The polymorphism of acetylcholinesterase: post-translational processing, quaternary associations and localization

Massoulié, Jean; Anselmet, Alain; Bon, Suzanne; Krejci, Éric; Legay, Claire; Morel, Nathalie; Simon, Stéphanie

doi:10.1016/s0009-2797(99)00011-3

Cited by 79 publications

(47 citation statements)

References 57 publications

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“…Furthermore, tetramerization via PRAD incubation did not occur with an AChE version lacking the C-terminal tail (not shown). Taken together, these results suggest that the tetramerization process faithfully reflects the physiological interaction between PRAD and WAT responsible for the generation of highly stable tetrameric forms of AChE (44).…”

Section: Fig 6 In Vitro Prad-mediated Tetramerization Of Rboachementioning

confidence: 54%

Hierarchy of Post-translational Modifications Involved in the Circulatory Longevity of Glycoproteins

Kronman

Chitlaru

Elhanany

et al. 2000

Journal of Biological Chemistry

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The tetrameric form of native serum-derived bovine acetylcholinesterase is retained in the circulation for much longer periods (mean residence time, MRT ‫؍‬ 1390 min) than recombinant bovine acetylcholinesterase (rBoAChE) produced in the HEK-293 cell system (MRT ‫؍‬ 57 min). Extensive matrix-assisted laser desorption ionization-time of flight analyses established that the basic structures of the N-glycans associated with the native and recombinant enzymes are similar (the major species (50 -60%) are of the biantennary fucosylated type and 20 -30% are of the triantennary type), yet the glycan termini of the native enzyme are mostly capped with sialic acid (82%) and ␣-galactose (12%), whereas glycans of the recombinant enzyme exhibit a high level of exposed ␤-galactose residues (50%) and a lack of ␣-galactose. Glycan termini of both fetal bovine serum and rBoAChE were altered in vitro using exoglycosidases and sialyltransferase or in vivo by a HEK-293 cell line developed specifically to allow efficient sialic acid capping of ␤-galactose-exposed termini. In addition, the dimeric and monomeric forms of rBoAChE were quantitatively converted to tetramers by complexation with a synthetic peptide representing the human ColQ-derived proline-rich attachment domain. Thus by controlling both the level and nature of N-glycan capping and subunit assembly, we generated and characterized 9 distinct bovine AChE glycoforms displaying a 400-fold difference in their circulatory lifetimes (MRT ‫؍‬ 3.5-1390 min). This revealed some general rules and a hierarchy of post-translation factors determining the circulatory profile of glycoproteins. Accordingly, an rBoAChE was generated that displayed a circulatory profile indistinguishable from the native form.

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Section: Fig 6 In Vitro Prad-mediated Tetramerization Of Rboachementioning

confidence: 54%

Hierarchy of Post-translational Modifications Involved in the Circulatory Longevity of Glycoproteins

Kronman

Chitlaru

Elhanany

et al. 2000

Journal of Biological Chemistry

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“…Thus, we performed a study using more detailed inhibitory curves ranging from 0.6 to 10% for different organic solvents. Of practical importance for the study of apolar compounds as potential inhibitors of AChE, which has hydrophobic interactions important for enzyme structure and catalysis (25). Our results demonstrate that the use of solvents such as acetone, acetonitrile and DMSO must be avoided.…”

Section: Discussionmentioning

confidence: 80%

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

et al. 2005

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Acetylcholinesterase (AChE) was studied in different rat brain regions (cerebellum, hypothalamus, striatum, hippocampus and cortex) in the presence of different organic solvents normally used in the in vitro assay. The organic solvents used were acetone (C3H6O), acetonitrile (C2H3N), ethyl alcohol (C2H6O), isopropyl alcohol (C3H8O), methyl alcohol (CH4O), tert-butyl alcohol (C4H10O) and dimethyl sulfoxide (DMSO, C2H6OS) ranging from 0.6 to 10%. Ethyl and methyl alcohol presented no effect on AChE activity at any of the concentrations and brain structures tested. In the hippocampus, isopropyl alcohol did not demonstrate a significant inhibitory effect, even at high concentrations. Tert-butyl alcohol presented an interesting result, increased AChE activity (P < .05) in the hypothalamus (1.8%), cortex (1.8 and 2.5) and striatum (1.2, 1.8 and 2.5%) and decreased activity at a concentration of 10% in the cortex (P < .05) and striatum (P < .01). Acetone and acetonitrile presented similar results, both significantly inhibiting AChE in all structures (5%, P < .05 and 10%, P < .01). DMSO exhibited a highly inhibitory effect at practically all concentrations tested (P < .01). In conclusion, for testing new compounds on AChE activity in vitro, methyl and ethyl alcohol may be the best organic solvent choice.

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“…Three distinct AChE polypeptides, resulting from alternate splicing at the C-terminus, yield a repertoire of isoforms [Li et al, 1991]. Although the catalytic properties of these isoforms are similar, they differ in quaternary structure and tissue distribution: The AChE-T transcript is the only one expressed in the brains and muscles of adult mammals [Seidman et al, 1995]; the AChE-H transcript produces glycophosphatidylinositol (GPI)-anchored dimers which, in higher vertebrates, are expressed mainly in embryonic tissue and on the surface of hematopoietic cells [Massoulié et al, 1999]; and the AChE-R is a read-through isoform that arises due to lack of splicing downstream of the common constitutive exons encoding the catalytic domain, resulting in a soluble monomer that is upregulated in the brain during stress [Soreq and Seidman, 2001].…”

Section: Introductionmentioning

confidence: 99%

A paradigm for single nucleotide polymorphism analysis: The case of the acetylcholinesterase gene

et al. 2004

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Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 96 unrelated control individuals from three distinct ethnic groups were analyzed. A total of 13 ACHE SNPs were identified, 10 of which are newly described, and five that should produce amino acid substitutions [c.101G>A (p.Arg34Gln), c.169G>A (p.Gly57Arg), c.1031A>G (p.Glu344Gly), c.1057C>A (p.His353Asn), and c.1775C>G (p.Pro592Arg)]. Population frequencies of 11 of the 13 SNPs were established in four different populations: African Americans, Ashkenazi Jews, Sephardic Jews, and Israeli Arabs; 15 haplotypes and five ethnospecific alleles were identified. The low number of SNPs identified until now in the ACHE gene is ascribed to technical hurdles arising from the high GC content and the presence of numerous repeat sequences, and does not reflect its intrinsic heterozygosity. Among the SNPs resulting in an amino acid substitution, three are within the mature protein, mapping on its external surface: they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes-such as adverse drug responses to AChE inhibitors employed in treatment of Alzheimer patients and hypersensitivity to pesticides.

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The polymorphism of acetylcholinesterase: post-translational processing, quaternary associations and localization

Cited by 79 publications

References 57 publications

Hierarchy of Post-translational Modifications Involved in the Circulatory Longevity of Glycoproteins

Hierarchy of Post-translational Modifications Involved in the Circulatory Longevity of Glycoproteins

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

A paradigm for single nucleotide polymorphism analysis: The case of the acetylcholinesterase gene

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