Student Projects for UMass Chemistry 423 Spring 2011: Difference between revisions

=='''Acetylcholinesterase bound by Tacrine'''==

Acetylcholinesterase breaks down acetylcholine into acetic acid and choline via a hydrolysis reaction.<ref>http://www.proteopedia.org/wiki/index.php/Acetylcholinesterase</ref> Acetylcholine is a neurotransmitter that signals muscle contraction. If acetylcholine is not broken down, then the chemical builds up in the synapses between nerve cells and muscle cells resulting in loss of muscle function and ultimately paralysis. The enzyme’s extremely fast reaction rate (approaching the diffusion limit) for breaking one acetylcholine into its two components indicates acetylcholinesterase’s biological importance. Many natural poisons and toxins work by inhibiting this enzyme, thus, paralyzing the victim.<ref>http://www.rcsb.org/pdb/101/motm.do?momID=54</ref>

The drug Tacrine, also known as Cognex, was the first acetylcholinesterase inhibitor approved to treat Alzheimer’s disease. Studies show that the drug only led to slight improvements in people who took it during early stages of the disease, but the drug did nothing to delay the onset of the disease.<ref>http://en.wikipedia.org/wiki/Tacrine</ref> Tacrine is not often used anymore because it has to be taken four times a day and has adverse side effects, including nausea, diarrhea, heartburn, muscle aches and headaches.<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000930/</ref>

Acetylcholinesterase (AChE) is an monomeric enzyme.  Most often, AChE forms a tetramer and binds with a molecule, collagen Q, to connect to the membrane of the neuromuscular junction. <ref>http://www.ncbi.nlm.nih.gov/pubmed/11804574</ref>.  From the <scene name='Sandbox11/Secondary_structure/3'>tertiary structure</scene>, it can be seen that there are 17 <scene name='Sandbox11/Alpha_helix_total/4'>alpha helices</scene> and 14 <scene name='Sandbox11/Beta_strands/3'>beta strands</scene>.  There  are 2 beta sheets formed from 3 anti-parallel and 11 anti-parallel beta sheets, respectively.  As the <scene name='Sandbox11/Original_structure/3'>space filling model</scene> shows, turns, alpha helices, and beta sheets all occupy a portion of the exterior of the protein.  The means that the turns must be composed primarily of polar side chains.  On the other hand, the alpha helices will be amphipathic with side chain order designated by the helical wheel;  the exterior will be filled with polar side chains that can hydrogen bond with water while the inside of the alpha helix will have nonpolar, hydrophobic groups.  The beta sheets must also be amphipathic, but the pattern of side chains is alternating polar and nonpolar.  In addition, in order to maintain its tertiary structure, the protein has three sulfide bonds, which are covalent bonds that form between cysteine residues.  The <scene name='Sandbox11/Disulfide_bond/3'>disulfide bond</scene> between cysteine 67 and cysteine 94 is 5.03 angstroms.

The active site of Torpedo californica acetylcholinesterase (TcAChE) is buried at the bottom of a narrow, deep gorge in the enzyme, and contains a <scene name='Sandbox11/Catalytic_triad/6'>catalytic triad</scene> consisting of Ser200, Glu327, and His440. When complexed with tacrine (THA), the aromatic rings of <scene name='Sandbox11/Aromatic_rings_trp_84_phe_330/1'>Trp84 and Phe330</scene> sandwich the THA’s acridine ring . The phenyl ring of Phe330 lies parallel to and in contact with THA. THA is stacked against Trp-84. Its ring nitrogen is H-bonded to the main chain carbonyl oxygen of Hist-440 and it’s amino nitrogen is H-bonded to a water molecule.

<scene name='Sandbox11/Rivastigmine_ache/4'>rotating.</scene>

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Introduction - Tyler Vlass