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Epoxide hydrolase active site

Bickers DR, Dutta-Choudhury T, Mukhtar H. 1982. Epidermis A site of drug metabolism in neonatal rat skin. Studies on cytochrome P-450 content and mixed-function oxidase and epoxide hydrolase activity. Mol Pharmacol 21 239-247. [Pg.249]

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]. 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].
Rui L, 1 Cao, W Chen, KF Reardon, TK Wood (2004) Active site engineering of the epoxide hydrolase from Agrobacterium radiobacter ADI to enhance aerobic mineralization of cw-l,2-dichloroethylene in cells expressing an evolved toluene ort/io-monooxygenase. J Biol Chem 279 46810-46817. [Pg.375]

The overall reaction catalyzed by epoxide hydrolases is the addition of a H20 molecule to an epoxide. Alkene oxides, thus, yield diols (Fig. 10.5), whereas arene oxides yield dihydrodiols (cf. Fig. 10.8). In earlier studies, it had been postulated that epoxide hydrolases act by enhancing the nucleo-philicity of a H20 molecule and directing it to attack an epoxide, as pictured in Fig. 10.5, a [59] [60], Further evidence such as the lack of incorporation of 180 from H2180 into the substrate, the isolation of an ester intermediate, and the effects of group-selective reagents and carefully designed inhibitors led to a more-elaborate model [59][61 - 67]. As pictured in Fig. 10.5,b, nucleophilic attack of the substrate is mediated by a carboxylate group in the catalytic site to form an ester intermediate. In a second step, an activated H20... [Pg.614]

Fig. 10.5. Catalytic models of epoxide hydrolase (modified from [59]). a) In an earlier model, a basic group in the enzyme activates a H20 molecule during nucleophilic attack on the epoxide, b) A more-elaborate model showing a carboxylate group in the catalytic site that carries out the nucleophilic attack on the substrate to form an ester intermediate. Only in the second step is the intermediate hydrolyzed by an activated H20 molecule, leading to enzyme reactivation and product liberation. [Pg.615]

G. Bellucci, G. Berti, R. Bianchini, P. Cetera, E. Mastrorilli, Stereoselectivity of the Epoxide Hydrolase Catalyzed Hydrolysis of the Stereoisomeric 3-ieri-Buty 1-1,2-epoxycyclohexane. Further Evidence for the Topology of the Enzyme Active Site ,. /. Org. Chem. 1982, 47, 3105 - 3112. [Pg.677]

We had for some time considered that aziridines, because of their increased basicity and hence reactivity at the active site of a glycan hydrolase, would prove to be better inhibitors than the epoxides in many respects. Conversely, the less basic thiirans would be expected to be poorer inhibitors than the corresponding epoxides. We thus embarked on a synthesis of the aziridine 30 and the thiiran 31. [Pg.196]

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. [Pg.582]

Figure 11.2-4. X-Ray structure of AgK bacuriuiv radiabactat epoxide hydrolase (P08-1 t H Y). t he catalytic residues Aspl 0 and His275) are located rt top of the core-domain at some distance Asp246 is shown, which is presumably involved in proton transfer. The o-fielsees at top left constitute the "cap-domain, which is covering the active site. Figure 11.2-4. X-Ray structure of AgK bacuriuiv radiabactat epoxide hydrolase (P08-1 t H Y). t he catalytic residues Aspl 0 and His275) are located rt top of the core-domain at some distance Asp246 is shown, which is presumably involved in proton transfer. The o-fielsees at top left constitute the "cap-domain, which is covering the active site.
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. [Pg.6]

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. 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.
Hydrolysis of epoxides, esters, amides, and related structures is an important biotransformation reaction that limits the therapeutic activity of many drugs and generates therapeutically active drugs from prodmg structures. In a few cases, hydrolytic reactions can generate a toxic structure. Epoxide hydrolases and esterases are members of the a/(3 hydrolase-fold family of enzymes (Morisseau and Hammock, 2005 Satoh and Hosokawa, 2006). Although their substrate specificities are radically different (e.g., lipids, peptides, epoxides, esters, amides, haloalkanes), their catalytic mechanisms are similar. All of these enzymes have an active site catalytic triad composed of a nucleophilic serine or cysteine residue (esterases/amidases), or aspartate residue (epoxide hydrolases) to activate the substrate, and histidine residue and glutamate or aspartate residues that act cooperatively in an acid—base reaction to activate a water molecule for the hydrolytic step. [Pg.28]

Figure 2.3 Serine protease and hydrolase ABPs. (A) Reaction of a general serine hydrolase probe containing a fluorophosphonate (FP) reactive electrophile. This class of probes has been used extensively to label various classes of serine hydrolases including proteases, esterases, lipases and others. (B) The peptide diphenyl phosphonate (DPP) reacts with the serine nucleophile in the active site of serine proteases. This probe is much less reactive than the FP class of probes but is more selective towards serine proteases over other types of serine hydrolases.(C) The natural product epoxomicin contains a keto-epoxide that selectively reacts with the catalytic N-terminal threonine of the proteasome P-subunit. This reaction results in the formation of a stable six-membered ring. This class of electrophile has been used in probes of the proteasome. Figure 2.3 Serine protease and hydrolase ABPs. (A) Reaction of a general serine hydrolase probe containing a fluorophosphonate (FP) reactive electrophile. This class of probes has been used extensively to label various classes of serine hydrolases including proteases, esterases, lipases and others. (B) The peptide diphenyl phosphonate (DPP) reacts with the serine nucleophile in the active site of serine proteases. This probe is much less reactive than the FP class of probes but is more selective towards serine proteases over other types of serine hydrolases.(C) The natural product epoxomicin contains a keto-epoxide that selectively reacts with the catalytic N-terminal threonine of the proteasome P-subunit. This reaction results in the formation of a stable six-membered ring. This class of electrophile has been used in probes of the proteasome.
Christianson, /. Biol. Chem., 275, 15265 (2000). Binding of the Alkylurea Inhibitors to Epoxide Hydrolase Implicates Active Site Tyrosines in Substrate Activation. [Pg.407]


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See also in sourсe #XX -- [ Pg.266 ]




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Epoxidation activity

Epoxide hydrolase

Epoxide hydrolase epoxides

Epoxide hydrolases

Epoxide hydrolases epoxides

Hydrolase activity

Hydrolases epoxide hydrolase

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