Sandbox Ben Whiteside: Difference between revisions
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==Introduction== | ==Introduction== | ||
When consuming food, the human body is tasked with secreting hormones and chemical messengers that will help regulate homeostasis. After a meal, the body has to maintain homeostasis by reducing blood glucose and signaling that enough nutrients have been consumed. During feeding, cells in the body will secrete the ligand, amylin. [https://en.wikipedia.org/wiki/Amylin Amylin] is a 37 amino acid glucoregulatory hormone that is produced within [https://en.wikipedia.org/wiki/Beta_cell beta cells] of the pancreas. When there is an influx of nutrients in the gastrointestinal tract, the ligand will bind to the heterodimeric receptor, activating the receptor and triggering the corresponding signaling cascade | When consuming food, the human body is tasked with secreting hormones and chemical messengers that will help regulate homeostasis. After a meal, the body has to maintain homeostasis by reducing blood glucose and signaling that enough nutrients have been consumed. During feeding, cells in the body will secrete the ligand, amylin. [https://en.wikipedia.org/wiki/Amylin Amylin] is a 37 amino acid glucoregulatory hormone that is produced within [https://en.wikipedia.org/wiki/Beta_cell beta cells] of the pancreas. When there is an influx of nutrients in the gastrointestinal tract, the ligand will bind to the heterodimeric receptor, activating the receptor and triggering the corresponding signaling cascade. The overall effect of this cascade is increased satiety, delayed gastric emptying, and inhibition of [https://en.wikipedia.org/wiki/Glucagon glucagon] secretion <ref name=”Bower”>PMID:27061187</ref>. The amylin receptors are widely distributed throughout the central nervous system <ref name=”Hay”>PMID:26071095</ref>. The amylin [https://en.wikipedia.org/wiki/G_protein-coupled_receptor g-protein coupled receptor] <scene name='10/1038828/Entire_protein_scene/4'>(AMYR) </scene>is a heterodimeric protein containing a [https://en.wikipedia.org/wiki/Calcitonin calcitonin] receptor domain, as well as one of three [https://en.wikipedia.org/wiki/Receptor_activity-modifying_protein receptor activity modifying proteins] (RAMP 1,2, or 3)<ref name=”Cao”>PMID:35324283</ref>. | ||
=== Transmembrane Domain === | === Transmembrane Domain === | ||
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It has been thought that [https://en.wikipedia.org/wiki/Missense_mutation missense mutations] in residues C2 and C7 of the amylin peptide could lead to an increased risk of Alzheimer's Disease (CITE) <ref name=”Grizzanti”>PMID: 30282360</ref>. Because of the rigidity these cysteine resides provide, reductions of their disulfide interaction leads to an increased risk of amyloid plaques due to amylin misfolding and forming aggregates. During drug design, pharmaceutical companies have focused on maintaining amylin residues C2 and C7, as well as K1, which forms a hydrogen bond donor for the <scene name='10/1038828/N_term_disulfidenew/1'>E294 Side Chain</scene> and main chain carbonyl. Additionally, pharmaceuticals companies have also opted to maintain residues <scene name='10/1038819/Amidated_c_term/9'>Y37 and T36</scene>, which are critical residues in stabilizing the C terminus of amylin to the receptor binding site. While there are hardly any differences in the helical portion of amylin and the synthetic analogue pramlintide, there is a difference in the extended random coil at the C terminus. | It has been thought that [https://en.wikipedia.org/wiki/Missense_mutation missense mutations] in residues C2 and C7 of the amylin peptide could lead to an increased risk of Alzheimer's Disease (CITE) <ref name=”Grizzanti”>PMID: 30282360</ref>. Because of the rigidity these cysteine resides provide, reductions of their disulfide interaction leads to an increased risk of amyloid plaques due to amylin misfolding and forming aggregates. During drug design, pharmaceutical companies have focused on maintaining amylin residues C2 and C7, as well as K1, which forms a hydrogen bond donor for the <scene name='10/1038828/N_term_disulfidenew/1'>E294 Side Chain</scene> and main chain carbonyl. Additionally, pharmaceuticals companies have also opted to maintain residues <scene name='10/1038819/Amidated_c_term/9'>Y37 and T36</scene>, which are critical residues in stabilizing the C terminus of amylin to the receptor binding site. While there are hardly any differences in the helical portion of amylin and the synthetic analogue pramlintide, there is a difference in the extended random coil at the C terminus. | ||
In order to restore basal amylin levels in mice, researchers have performed PEGylation, the addition of poly ethylene glycol, to amylin within residues 1-11 of the peptide, most likely at the two amine groups of K1<ref name=”Guerreiro”>PMID: 23818080</ref>. Administration of the modified amylin in mice showed evidence of reduced glycemia and prolonged action compared to endogenous amylin<ref name=”Guerreiro”>PMID: 23818080</ref>. | |||
[[Image:align.png|300px|left|thumb|Figure 3:Amylin (green) aligned with Pramlintide (red)]] | [[Image:align.png|300px|left|thumb|Figure 3:Amylin (green) aligned with Pramlintide (red)]] | ||
[[Image:align.png|300px|left|thumb|Figure 4:Amylin (green) aligned with Pramlintide (red)]] | [[Image:align.png|300px|left|thumb|Figure 4:Amylin (green) aligned with Pramlintide (red)]] | ||