Multiplicity and ligand selectivity

CESs are largely microsomal in origin, with molecular weights of 55-60 kDa. At least four families (CES1-CES4, EC exist, based on sequence similarity, and in humans, the liver (CES1A1, hCE1) and intestinal forms (CES2, hCE2) appear to play the most important roles in detoxication/bioactivation of xenobiotics.95 hCE1 metabolizes heroin and cocaine and is relatively selective for several of the angiotensin-converting enzyme inhibitors, such as delapril and imidapril, whereas hCE2 is more selective for irinotecan and oxybutynin. Therefore, hCE1 often appears to be associated with the removal of small (methyl, ethyl) groups, whereas hCE2 seems to prefer larger moieties, although this is far from a strict rule.92

Some broad-spectrum esterase inhibitors have been in use for many years. Liver and intestinal microsomal esterases can be inhibited by compounds such as bis-nitrophenyl phosphate (BNPP), which phosphonylates an active-site serine residue in the B-esterases. A-esterases can be inhibited by ^-chloromercurobenzoate. More recently, aromatic diones, such as benzil, have been identified as general inhibitors of the CESs, and a series of benzene sulfonamides have been described that act as selective potent inhibitors of hCE2.96 Structure

Microsomal CESs are typically about 60 kDa in size and glycosylated, with the carbohydrate modification seemingly necessary for activity. The crystal structure of hCE1 in complex with various ligands has been solved, revealing the serine hydrolase fold common to the esterase family (see Figure 2 for an example). The enzyme exhibits a large, hydrophobic active site cavity some 15 A deep, suitable for the binding of a wide variety of substrate molecules, as has been observed experimentally.97

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