Sandbox Reserved 425
From Proteopedia
(→Introduction) |
|||
| Line 1: | Line 1: | ||
| - | + | <!-- DO NOT DELETE THE TEMPLATE LINE --> | |
{{Template:Sandbox Reserved Lynmarie Thompson}} | {{Template:Sandbox Reserved Lynmarie Thompson}} | ||
<!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> | <!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> | ||
Revision as of 17:19, 22 April 2012
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Contents |
Catechol-O-Methyltransferase
Introduction
|
Catechol-O-Methyltransferase (COMT) is an enzyme, which can be either soluble or membrane-bound, that is responsible for the degradation of catecholamine neurotransmitters. This inactivation is accomplished by transferring a methyl group from S-adenosyl methionine (SAM) to the catecholamine, seen . In this scene, the catecholamine 3,5-dinitrocatechol is represented in blue and SAM is represented in yellow and red, with the red indicating the methyl group being transferred.
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.
Overall Structure
|
The Catechol-O-Methyltransferase complex, 4PCM, with a coumarine inhibitor is a monomer that is made up of eight . These sheets are all parallel except for one. The monomer is also comprised of alpha helices. The beta sheets are on the inside of the complex where the alpha helices are on the outside and enclose the beta strands. The 4PCM complex also has and non polar residues on the outside of the complex on the alpha helices. This is because this 4PCM complex can be both trans membrane protein or a peripheral membrane.
Catechol-O-Methyl Transferase in complex with an inhibitor, COMT, can normally form a . For previous inhibitors that have been used and studied this is true. 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 so that the two monomers fit together nicely and have flexibility. In this pocket the S-Adenosyl Methionine, , donates a methyl group to each of the ligand present that have the magnesium ion attached. The distance between the SAM molecules and the ligand are almost exactly equal distances apart from each other creating an even spacing pocket to form. Our coumarine ligand does not allow for such a convenient between the SAM molecule and ligand to form when bound together. Even though are complex is more restricted it is the first ligand complex to be studied that does not have a toxicity issue.
Binding Interactions
|
Met 40, Leu 198, and Tyr 200 define the for the 4-phenyl-7, 8-dihydroxycoumarine (4PCM) ligand binding site. This also allows us to see how, unlike the ligand described in the Overall Structure section, 4PCM is sterically constrained and unable to form necessary interactions for a dimer configuration. Trp 38 and Pro 174 make interactions with the 4PCM. The magnesium ion interacts with the two of the 4PCM. The magnesium ion also aids in the protonation of , causing an electrostatic interaction with a hydroxyl group of 4PCM. The other end of this Lys 144 then acts a hydrogen bond donor for a water molecule in the binding pocket. This water molecule then acts a hydrogen bond donor for the carbonyl group of 4PCM, 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. In our 4PCM, we can see a bond angle between the sulfur and carbon atoms of to be significantly less than that of the Met 40 in a COMT complex using as an inhibitor instead; the change is about 96o. This interaction, as well as the constraining effects of Trp 38 and Pro 174 interactions, actually make 4PCM less stable than nitrocatchetol inhibitors currently being used to treat PD. However, nitrocatchetol inhibitors act as uncouplers, making 4PCM side effects less complex and more attractive.
Additional Features
In addition to variation in the gene itself, the COMT gene is also associated with 22q11.2 deletion syndrome, which is characterized by an approximately 3 million base pair deletion on the long arm of chromosome 22 near the q11.2 locus. Deletion of this segment results in the loss of 30 to 40 genes, including the COMT gene, which leads to abnormal regulation of catechol-O-methyltranferase in the brain. Affected persons have only one copy of the gene in each somatic cell and may have symptoms that include heart defects, cleft palate, facial feature differences, recurrent infections, autoimmune disorders, kidney abnormalities, low blood calcium, seizures, thrombocytopenia, feeding difficulties, skeletal differences, hearing loss, learning disabilities, schizophrenia, depression, anxiety, bipolar disorder, ADHD, and autism. Deletion of COMT may explain the increased risk of mental problems, which may result from changes in dopamine concentrations.
Variations in the COMT gene such as the Val158Met single-nucleotide polymorphism may increase the risk for mental problems. This mutation is a gain-of-function mutation that allows COMT to catabolize dopamine at up to four times the rate of the normal variant, resulting in lower levels of dopamine and reduced stimulation of post-synaptic neurons. This variant is associated with an increased risk for schizophrenia, difficulties in emotional processing, and has been shown to affect executive functions such as set shifting, response inhibition, abstract thought, and acquisition of rules or task structure.
Inhibition of COMT increases the lifetime of dopamine and is therefore an attractive drug target for diseases involving low dopamine levels. Until recently, inhibitors were all of the nitrocatechol structure and included such drugs as entacapone, carbidopa, and benserazide. These nitrocatechol drugs may inhibit oxidative phosphorylation in mitochondria by allowing oxidation to proceed without the production of ATP, thereby uncoupling mitochondria energy production. Newer classes of drugs are hoped to be more effective by being able to inhibit COMT without the risk of uncoupling.
Credits
Introduction - Jessica Royal
Overall Structure - Stephanie Bristol
Drug Binding Site - Emily Brackett
Additional Features - Anh Huynh
References
Tsuji, E., Okazaki, K., & Takeda, K. (2009). Crystal structures of rat catechol-O-methyltransferase complexed with coumarine-based inhibitor. Biochemical and Biophysical Research Communications, 378(3), 494-497.
