A new class of mammalian carboxylesterase CES6

Abstract

Mammalian carboxylesterases (CES) exhibit broad substrate specificities, catalyse hydrolytic and transesterification reactions with a wide range of drugs and xenobiotics and are widely distributed in the body. Four CES classes have been previously described, namely CES1 (major liver form); CES2 (major intestinal form); CES3 (highest activity in the colon); and CES5, a secreted enzyme found in mammalian kidney and male reproductive fluids. In silico methods were used to predict the amino acid sequences, structures and gene locations for a new class of CES genes and proteins, designated as CES6. Mammalian CES6 amino acid sequence alignments and predicted secondary and tertiary structures enabled the identification of key CES sequences previously reported for human CES1, but with CES6 specific sequences and properties: high isoelectric points (pI values of 8.8 -9.4 compared with 5.4 -6.2 for human CES1, CES2, CES3 and CES5); being predicted for secretion into body fluids compared with human CES1, human CES2 and CES3, which are membrane bound; and having Asn or Glu residues at the predicted CES1 Z-site for which a Gly residue plays a major role in cholesterol binding. Mammalian CES6 genes are located in tandem with CES2 and CES3 genes, are transcribed on the positive DNA strand and contain 14 exons. Human and mouse CES6-like transcripts have been previously reported to be widely distributed in the body but are localized in specific regions of the brain, including the cerebellum. CES6 may play a role in the detoxification of drugs and xenobiotics in neural and other tissues of the body and in the cerebrospinal fluid.

Mammalian carboxylesterase 3: comparative genomics and proteomics

“…This study also tests an hypothesis that mammalian CES3 genes are members of a distinct CES gene family to those previously reported, including CES1 (encoding the major liver isozyme) (Munger et al 1991), CES2 (encoding the major intestinal CES) (Schewer et al 1997), CES5 (also called ‘cauxin’ or CES7) (Holmes et al 2008b) and CES6 (transcribed in human brain and also called CES8) (Holmes et al 2009d). …”

“…Mammalian CES genes usually contain 12–14 exons of DNA encoding CES enzyme sequences which may undergo exon shuffling generating several CES isoproteins in each case (Thierry-Mieg and Thierry-Mieg 2006). There are similarities for the exon boundaries for each of the mammalian CES genes (Holmes et al 2008a, b, 2009a, b, c, d) as well as significant sequence identities, especially for key regions previously identified for the major human liver CES1 (Bencharit et al 2003, 2006; Fleming et al 2005). Three-dimensional structural analyses of human CES1 have identified three major ligand binding sites, including the promiscuous active site, ‘side door’ and ‘Z-site’, where substrates, fatty acids and cholesterol analogues, respectively, are bound; and the ‘gate’, reportedly functioning in product release (Bencharit et al 2003, 2006; Fleming et al 2005).…”

“…At least five families of mammalian carboxylesterases (CES; E.C.3.1.1.1) have been reported (Holmes et al 2008a, b, 2009a, b, c, d) including CES1, the major liver enzyme (Munger et al 1991; Shibita et al 1993; Ghosh 2000; Holmes et al 2009a); CES2, the major intestinal enzyme (Langmann et al 1997; Schewer et al 1997; Holmes et al 2009a); CES3, expressed in liver, colon and brain (Sanghani et al 2004; Holmes et al 2009a, b, c); CES5 (also called CES7 or ‘cauxin’), a major urinary protein of the domestic cat (Miyazaki et al 2003, 2006; Holmes et al 2008b); and CES6, a predicted CES-like enzyme in brain (Clark et al 2003; Holmes et al 2009d). These enzymes catalyze hydrolytic and transesterification reactions with xenobiotics, anticancer pro-drugs and narcotics (Satoh and Hosokawa 1998, 2006; Satoh et al 2002; Ohtsuka et al 2003; Redinbo and Potter 2005), and detoxify organophosphates and insecticides (Ahmad and Forgash 1976; Leinweber 1987).…”

Carboxylesterases Are Uniquely Expressed among Tissues and Regulated by Nuclear Hormone Receptors in the Mouse

“…Numerous reports have appeared describing the distribution, regulation and function of various carboxylesterases in the mouse model (Poole et al, 2001;Holmes et al, 2009Holmes et al, , 2010aXu et al, 2009;Staudinger et al, 2010;Zhang et al, 2012). However, with the confusion regarding Carboxylesterase mRNA Distribution and Regulation in Mice nomenclature and ortholog assignment, and the nonselectivity of some oligonucleotide and antibody probes, the reliability of these findings has been uncertain.…”

The Measurements Of The Cholinesterase Activity Of Brain And Plasma In Rabbits By Using Modified Michel And Ellman Assays

“…The second type of Cholinesterase is B-esterase which is mainly found in tissues and it is inhibited by organophosphorus compounds. Some important subtypes of B-esterase [10] are specific acetylcholinestrase EC3.1.1.7/acetylcholine acetylhydrolase [11], neurotoxic esterase, Carboxylesterase EC 3.1.1.1 [12] and non-specific pseudocholinesterase EC3.1.1.8/Acylcholine acylhydrolase/Butyrylcholinestrase [13,14]. Acetylcholinesterase exhibits irritation ability in the Cholinergic synapses, liver and plasma within the HLD, neuromuscular junction in musclotendinous, neuron body, neuron axis, central nervous system (spinal cord and brain), blood serum, red blood cells, platelets in the pancreas, T-lymphocytes, motor end plate and Neural fibers [15,16].…”