Sandbox Reserved 425
From Proteopedia
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| 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 |
YourMacromolecule
Introduction
- COMT responsible for degradation of catchol neurotransmitters including DA
- PD symptoms result from low levels of DA
- inhibiting COMT has potential to treat PD in conjunction with L-DOPA (a DA precursor currently used to treat PD) by increasing the bioavailability and stability of L-DOPA
- 4PCM is a COMT inhibitor being studied to better understand inhibitor interactions with COMT in order to develop better inhibitors
- carbonyl oxygen of 4PCM interacts with
Overall Structure
Biological Unit with DNA - green scene
Polar/nonpolar regions green scene
Secondary Structure green scene
-alpha helixes-phi and psi angles in one helix-how many-location
-beta sheets-kinds-how many-locations
Ligand structure KOM-AC3, MG-AC1, SAM-AC2 ball and stick green scene
Binding Interactions
Met 40, Leu 198, Tyr 200, Trp 38, and Pro 174 pocket for 4-phenyl-7, 8-dihydroxycoumarine (4PCM) These are mostly hydrophobic interactions. Van der Waals interactions with these molecules, especially M40, and hydrogen bonds between W48 and K144 stabilize 4PCM. P174 restricts 4PCM mobility and limits interactions with the COMT protein. These stabilizing residues and evolutionarily conserved.
Additional Features
Other health condition that relates to COMT gene.
22q11.2 deletion syndrome - associated with the COMT gene:
The characteristic signs and symptoms of 22q11.2 deletion syndrome result from a deletion of a small piece of chromosome 22. The chromosomal region that is typically deleted contains 30 to 40 genes, including the COMT gene. As a result of the deletion, people with this disorder have only one copy of the COMT gene in each cell instead of the usual two copies. A loss of one copy of the COMT gene in each cell leads to abnormal regulation of catechol-O-methyltransferase levels in the brain. Researchers believe that changes involving this enzyme in the prefrontal cortex may help explain the increased risk of behavioral problems and mental illness associated with 22q11.2 deletion syndrome. People with 22q11.2 deletion syndrome are much more likely than people without the condition to develop schizophrenia, depression, anxiety, and bipolar disorder.
Variations in the COMT gene also may be associated with mental illness in people without 22q11.2 deletion syndrome. Researchers have looked extensively at the potential connection between changes in the COMT gene and the risk of developing schizophrenia. Most studies have focused on the effects of a particular common variation (polymorphism) in catechol-O-methyltransferase. This variation alters a single protein building block (amino acid) in the enzyme, replacing the amino acid valine with the amino acid methionine. In the longer form of the enzyme, this variation occurs at position 158 (written as Val158Met). In the shorter form of the enzyme, it occurs at position 108 (written as Val108Met). Researchers often shorten this notation to Val108/158Met. The change affects the stability and activity of catechol-O-methyltransferase, which alters the enzyme's ability to break down neurotransmitters in the prefrontal cortex.
Credits
Introduction - Jessica Royal
Overall Structure - Stephanie Bristol
Drug Binding Site - Emily Brackett
Additional Features - Anh Huynh
