Acetylcholinesterase primary

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

The primary function of acetylcholinesterase is to terminate the activity of the neurotransmitter, acetylcholine (Fig. 6.4), through hydrolysis at the various cholinergic nerve endings. In this regard, it is probably the most highly efficient enzyme that operates in the human. It is capable of hydrolyzing 300,000 molecules of acetylcholine per molecule of enzyme... 

Schumacher, M. Camp, S. Maulet, Y. Newton, M. MacPhee-Quigley, K. Taylor, S. S. Friedmann, T. Taylor, P. Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature 1986, 319, 407 09. 

At the physiological level it is well established that vital dyes such as nile blue, neutral red and methylene blue retard larval development under normal lighting conditions (12L/12D with source unspecified) (25 27). Female but not male pupal weights are also reduced. Unfortunately experiments were conducted without dark controls so that it is difficult to evaluate the role of photosensitization in these effects. As house flies and fire ants succumb to photosensitization, they lose motor control and become more excitable (28). This suggested a neurotoxic effect and investigation of fire ant acetylcholinesterase vitro revealed that this enzyme was sensitive to photo-oxidation. vivo results, however, revealed no effect on the enzyme which suggests another mode of action. Epoxldatlon of cholesterol and membrane lysis may be alternative primary sites. If this were the case ecdysone metabolism of insects would probably also be effected. 

The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. 

Acetylcholinesterase is the primary target of these drugs, but butyrylcholinesterase is also inhibited. Acetylcholinesterase is an extremely active enzyme. In the initial catalytic step, acetylcholine binds to the enzyme s active site and is hydrolyzed, yielding free choline and the acetylated enzyme. In the second step, the covalent acetyl-enzyme bond is split, with the addition of water (hydration). The entire process occurs in approximately 150 microseconds. 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

J.A. Doom, D.A. Gage, M. Schall, T.T. Talley, C.M. Thompson and R.J. Richardson, Inhibition of acetylcholinesterase by (1S, 3,Y)-isomalalhion proceeds with loss of thiomethyl Kinetic and Mass Spectral Evidence for an Unexpected Primary Leaving Group, Chem. Res. Toxicol., 13, 1313-1320 (2000). 

Clarke S, Rivier F. 1998. Compartments within human primary auditory cortx evidence from cytochrome oxidase and acetylcholinesterase staining. Eur J Neurosci 10 741-745. 

Doom, J.A., Gage, D.A., Schall, M., Talley, T.T., Thompson, C.M., Richardson, R.J. (2000). Inhibition of acetylcholinesterase by (15,35)-isomalathion proceeds with loss of thio-methyl kinetic and mass spectral evidence for an unexpected primary leaving group. Chem. Res. Toxicol. 13 1313-20. 

In liver disease, increased amounts of D-tubocurarine may be reqnired. In the past it has been suggested that this could be due to reduced synthesis of acetylcholinesterase, or to increased concentrations of gammaglobulins binding the relaxant (14), although this is disputed (15). Similar kinetic mechanisms to those suggested for pancuronium may be involved, but there are no studies on D-tubocurarine. In primary liver cancer in children, resistance to D-tubocurarine (and alcuronium) has been reported (SEDA-13,104) (16). 

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