Enzymic Hydrolysis Of Acetylcholine Biology Essay

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INTRODUCTION

The enzymic hydrolysis of acetylcholine in nervous tissue was suggested 57 years ago by Dale as a method for the rapid removal of this substance after it had served as a neurohumoral transmitter in nervous function. Later, cholinesterase activity was found in blood and it was shown that there are at least two distinct enzymes, one in red cells and one in serum. The kinetic properties of these two enzymes have become the basis for classifying enzymes in other tissues. The red cell type called acetylcholinesterase (acetylcholine hydrolase EC 3.1.1.7) hydrolyzes acetylcholine far more rapidly than butyryl-choline whereas the serus tupe, called butyrylcholinesterase, hydrolyzes butyrylcholine about four times more rapidly than acetylcholine.

Figure 1: Enzymic Hydrolysis of Acetylcholine

In contrast to butyrylcholinesterase, acetylcholinesterase is subject to marked substrate inhibition and hydrolyzed D-β-methyl acetylcholine. Neither enzyme is completely specific for choline esters. For example, acetylcholinesterase can hydrolyze ethyl acetate and phenyl acetate. The former is a poor substrate while the latter is a good substrate.

Acetylcholinesterase is found in nervous tissue of all species of animals and besides its hydrolytic activity there has been some suggestion that it may function as a physiological receptor. Inhibitors of the enzyme are toxic, and some anticholinesterases are used as war gases and as insectisides. Others find use in the treatment of glaucoma and myasthenia gravis. (1)

STRUCTURE

Acetylcholine is synthesized from choline and acetyl coenzyme A through the action of the enzyme choline acetyltransferase and becomes packaged into membrane-bound vesicles . For the nerve signal to continue, acetylcholine must diffuse to another nearby neuron or muscle cell, where it will bind and activate a receptor protein.

There are two main types of cholinergic receptors, nicotinic and muscarinic. Nicotinic receptors are located at synapses between two neurons and at synapses between neurons and skeletal muscle cells. Upon activation a nicotinic receptor acts as a channel for the movement of ions into and out of the neuron, directly resulting in depolarization of the neuron. Muscarinic receptors, located at the synapses of nerves with smooth or cardiac muscle, trigger a chain of chemical events referred to as signal transduction. (5)

MECHANISM OF CATALYSIS

Acetylcholinesterase (AChE) is essential for hydrolysis of the neurotransmitter acetylcholine (ACh), and, therefore, for termination of impulse transmission at cholinergic synapses (Figure 2). Irreversible inhibition of AChE can result in accumulation of ACh at cholinergic synapses and, ultimately, to death. AChE has a deep (20Å) and narrow (5Å) gorge lined with 14 aromatic residues, with its active site located near the bottom of the gorge[2]. Initially, ACh binds to the peripheral anionic site (PAS) of AChE, and is funneled down the gorge to the active site by interactions between its quaternary ammonium group and the aromatic rings of 14 aromatic amino acid residues lining the gorge. The Hostos-Lincoln Academy Students Modeling A Research Topic (S.M.A.R.T) team and the Center for BioMolecular Modeling have designed and fabricated two physical models using a combination of computational molecular modeling and three-dimensional (3D) printing technology: Torpedo californica (Tc) AChE complexed with a modeled ACh molecule ligand, and a complex of FAS-II with TcAChE. (4)

KINETICS OF REACTION

Acetylcholinesterase (AChE) is an enzyme that catalyses the hydrolysis of the neurotransmitter acetylcholine (ACh) to acetate and choline, and plays a crucial role in terminating the nerve impulse at cholinergic synapses. Additionally, the structure of the ternary complex of the aged AChE complex with 2-PAM, revealed that the oxime functional group is not optimally positioned for nucleophilic attack on the phosphorous atom.

ACh is a neurotransmitter that is essential for nerve transmission at the cholinergic synapse. In the beginning a nerve impulse reaches the presynaptic membrane which acts upon vesicles that contain ACh. Afterwards, ACh diffuses across the synapse where it binds and activates receptors on the postsynaptic neuron. It is also important to terminate the impulse by breaking down ACh into acetyl and choline portions by AChE.

AChE is a very fast enzyme[2]and even though the active site is at the bottom of a deep (~20 Â) and narrow (~5 Â) gorge, it has several features that ensure rapid catalysis. Primarily,

1. 14 aromatic residues line the active site and filter ACh, by cation-Ï€ interactions, from the surface of AChE to the catalytic triad (Ser200, Glu327 and His440).

2. AChE has a dipole that helps "attract" to the active site. (3)

ASSOCIATED DISEASES AND APPLICATION

The effect that a specific AChE inhibitor can have on the body depends largely on the chemical properties of the molecule and the strength of the bond it forms with AChE. These bonds can resist hydrolytic cleavage for up to several hours, meanwhile inhibiting all normal AChE activity and leading to an excessive, and possibly toxic, build-up of ACh at cholinergic synapses.

In the early 1930's, parathion, an irreversible AChE inhibitor, was manufactured for use as an insecticide. These chemicals successfully break up the toxin-enzyme complex, freeing the enzyme and allowing for the breakdown of accumulated ACh.

Not all ACh inhibitors are as toxic as the irreversible/competitive compounds. Reversible AChE inhibitors are considered non-competitive because they can only bind to AChE for a limited amount of time before the unstable complex dissociates and ACh can once again bind to the enzyme. The bond formed with AChE is, however, broken before the accumulation of ACh in the synapse can become toxic.

Reversible AChE inhibitors are used to treat myasthenia gravis, an autoimmune disorder characterized by debilitating muscle weakness. By causing a temporary excess of ACh at the synapse, non-competitive anti-AChEs are helpful in utilizing each remaining receptor molecule to its fullest capacity.

Pyridostigmine bromide, marketed under the name Mestinon or Regonol, is the most widely used anti-AChE in the treatment of Myasthenia gravis. Because of this, they can be administered to treat muscle weakness, without causing the psychotropic side-effects they might if they could penetrate the cholinergic pathways of the central nervous system.

Reversible AChE inhibitors are also used in the treatment of Alzheimer's disease, a serious brain disorder in which the gradual death of cholinergic brain cells results in a progressive and significant loss of cognitive and behavioral function. (2)

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