Sandbox Reserved 911: Difference between revisions

Fatty acid amide hydrolase (FAAH) degrades fatty acid amides to terminate their signaling activity <ref name="1MT5">PMID:12459591</ref>. A serine hydrolase from the [http://en.wikipedia.org/wiki/Amidase Amidase] signature superfamily of enzymes ([http://proteopedia.org/wiki/index.php/Category:Amidase other amidases]), FAAH degrades endocannabinoid signaling lipids, molecules associated with pain relief <ref name="2VYA">PMID:18753625</ref>. Because [http://en.wikipedia.org/wiki/Endocannabinoid_system endocannabinoids] are lipid molecules, they cannot be compartmentalized in vesicles (the degradation method for other neurotransmitters) and must instead be degraded in the bilayer of the cell membrane. FAAH is an [http://stevens.scripps.edu/images/faah_fig2.jpg integral membrane protein] that degrades FAAs as they enter the membrane bilayer, allowing the cell to terminate the activity of signaling molecules that cannot be contained within a vesicle for degredation <ref name="1MT5"/>. Current FAAH research aims to find inhibitors for the enzyme, which would prolong the pain alleviation provided by endocannabinoid molecules <ref name="2VYA"/>.

Crystal structures of FAAH show that the enzyme is a <scene name='57/573125/2vya/1'>homodimer</scene> with <scene name='57/573125/2vya/3'>PF-750 inhibitor</scene> in solution, with each subunit having a mass of 63 kD. The protein's <scene name='57/573125/2vya/8'>twisted Beta sheet core</scene> of 11 strands is surrounded by 24 alpha helices. The enzyme is embedded in the cell <scene name='57/573125/2vya/5'>membrane</scene> to catch the lipid signaling molecules that can diffuse through membranes. The FAAH structure shows an entry channel leading from the lipid bilayer to the enzyme's active site, providing a path for endocannabinoids to enter the hydrolase. This entry channel is amphipathic to accommodate the entire lipid signaling molecule. Hydrophobic amino acid residues interact with the lipid signaling molecules' nonpolar tails, while charged R486 and D403 residues in the entry channel accommodate the polar head groups. In addition, FAAH possesses a channel leading from the active site to the cell's cytoplasm, allowing the release of polar compounds released from lipid cleavage and the entry of water molecules necessary for the FAAH mechanism to proceed <ref name="1MT5"/>. This hydrolase has a membrane binding cap, a <scene name='57/573125/2vya/7'>helix-turn-helix motif</scene> consisting of alpha helices 18 and 19. These helices present hydrophobic amino acid residues that help FAAH interact with the hydrophobic region of the lipid bilayer <ref name="1MT5"/>. Different inhibitors have been designed to learn more about species selectivity <ref name="2VYA"/> and binding flexibility <ref>PMID:19722626</ref>.  

The human nervous system has several types of chemical messengers, including amino acids, lipids, peptide hormones, and [http://en.wikipedia.org/wiki/Monoamine_neurotransmitter monoamines] <ref name="1MT5"/>. FAAH primarily degrades [http://www.chm.bris.ac.uk/motm/anandamide/ananh.htm anandamide] (AEA), a naturally-occurring signaling lipid that functions in the brain. AEA brings pain relief to the body. Inhibiting FAAH would likely sustain AEA signaling, leading to prolonged pain relief and decreased inflammation <ref name="2VYA"/>.

FAAH plays a role in endocannabinoid signaling that has intriguing potential as a drug target. This signaling system consists of endocannabinoid ligands (such as AEA), two G protein-coupled receptors (CB1 and CB2), and the enzymes that synthesize and degrade (such as FAAH) the signaling lipids. Previous research has explored the potential of regulating endocannabinoid signaling through the CB1 and CB2 receptors. However, molecules found to activate these receptors (such as [http://www.ch.ic.ac.uk/vchemlib/mim/bristol/thc/thc_text.htm tetrahydrocannabinol] (THC), the main psychoactive ingredient of [http://en.wikipedia.org/wiki/Cannabis_(drug) marijuana]), while providing the intended pain relief, also produce many undesirable side effects, such as decreased cognition and motor control. On the other hand, research involving FAAH inhibitors has shown that blocking this part of the pathway reduces pain without the unwanted side effects seen through CB1/CB2 activation. Thus, exploring the possibility of using FAAH inhibition to decrease pain relief with minimal side effects could lead to new pain treatment solutions <ref name="2VYA"/>.