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Acetylcholine Esterase Symptomatic Target Biology Essay

Acetyl choline esterase is one of the neurotransmitter in the peripheral nervous system and central nervous system. It is dominantly present in the somatic nervous system.

Choline and acetyl Co-A in the presence of choline acetyltransferase leads to the formation of Acetylcholine (Ach).

Acetyl choline in presence of acetyl cholinesterase converted into inactive metabolite choline and acetate. More amount of enzyme was found to be present in the synaptic cleft. The clearance of free acetylcholine occurs rapidly at the synaptic cleft for the proper muscle function.

Excess amount of Ach is found at the neuromuscular junction due to the inhibition of AchE by neurotoxins. This leads to paralysis of the respiratory muscles and ceasing of the heart functioning.

Acetylcholine at the synaptic cleft as well at autonomic ganglia involve in the cell signalling through second messengers. Degradation of Ach by acetyl cholinesterase leads to Myasthenia gravis, Alzheimer’s disease, and Glaucoma.

The thorough study on the molecular basis, the pathological signs of neuronal degeneration (biomarkers) paves the way for treating AD.

MOLECULAR BASIS OF ACETYLCHOLINE ESTERASE AND ITS ACTIVE SITE:

AchE falls into two structural classes namely homomeric oligomers and heteromeric forms. Homomeric oligomers with catalytic subunits are soluble in cell. The presence of hydrophobic amino acids sequence makes it to be associated with the glycophospholipid (outer membrane of the cell).Heterologous type is found in neuronal synapse as a tetramer with catalytic subunits of disulfide- linked to lipid with molecular weight of 20,000 Daltons and they found to be attached to the outer surface of the cell membrane through glycophospholipid.

Fig: I 3-dimensional structural image (ribbon-like) of Acetylcholine esterase

From the 3-dimensional structure of AchE, the active site was found to be present at the centerosymmetric to each subunit and present at the base of the gorge about 20Å in depth (Sussman et al, 1995). Serine 203, Histidine 447, and glutamate 334 were the amino acid residue of catalytic triad lies at the base of the gorge.

The serine hydroxyl group is highly nucleophilic due to the charge relay system involving the carboxyl group from glutamate, the Imidazole on the Histidine; this resembles the catalytic mechanism of hydrolases.

AchE forms a tetrahedral intermediate (acyl enzyme) with the substrate (Ach) and this conjugate concomitantly release the choline part of the substrate followed by the formation of acetate (CH3COO-) and active enzyme (AchE). One AchE molecule hydrolyses 600,000 acetylcholine molecules per minute.

MOLECULAR BASIS OF ALZHIEMERS DISEASE:

The exact molecular basis of AD is complex but the evidence for possible mechanism of neuronal degeneration is available.

The human brain is the remarkable organ with complex, chemical and electrical process occurs. The various processes like speaking, moving, seeing, remembering, feeling emotions and taking decision were executed by different parts of the brain.

In normal healthy brain, billion of cells called neurons constantly communicate with one and another. The messages from each neurons travel along the axons as the electric charges to the end of neuron. The electrical charges releases chemical messengers called neurotransmitters, they move across the microscopic gapes or synapses between neurons. They find receptors on dendrites on the post synaptic neuron (next neurons) and bind to it. This cellular circuit enables communication within the brain. Healthy neurotransmission is necessary for the proper functioning of the brain.

In AD, the disruption of the intricate interplay occurs by compromising the ability of neurons to communicate with one another and on overtime destroys memory and thinking skills. The scientific research revealed some other brain changes that take places in brain, showing abnormal structures of biological hallmarks called beta amyloid and tangles (Arnold et al., 1991; Braak, 1994).

In the forebrain (nucleus basalis of Meynert) the subcortical cholinergic neurons degeneration that provide cholinergic innervations to the whole cerebral cortex and atrophy are anatomical basis of the cholinergic deficit (Johnston, 1992)

The selective deficiency of acetylcholine as well as the observation that central cholinergic antagonists such as atropine can induce a confusional state that bears some resemblance to the dementia of AD, has given rise to the "cholinergic hypothesis," which proposes that a deficiency of acetylcholine is critical in the genesis of the symptoms of AD (Perry,1986).

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Fig IV: Neuronal pathways and signalling of parasympathetic nerve fibres

Involved in normal versus Alzheimer’s disease

The specific proteins in the neuronal cell membrane are processed differently. Normally an enzyme called alpha secretase sniffs a part of amyloid precursor protein (APP) releasing a fragment. Similarly, a second enzyme called gamma secretase also sniffs remaining portion of APP. The released fragment doesn’t cause any harm to neurons. In AD, the different enzyme called beta secretase performs the first sniff of APP and followed remaining part of APP sniffing by gamma secretase which is a short fragment called beta amyloid. These short fragments combine together and become toxic thereby interfering with the functioning of the neurons. As the number of fragments (beta amyloid) adding upon increases, they become insoluble and eventually results in the beta amyloid plaque formation.

The modification of Tau protein leads to the formation of neurofibrillary tangles. In normal brain cells, tau stabilizes structures critical to the cells in terminal transport system. Nutrients and other soluble cargo are carried up and down in the structures called microtubules to all parts of the neurons. In AD the abnormal tau proteins separates from the microtubule, and combine together to form strands called neurofibrillary tangles inside the neurons. This tangle formation disables the neuronal transport system and destroying the cells.

In certain regions of the brain the neurons get disconnected from each other and eventually die, causing memory loss. As these processes continues the brain shrinks and loses its function.


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