Hydrolases design

Table 18.1 summarizes the scheme that the Enzyme Commission has adopted to classify hydrolases. Each major division or class of hydrolase designates the chem-... 

Morisseau C, Hammock BD. Epoxide hydrolases mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 2005 45 311-333. 

Many studies have been performed in laboratory animals to better characterize the distribution, nature, regulation, kinetic properties, and substrate specificity of aspirin hydrolases, as they are sometimes designated (e.g., [41] [84-86]). 

C. B. Millard, O. Lockridge, C. A. Broomfield, Design and Expression of Organophos-phorus Acid Anhydride Hydrolase Activity in Human Butyrylcholinesterase , Biochemistry 1995, 34, 15925-15933. 

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... 

Enzymes with this designation [EC 3.4.11.x] are a-aminoacylpeptide hydrolases. See also specific amino-peptidase... 

A synthetically derivatized substrate designed to undergo a change in absorption and/or fluorescence spectrum upon its enzymatic conversion to product. Chromo-genie substrates provide valuable assays for enzymes that otherwise fail to produce a spectral change, especially phosphotransferases, amide bond synthases, isomerases, and hydrolases. 

On the basis of a similar approach used with MDL 101731, irreversible inhibitors of SAH hydrolase have been designed.However, the supposed addition-elimination mechanism of a nucleophile of the enzyme onto the Michael acceptor has been ruled out the hydrolysis of the vinyl fluoride into aldehyde is responsible for the irreversible inhibition (Figure 7.59). ° ... 

Genetic engineering. The X-ray structures are known for many hydrolases, allowing for modeling of the substrate in the active site as well as structurally based, random or rational protein mutation to magnify or invert enantioselectivity. An example of the latter is provided by the rational design of a mutant of Candida antarctica lipase (CALB), which, instead of the wild-type R-selectivity, displayed... 

The International Union of Biochemistry and Molecular Biology recommends that the term peptidase be used synonymously with the term peptide hydrolase (IUBMB, 1992). Thus, in this unit the term peptidase is used in reference to any enzyme that catalyzes the hydrolysis of peptide bonds, without distinguishing between exo- and endopeptidase activities. Peptidases may be assayed using native or modified proteins, peptides, or synthetic substrates. In this unit, the focus is on assays based on the hydrolysis of common, commercially available, protein substrates. Thus, the assays are not intended to be selective for a given peptidase they are designed to provide estimates of overall peptidase activity. Other units in this publication focus on synthetic or model substrates, which can be designed for the measurement of specific endo- and/or exopeptidase activities. 

Tarzia, G., Duranti, A., Tontini, A., Piersanti, G., Mor, M., Rivara, S., Plazzi, P. V., Park, C., Kathuria, S., and Piomelli, D. (2003). Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acidamide hydrolase inhibitors. J. Med. Chem. 

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