Hydrolases reversible inhibitors

Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C, Boger DL, Cravatt BF (2004) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311 441 48... 

Regardless of their origin, the structures of most inhibitors of the zinc-dependent HDAC inhibitors can be easily rationalized. They conform to the classical medicinal chemistry dogma for modulating hydrolase enzymes with a catalytic metal at the active site by competitive reversible inhibitors. Such compounds have two key features ... 

Maltosylamine has proved to be an effective specific inhibitor of sweet potato /3-amylase.This result extends the observation that 1-aminoglycosides are specific inhibitors of glycoside hydrolases, and also demonstrates that enzymes acting with inversion, as well as those acting with retention, of anomeric configuration can be inhibited by glycosylamines. /3-Maltosylamine, which acted as a reversible inhibitor, appeared to be directed to the active-site... 

It is noteworthy that qualitative differences exist between the 25( ) and 26(Z) 5 -chloromethylene isomers with respect to inhibition of AdoHcy hydrolase. The authentic Z-isomer 26 is a time-dependent inactivator with potency comparable to that of its 5 -fluoromethylene analogue 15 (Table 2). In contrast, the -isomer 25 showed little activity in our preliminary screen (Table 1) and was reported to be a reversible inhibitor in another study (in which the Z-configuration had been tentatively assigned). ... 

Glycopeptides containing glycosyl L-aspara-gine, L-serine, and L-threonine, developments in, 50,277-310 Glycoside hydrolases, mechanistic information firm studies with reversible and irreversible inhibitors, 48, 319-384 Glycoside synthesis, anomeric-oxygen activation for (trichloroacetimidate method), 50,21 -123... 

G. Legler, Glycoside hydrolases Mechanistic information from studies with reversible and irreversible inhibitors, Adv. Carbohydr. Chem. Biochem., 48 (1990) 319—384. 

Boger, D.L., Miyauchi, H., Du, W., Hardouin, C., Fecik, R. A., Cheng, H., Hwang, I., Hedrick, M. P., Leung, D., Acevedo, O., Guimaraes, C. R., Jorgensen, W. L. and Cravatt, B. F., Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics, J Med Chem, 48 (2005) 1849-1856. 

Compound 104 was shown to be a potent, selective, and reversible non-covalent FAAH (fatty acid amide hydrolase) inhibitor for the treatment of inflammatory and neuropathic pain. With respect to other inhibitors proposed before, the peculiarities that make it so effective and promising are the reversible binding with the FAAH and the replacement of the classical and weU-assessed pyrazole ring with an oxazole ring (14AMCL717). 

As reversible, competitive inhibitors of enzymes, porphyrins can be used for identification and quantification of a substrate or other competitive inhibitors of enzymes. This approach has been successful in the development of cholinesterase and organophosphorus hydrolase bearing glass surfaces for the detection of substrates and inhibitors, including organophosphate compounds. The technique has demonstrated detection limits for sarin (GB) below the Immediately Dangerous to Life or Health levels mdicated by CDC/NIOSH. 

The enzyme catalysing the reversible cyclization of carbamoyl aspartate to dihydro-orotate is called dihydro-orotase (L-4,5-dihydro-orotate amino-hydrolase, EC 3.5.2.3). Dihydro-orotase was found in various animal tissues and for the catalytic function requires Zn + ions [98]. Orotic acid was found to be a competitive inhibitor of dihydro-orotate synthesis though a variety of other pyrimidines had no effect on enzyme activity [99]. 

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