydrolases structure, function, mechanism, and assay, Methods in Enzymology, 400, 569-588. 

J. Zou, B. M. Hallberg, T. Bergfors, F. Oesch, M. Arand S. L. Mowbray, T. A. Jones, Structure of Aspergillus tiiger Epoxide Hydrolase at 1. 8 A Resolution Implications for the Structure and Function of the Mammalian Microsomal Class of Epoxide Hydrolases , Structure 2000, 8, 111 - 122. 

Leukotriene A4 hydrolase is a unique cytosolic epoxide hydrolase, structurally dissimilar to the cytosolic enzyme described above. Its substrate specificity is narrow, being restricted to leukotriene A4, (5(S)-trans-5,6-oxido-7,9-cis-ll,l4-trans-eicosatetraenoic acid), and related fatty acids. 

Zha D, Wilensek S, Hermes M, Jaeger K-E, Reetz MT (2001) Complete reversal of enantioselectivity of an enzyme-catalyzed reaction by directed evolution. Chem Commun (Cambridge UK) 2664-2665 Zou JY, Hallberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA (2000) Structure of Aspergillus niger epoxide hydrolase at 1.8 resolution Implications for the structure and function of the mammalian microsomal class of epoxide hydrolases. Structure (London) 8 111-122... 

Figure 2.14 CASTing of the epoxide hydrolase from A. niger (ANEH) based on the X-ray structure of the WT [61]. (a) Defined randomization sites A-E (b) top view of tunnel-like binding pocket showing sites A-E (blue) and the catalytically active D192 (red) [23].

Lewis DF, Lake BG, Bird MG. Molecular modelling of human microsomal epoxide hydrolase (EH) by homology with a fungal (Aspergillus niger) EH crystal structure of 1.8 A resolution structure-activity relationships in epoxides inhibiting EH activity. Toxicol In Vitro 2005 19 517-22. 

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 43 4716-23. 

Rink R, M Eennema, M Smids, U Dehmel, DB Janssen (1997) Primary structure and catalytic mechanism of the epoxide hydrolase from Agrobacterium radiobacter ADI. J Biol Chem 272 14650-14657. 

The data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

C. Hassett, K. B. Robinson, N. B. Beck, C. J. Omiecinski, The Human Microsomal Epoxide Hydrolase Gene (EPHX1) Complete Nucleotide Sequences and Structural Characterization , Genomics 1994, 23, 433 - 442. 

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

R. N. Armstrong, C. S. Cassidy, New Structural and Chemical Insight into the Catalytic Mechanism of Epoxide Hydrolases , Drug Metab. Rev. 2000, 32, 327 - 338. 

D. C. Zeldin, S. Wei, J. R. Falck, B. D. Hammock, J. P. Snapper, J. H. Capdevilla, Metabolism of Epoxyeicosatrienoic Acids by Cytosolic Epoxide Hydrolase Substrate Structural Determinants of Asymmetric Catalysis , Arch. Biochem. Biophys. 1995, 316, 443 - 451. 

The use of enzymes and whole cells as catalysts in organic chemistry is described. Emphasis is put on the chemical reactions and the importance of providing enantiopure synthons. In particular kinetics of resolution is in focus. Among the topics covered are enzyme classification, structure and mechanism of action of enzymes. Examples are given on the use of hydrolytic enzymes such as esterases, proteases, lipases, epoxide hydrolases, acylases and amidases both in aqueous and low-water media. Reductions and oxidations are treated both using whole cells and pure enzymes. Moreover, use of enzymes in sngar chemistiy and to prodnce amino acids and peptides are discnssed. 

Hydration, in the context of metabolism, is the addition of water to a structure. Epoxides are readily hydrated to diols (see carbamazepine, Table 9.1), the reaction being catalysed by the enzyme epoxide hydrolase. 

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... 

The existence of a cytosolic epoxide hydrolase was first indicated by its ability to hydrolyze analogs of insect juvenile hormone not readily hydrolyzed by microsomal epoxide hydrolase. Subsequent studies demonstrated a unique cytosolic enzyme catalytically and structurally distinct from the microsomal enzyme. It appears probable that the cytosolic enzyme is peroxisomal in origin. Both enzymes are broadly nonspecific and have many substrates in common. It is clear, however, that many substrates hydrolyzed well by cytosolic epoxide hydrolase are hydrolyzed poorly by microsomal epoxide hydrolase and vice versa. For example, l-(4 -ethylphenoxy)-3,7-dimethy I -6,7-epoxy-//7//i,v-2-octene, a substituted geranyl epoxide insect juvenile hormone mimic, is hydrolyzed 10 times more rapidly by the cytosolic enzyme than by the microsomal one. In any series, such as the substituted styrene oxides, the trans configuration is hydrolyzed more rapidly by the cytosolic epoxide hydrolase than is the cis isomer. At the same time, it should remembered that in this and other series,... 

Enzyme-catalyzed epoxide ring opening including discussion of convergent families of epoxide hydrolases, the catalytic mechanism of microsomal epoxide hydrolases, epoxide hydrolases in metabolism, and the synthesis, structure, and mechanism of leukotriene A4 hydrolase, and glutathione transferase has been reviewed by Armstrong <1999CONAP(5)51>. 

Clan SC peptidases are a/p hydrolase-fold enzymes that consist of parallel P-strands surrounded by a-helices. The a/p hydrolase-fold provides a versatile catalytic platform that, in addition to achieving proteolytic activity, can either act as an esterase, lipase, dehalogenase, haloperoxidase, lyase, or epoxide hydrolase (18). Six phylogenetically distinct families of clan SC are known, and oifly four of them have known structure. Catalytic amenability of the a/p hydrolase-fold may underlie why clan SC peptidases are the second largest family of serine peptidases in the human genome. Other mechanistic classes need not use the catalytic serine and instead use cysteine or glutamic acid (19). Clan SC peptidases present an identical geometry to the catalytic triad observed in clans PA and SB, yet this constellation is ordered differently in the polypeptide sequence. Substrate selectivity develops from the a-helices that surround the central P-sheet core. Within clan SC, carboxypeptidases from family SIO are unique for their ability to maintain... 

The primary goal of initial studies of the microsomal and purified epoxide-hydrolase catalyzed hydration of arene oxides of polycyclic aromatic hydrocarbons was an attempt to identify structure-activity relationships. To this end, some selected values for the hydration of a series of arene oxides are given in Table 2. One of the more obvious aspects of this study was that there is no apparent relation-... 

Metabolic activation of carcinogens involves many enzymatic systems, known as phase I enzymes. The most important is the cytochrome P450 complex, consisting of several different isoenzymes, which are particularly active in the liver. Other enzymes include peroxidases, quinone reductases, epoxide hydrolases, sulfotrans-ferases, and others. Their variety reflects the diversity of chemical structures of compounds to which an organism is exposed. These may be harmful substances or needed ones, or even those indispensable for its proper functioning. One could argue that the activation of carcinogens is an undesirable side effect of metabolic pathways,... 

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