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| - | =='''Catechol-O-Methyltransferase'''== | + | |
| | + | =='''YourMacromolecule'''== |
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| | ===Introduction=== | | ===Introduction=== |
| - | <Structure load='3bwm' size='500' frame='true' align='right' caption='COMT transfer of methyl group from SAM to catecholamine inactivates catecholamine' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| - | Catechol-O-Methyltransferase (COMT) is an enzyme, which can be either soluble or membrane-bound, that is responsible for the degradation of catecholamine neurotransmitters <ref>PMID:16618795</ref>. This inactivation is accomplished by transferring a <font color='red'>methyl group</font> from <font color='green'>S-adenosyl methionine (SAM)</font> to the <font color='blue'>catecholamine</font>, seen <scene name='Sandbox_Reserved_425/Sam-catecholamine_interaction/9'>here</scene><ref>Grossman, MH, Emanuel, BS, Budarf, ML. Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2. (1992). Genomics, 12(4), 822-825.</ref>.
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| - | One neurotransmitter in this catecholamine family targeted by COMT is dopamine, the neurotransmitter most closely associated with Parkinson's disease. Parkinson's Disease arises out of a lack of dopamine and is characterized by uncontrollable tremors, muscular rigidity, postural instability. At a functional synapse, the action potential prompts release of neurotransmitters like dopamine at the synapse. These neurotransmitters bind to receptors on the postsynaptic membrane, perpetuating the signal. Once the signal has been transmitted, the neurotransmitters are removed from the synapse via reuptake or degradation by enzymes such as COMT. In a person with Parkinson's Disease, dopamine levels are often too low to adequately continue the message to the next neuron. The disease is currently treated with L-DOPA, a dopamine precursor that is converted to dopamine within the brain. However the bioavailability and stability of L-DOPA when used alone is limited. COMT is being investigated as a target for therapeutic agents that would increase the efficacy of L-DOPA. Inhibition of COMT would prevent inactivation of dopamine, leaving higher levels of active dopamine at the synapse and increasing the likelihood of perpetuation of the message to the postsynaptic neuron<ref>Espinoza, S, Manago, F, Leo, D, Sotnikova, TD, Gainetdinov, RR. Role of catechol-O-methyltransferase (COMT)-dependent processes in Parkinson's Disease and L-DOPA treatment. (2012). CNS Neurological Disorder Drug Targets.</ref>.
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| | ===Overall Structure=== | | ===Overall Structure=== |
| - | <Structure load='2zvj' size='500' frame='true' align='right' caption='The structural differences between Catechol-O-Methyltransferase with a coumarine inhibitor, pdb code 2zvj, compared to a carecholic inhibitor, pdb code 2cl5. ' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, insert caption here' scene='Sandbox_Reserved_430/Intra-strand_phosphate/1' /> |
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| - | The Catechol-O-Methyltransferase complex, with a coumarine inhibitor, is a monomer that is made up of <font color='deepskyblue'>eight</font> <scene name='Sandbox_Reserved_425/Beta_sheets/1'>Beta Sheets</scene>. These sheets are all parallel except for one. The monomer is also comprised of <scene name='Sandbox_Reserved_425/Alpha_helices/1'>eight</scene> <font color='deepskyblue'>alpha helices</font>. The beta sheets are on the inside of the complex where the alpha helices are on the outside and enclose the beta strands. The Catechol-O-Methyltransferase can either be membrane bound or soluble. Because it can be either, the <font color='magenta'>polar</font> and '''<font color='darkgray'>nonpolar</font>''' residues are seen <scene name='Sandbox_Reserved_425/Polor_and_nonpolar/1'>here</scene>.<ref>PMID:19056347</ref>
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| - | Catechol-O-Methyl Transferase in complex with a catcholic inhibitor which is a '''non-coumarine inihibitor''' can normally form a <scene name='Sandbox_Reserved_425/Dimer_2cl5/1'>dimer</scene> (pdb code 2cl5). For previous inhibitors that have been used and studied this is true but not for the coumarine inhibitor. This dimer can be formed because the ligand that is attached, which in this case in a bacterial inhibitor, BIE, allows the complex to be structurally flexible. The dimer that forms creates a <scene name='Sandbox_Reserved_425/Dimer_pocket/1'>Pocket</scene>, the <font color='deepskyblue'>ligands</font> are enclosed in the center so that the two monomers fit together nicely and have flexibility. As you can see the two ligands slide pass each other and the two <scene name='Sandbox_Reserved_425/Base_stacking/1'>aromatic</scene> rings look as if they are stacked on top of each other. In this pocket the <font color='blue'>S-Adenosyl Methionine</font>, <scene name='Sandbox_Reserved_425/Distance/1'>SAM</scene>, donates a methyl group to each of the ligands present that have the <font color='lime'>magnesium ion</font> attached. The distance between the <font color='blue'>SAM</font> molecules and the ligands are almost exactly equal distances apart from each other creating an even spacing pocket to form making the dimer very symmetric.<ref>PMID:16618795</ref>
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| - | The complex with the coumarine ligand, pdb code 2zvj, does not allow for such a convenient <scene name='Sandbox_Reserved_425/Monomer_sam_methyl_transfer/1'>distance</scene> between the SAM molecule and ligand to form when they are bound together. Also, with a coumarine inhibitor, the aromatic ring stacking that we saw with the non-coumarine inhibitor does not occur. This asymmetric structure has effects on the binding interactions and therefore the function of the complex.<ref>PMID:19056347</ref>
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| | ===Binding Interactions=== | | ===Binding Interactions=== |
| - | <Structure load='2zvj' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | <font color='cyan'>Met 40</font>, <font color='magenta'>Leu 198</font>, and <font color='midnightblue'>Tyr 200</font> define the <scene name='Sandbox_Reserved_425/Pocket/3'>pocket</scene> for the 4-phenyl-7, 8-dihydroxycoumarine (<font color='dimgray'>4PCM</font>) ligand binding site. <font color='gold'>Trp 38</font> and <font color='darkorange'>Pro 174</font> make <scene name='Sandbox_Reserved_425/Vanderwaals/5'>Van der Waals</scene> interactions with the <font color='dimgray'>4PCM</font>. This also allows us to see how, unlike the ligand described in the Overall Structure section, <font color='dimgray'>4PCM</font> is sterically constrained and unable to form necessary interactions for a dimer configuration. The <font color='lime'>magnesium ion</font> interacts with the two <scene name='Sandbox_Reserved_425/Hydroxyl_groups/1'>hydroxyl groups</scene> of the <font color='dimgray'>4PCM</font>. The <font color='lime'>magnesium ion</font> also aids in the <scene name='Sandbox_Reserved_425/Lys_144/2'>protonation</scene> of <font color='violet'>Lys 144</font>, causing an electrostatic interaction with a hydroxyl group of <font color='dimgray'>4PCM</font>. The other end of this <font color='violet'>Lys 144</font> then acts a hydrogen bond donor for a <font color='darkblue'>water</font> molecule in the binding pocket. This <font color='darkblue'>water</font> molecule then acts a hydrogen bond donor for the carbonyl group of <font color='dimgray'>4PCM</font>, creating an interesting network of hydrogen bonds. The above interactions stabilize the ligand in the binding pocket. These interactions are somewhat similar to other inhibitors previously used, however some differences do occur that make past inhibitors more stable.<ref>PMID:16618795</ref> In our <font color='dimgray'>4PCM</font>, we can see a <scene name='Sandbox_Reserved_425/Met_40/2'>dihedral angle</scene> between the sulfur and carbon atoms of <font color='cyan'>Met 40</font> to be significantly less than <scene name='Sandbox_Reserved_425/3_5-dinitrocatchetol/4'>that</scene> of the <font color='cyan'>Met 40</font> in a COMT complex using <font color='darkred'>3,5-dinitrocatchetol</font><ref>PMID:8127373</ref> as an inhibitor instead; the change is about 96 degrees. This interaction disrupts the favorable binding stabilization interactions of <font color='dimgray'>4PCM</font> with COMT. This interaction, as well as the constraining effects of <font color='gold'>Trp 38</font> and <font color='darkorange'>Pro 174</font> interactions, make <font color='dimgray'>4PCM</font> less stable than nitrocatchetol inhibitors currently being used to treat PD. However, nitrocatchetol inhibitors act as uncouplers, making <font color='dimgray'>4PCM</font> side effects less complex and more attractive. | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| | ===Additional Features=== | | ===Additional Features=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | <Structure load='2zvj' size='500' frame='true' align='right' caption='The location at position 158 where valine replaces with methionine (Val148Met) in the COMT enzyme activity' scene='Insert optional scene name here'/> | + | ===Quiz Question 1=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | In the gene for COMT, there is a functional single-nucleotide polymorphism that switches from valine to methionine mutation at position 158 (Va <scene name='Sandbox_Reserved_425/158/1'>158</scene>Met). The Val variations can breakdowns dopamine as high as four times the rate as its methionine. As a result, neurotransmitter is then release due to the lower dopamine levels. Since COMT's role is to degraded dopamine, the Val158Met polymorphism is told to utilize its effects on cognition by regulating dopamine signaling in the front area of the human brain. <ref>Rakvåg TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F. "Molecular Pain | Full Text | Genetic Variation in the Catechol-O-Methyltransferase (COMT) Gene and Morphine Requirements in Cancer Patients with Pain." Molecular Pain. Web. 25 Apr. 2012. <http://www.molecularpain.com/content/4/1/64>.</ref> There are drugs in the market that could focus only in the frontal lobes and prevent Val158Met to happen. The two common <font color='blue'>major</font> inhibitor drugs (<font color='darkorchid'>tolcapone </font>and <font color='green'>entacapone</font>) that are sold on the market, inhibit the action of COMT. These drugs effectively reduce / inhibit COMT’s ability to degrade neurotransmitters. As mentioned earlier, these drugs are mainly used to combat Parkinson’s Disease.
| + | ===Quiz Question 2=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | <font color='darkorchid'>Tolcapone </font>, which inhibits COMT from immediately converting L-DOPA into 3-O-methyldopa, has the ability to facilitate higher levels of L-DOPA conversion in the central nervous system. Additionally, it allows dopamine to hang around longer by preventing its degradation. Unfortunately, this has also lead to the discovery that Tolcapone promotes high levels of hepatotoxicity (chemical-driven liver damage). This negative side effect has limited the usage of Tolcapone and promoted the selection of another inhibitor drug: Entacapone. <ref>"Why is this medication prescribed?" Entacapone. 18 Dec. -0001. U.S. National Library of Medicine. 25 Apr. 2012 <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000168/>.</ref>
| + | ===Credits=== |
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| - | <font color='green'>Entacapone</font>, unlike Tolcapone, does not easily cross the blood-brain barrier. As a result, it does not cause hepatotoxicity, and is therefore a very common choice. It is typically used to treat the “end-of-dose ‘wearing-off’ symptoms of Parkinson’s Disease. Entacapone is typically used with Levodopa and its role is to prevent the breakdown of L-DOPA OUTSIDE of the brain. Recall that L-DOPA can be broken down into Dopamine, but too much Dopamine throughout the body could be harmful. As a result, Entacapone restores normal cognitive function in patients but also limits the side effects of dopamine on the rest of the body. <ref>"Why is this medication prescribed?" Entacapone. 18 Dec. -0001. U.S. National Library of Medicine. 25 Apr. 2012 <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000168/>.</ref>
| + | Introduction - name of team member |
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| - | ===Credits===
| + | Overall Structure - name of team member |
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| - | Introduction - Jessica Royal
| + | Drug Binding Site - name of team member |
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| - | Overall Structure - Stephanie Bristol
| + | Additional Features - name of team member |
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| - | Drug Binding Site - Emily Brackett
| + | Quiz Question 1 - name of team member |
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| - | Additional Features - Anh Huynh
| + | Quiz Question 2 - name of team member |
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| | ===References=== | | ===References=== |
| | <references/> | | <references/> |
