Sandbox 250: Difference between revisions
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==='''Introduction'''=== | ==='''Introduction'''=== | ||
Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh | Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh), and therefore the termination of the nerve impulse in cholinergic synapses(Figure 2). Irreversible inhibition of AChE can lead to increased levels of ACh in cholinergic synapses and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease<ref>PMD:14501022</ref>. AChE has a deep(20Å) and narrow(5Å) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge<ref>PMD:1678899</ref>. Initially, ACh binds to the peripheral anionic site(PAS) of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II (FAS-II)toxin, a component of the East African Green Mamba snake(''Dendroaspis angusticeps'') venom, inhibits AChE by binding to the top of the active-site gorge, including residues that form the PAS; thus preventing ACh from entering the active-site gorge<ref>PMD:8747462</ref>. 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 in complex with a modeled ACh ligand and ''Tc''AChE in complex with FAS-II. | ||
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When a nerve impulse reaches the presynaptic nerve terminal, where it stimulates the release of the neurotransmitter, ACh, into the cholinergic synapse. ACh diffuses across the synapse to the postsynaptic nerve terminal, and binds to receptors embedded in the membrane of the postsynaptic nerve terminal. The binding of ACh to receptors in the postsynaptic neuron re-initiates the nerve impulse. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal, hydrolyzes ACh to acetate and choline resulting in the termination of the nerve impulse at the synapse. | When a nerve impulse reaches the presynaptic nerve terminal, where it stimulates the release of the neurotransmitter, ACh(Figure 1), into the cholinergic synapse. ACh diffuses across the synapse to the postsynaptic nerve terminal, and binds to receptors embedded in the membrane of the postsynaptic nerve terminal. The binding of ACh to receptors in the postsynaptic neuron re-initiates the nerve impulse. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal(Figure 2), hydrolyzes ACh to acetate and choline resulting in the termination of the nerve impulse at the synapse. | ||
[[Image:AChE-Page-ACh_shematic.JPG|left|thumb|alt= Alt text| Figure 1. Chemical Structure of Acetylcholine |275px]] | [[Image:AChE-Page-ACh_shematic.JPG|left|thumb|alt= Alt text| Figure 1. Chemical Structure of Acetylcholine |275px]] | ||
Inhibition of AChE may result in different outcomes, depending on the physiological context. Toxins such as FAS-II from the East African Green Mamba snake inhibit AChE and ultimately lead to death. Conversely, reversible inhibition of AChE, in patients with Alzheimer’s disease, is an effective way to improve their symptoms, including memory loss and disorientation. | Inhibition of AChE may result in different outcomes, depending on the physiological context. Toxins such as FAS-II from the East African Green Mamba snake inhibit AChE and ultimately lead to death. Conversely, reversible inhibition of AChE, in patients with Alzheimer’s disease, is an effective way to improve their symptoms, including memory loss and disorientation. | ||