Cholinesterases molecular forms

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 ... 

Cholinesterase. Figure 1 Shown are the seven subgroups of ChEs Molecular forms Top, in green monomeric, dimeric and tetrameric AChE-S forms (G1, G2, G4 and PRiMA). Middle, in green ColQtailed AChE-S forms (A4, A8 and A12). Parallel forms exist for BChE. Down other AChE splicing variants (AChE-R, AChE-E, N-AChE). 

Cholinesterases are subdivided into acetylcholinesterase and cholinesterase, one with a narrow, the other with broad substrate specificity [109-112], Both enzymes exist in multiple molecular forms distinguishable by their subunits association (Fig. 2.4). The hydrodynamic properties of these associations have allowed globular (G) and asymmetric (A) forms to be distinguished. The G forms can be hydrophilic (water-soluble, and excreted into body fluids) or amphiphilic (membrane-bound). The homomeric class exists... 

Rakonczay, Z. (1988). Cholinesterase and its molecular forms in pathological states. Prog. Neurobiol. 31 311-30. 

Figure 1 Subunit structure of the multiple molecular forms of ChEs. G, globular forms A, asymmetric forms with collagen-like tails. Each circle is a catalytic subunit disulfide bridges indicated by S-S as found in the electric organ of the electric eel. (Modified from Brimijoin WS (1992) US EPA Workshop on Cholinesterase Methodologies.)...

Modern techniques for protein separation have been used to demonstrate the existence of multiple molecular forms of cholinesterase. Such entities, which are groups of isoenzymes, can be separated either by electrophoresis or by chromatography (H8) moreover, they can be distinguished by kinetic means (e.g., R3). 

Multiple Molecular Forms of Human Plasma Cholinesterase... 

L12. LaMotta, R. V., Woronick, C. L., and Reinfrank, R. F., Multiple forms of serum cholinesterase Molecular weights of the isoenzymes. Arch. Biochem. Biophys. 136, 448-451 (1970). 

Scarsella, G., G. Toschi, S. R. Bareggi, and E. Giacobini. 1979. Molecular forms of cholinesterase in cerebrospinal fluid, blood plasma and brain tissue of the beagle dog. Journal of Neuroscience Research 4 19-24. 

Gibney, G., MaePhee-Quigley, K., Thompson, B., Vedvick. T., lutw. M. G.. Taylor, S. S.. and Taylor, P. (1988). Divergence in primary structure between the molecular forms of aceiyl-cholinesterase. J. Biol. Chem. 2<3, 1140-1145. 

The two cholinesterase enzymes, acetyl (AChE) and butyryl (BuChE), although closely related, show differences both in their occurrence in the body (leading to their older vernacular names of erythrocyte, red cell, or true cholinesterase in the case of AChE and plasma or pseudo-cholinestcrase for BuChE) and in their substrate specificity. AChE is more correctly called acetylcholine acetylhy-drolase (EC 3.1.1.7), and BuChE is more correctly called acylcholinc acylhydrola.se (EC 3.1.18). AChE is present in most vertebrates in several molecular forms, whereas BuChE is present in only c te, the tctramcric T form (Massoulie, 2002). 

The classic view of two cholinesterases whose sole function is to terminate cholinergic signals at the synapse has been repeatedly challenged by observations that were incongruent with this view and suggested a far more complex picture of multiple molecular forms with distinct temporal and spatial expression patterns. This complexity mainly results from alternative splicing... 

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.

ANTICHOLINESTERASES are agents that inhibit cholinesterases, enzymes that fall into two main families -acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). These enzymes are of related molecular structures but have different distributions, genes and substrate preferences. The enzymes have globular catalytic subunits that are the soluble form of the esterases (as in plasma or CSF), or they can be attached via long collagen tails to the cell membrane. 

Aggregation of enzyme molecules with each other or with nonenzymatic proteins may give rise to multiple forms that can be separated by techniques that depend on differences in molecular size. For example, four catalytically active cholinesterase components with molecular weights ranging from about 80,000 to 340,000 are found in most sera, with the heaviest component, C4, contributing most of the enzyme activity. Other enzyme forms are also occasionally present, but it appears that the principal serum cholinesterase fractions can be attributed to different states of aggregation of a single monomer. 

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