Cholinesterase, polymorphisms

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... 

Fig. 2.4. Schematic model of the molecular polymorphism of acetylcholinesterase and cholinesterase [110][112a]. Open circles represent the globular (G) catalytic subunits. Disulfide bonds are indicated by S-S. The homomeric class exists as monomers (Gl), dimers (G2), and tetramers (G4) and can be subdivided into hydrophilic (water-soluble) and amphiphilic (membrane-bound) forms. The G2 amphiphilic forms of erythrocytes have a glycophospholipid anchor. The heteromeric class exists as amphiphilic G4 and as asymmetric forms (A) containing one to three tetramers. Thus, heteromeric G4 forms found in brain are anchored into a phospholipid membrane through a 20 kDa anchor. The asymmetric A12 forms have three hydrophilic G4 heads linked to a collagen tail via disulfide bonds.

Mercury, lead, cotinine, pesticides, phthalates, PAHs, PAH-DNA adducts, allergens, endotoxin, antioxidant micronutrients, cytokines, immunoglobulin E, cholinesterase, thyroid hormones, DNA polymorphisms... 

Improvements in medication by use of acetyl cholinesterase inhibitors and general therapy significantly reduce symptoms at the onset of the disease [3, 4] but do not address the severe mortality in the final stages. A causal therapy is, therefore, still very much in demand, because no existing therapy effectively stops or even cures the disease. Identification of gene mutations linked to Alzheimer s disease-afflicted families in London and Sweden and additional polymorphisms that either cause or promote Alzheimer s disease have provided some insight into the biological pathways and the involvement of the amyloid precursor protein (APP) [5-8],... 

A polymorphism in serum cholinesterase is one of the oldest polymorphisms known. It leads to prolonged muscle relation or prolonged paralysis after administration of the muscle relaxant succinylcholine. Several mutants occur, the most common is a point mutation causing the substitution of glycine for aspartic acid at position 70. This variant shows defective binding of choline esters to the anionic binding site but has normal activity with neutral or positively charged esters. There also numerous other variants, many with partial or complete loss of activity. 

Another early example of polymorphism involves the drug succinylcholine (suxamethonium), a muscle relaxant used primarily during surgery. Its action lasts only a few minutes because it is very efficiently metabolized by cholinesterases present in the liver and plasma. A few people, about 1 in 3000 who genetically lack this enzyme, develop sustained apnoea as a result of paralysis because its effect is prolonged from 30 minutes to hours. 

Brock A and Brock V (1993). Factors affecting interindividual variation in human plasma cholinesterase activity body weight, height, sex, genetic polymorphisms and age. Arch Environ Contam Toxicol, 24, 93-99. 

Many individuals have genetic susceptibility to certain chemicals (Calabrese 1978). The influence of these genetic differences likely produces sub- and supersensitivity to OP insecticides and warfare agents (Russell and Overstreet 1987). Several enzymes with variations or polymorphisms control sensitivity to OPs red blood cell acetylcholinesterase, serum cholinesterase or pseudocholinesterase, lymphocyte neuropathy target esterase or platelet neuropathy target esterase (NTE), serum paroxonase, butyrylcholinesterase, and serum arylesterase (Costa et al. 1999 LaDu 1988 Li et al. 1993 Mutch et al. 1992). Inhibition of red blood cell acetylcholinesterase, in both the central and the peripheral nervous systems, produces acute symptoms (Mutch et al. 1992). Paroxonase and arylesterase further modify the response (LaDu 1988 Li et al. 1993). Variant, inactive butyrylcho-linesterases increase sensitivity to OPs (Lockridge and Masson 2000 Schwarz et al. 1995). OP-induced delayed polyneuropathy results... 

There are two main enzymes of interest. Acetylcholinesterase (AChE EC 3.1.1.7) has an affinity for the substrate acetylcholine and it is found in the erythrocytes and nervous tissue. The enzyme is sometimes referred to as true cholinesterase, and it exists in differing polymorphic forms (Skau 1985). Butyrylcholinesterase (BuChE, acylcholine acylhydrolase, EC 3.1.1.8)—also known as pseudocholinesterase or nonspecific cholinesterase— has affinities for the substrates butyrylcholine and/or pro-pionylcholine, which are dependent on the animal species (Myers 1953 Ecobichon and Comeau 1973 Scarsella et al. 1979 Unakami et al. 1987 Evans 1990 Matthew and Chapin 1990 Woodard et al. 1994). 

Howard, T.D., Hsu, F.C, Grzywacz, J.G., et al., 2010. Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides association of single nucleotide polymorphisms in BCHE. Environ. Health Perspect. 118, 1395-1399. 

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