Acetylcholinesterase and Butyrylcholinesterase Substrate Selectivity and Various Acting Cholinesterase Inhibitors

2308 Words Feb 27th, 2011 10 Pages
Acetylcholinesterase and Butyrylcholinesterase substrate selectivity and various acting cholinesterase inhibitors
Introduction
Cholinesterases are a group of enzymes present in mammals which breakdown certain neurotransmitters by hydrolyzing the ester bonds within a molecule (Rang & Dale, 2007). There are two major types of enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Though similar in structure, they differ in distribution, function and substrate specificity.
AChE is found in red blood cells, cholinergic fibres and muscle (motor end-plate), existing as mainly membrane bound (Rang & Dale, 2007). It is highly specific for the neurotransmitter acetylcholine (ACh) and its principle role is termination of impulse
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Chatonnet & Lockridge (1989) indicate suxamethonium is rapidly hydrolysed by BChE, which is contrary to our findings (Figure1). This paper highlights genetic variation between enzymes may result in varied enzyme kinetics, possibly explaining the discretion in results.
AChE hydrolysed methacholine at a high velocity (57.1%) with BChE proving much less effective with a theoretical hydrolization velocity (0.6%) (Figure1). Though structurally similar to ACh, Methacholine contains a β-methyl group adjacent its ester group. In terms of AChE this creates slight steric hindrance, complicating methacholine’s access to the AChE active site consequently slowing hydrolisation (Soukupova et al 2008). The β-methyl group creates a greater degree of steric hindrance in relation to BChE, and is hence more resistant to its destruction. These findings are concurrent with Herz and Caplan (1975).
Hydrolysis of carbachol was not recorded by either BChE or AChE and it was also effective in inhibition with relative velocities of 10% and 10.8% (Figures1,2). The carbamic ester acts as very poor substrate for both AChE and BChE, proving much more difficult to hydrolyse when compared to a standard ester (Rosenbury et al., 2008).
Medium-length inhibitors Neostigmine and Physostigmine displayed greater inhibition when compared to the short-acting Edrophonium (Figure X). Edrophonium contains a quaternary ammonium group that binds rapidly and reversibly to the anionic site of AChE,

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