Fatty acid amide hydrolase: Difference between revisions

==Introduction==

Fatty acid amide hydrolase (FAAH) degrades fatty acid amides (FAAs) 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="2WAP">PMID:19389627</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="2WAP"/>.

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This evidence of convergent evolution between FAAH and other amidase signature enzymes supports the [http://euch6f.chem.emory.edu/burgidunitz.html Bürgi-Dunitz theory]. The Bürgi-Dunitz theory proposes that nucleophiles tend to follow a specific trajectory when attacking a carbonyl, resulting in many enzyme mechanisms having the same angle between an incoming nucleophile and the carbonyl it attacks [http://www.nature.com/nrd/journal/v11/n4/images/nrd3673-f4.jpg (FAAH bound to inhibitor)]. Water molecules in the active sites of enzymes are specifically positioned to force the nucleophile to approach at the exact [http://3.bp.blogspot.com/-NvsQyVPnLIw/UO91-BQTVgI/AAAAAAAAExw/-seGZcjU3DE/s400/burgi-duntz+trajectory.png "Bürgi-Dunitz angle"] of 107°. The determination that FAAH also has water molecules in its active site, helping the nucleophile to attack the amide carbonyl at a specific angle, adds additional support to the Bürgi-Dunitz theory <ref name="3LJ6"/>.  

==Applications==

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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. For example, the [http://drugdiscoveryopinion.com/2009/04/pf-3845-%E2%80%93-a-potent-and-selective-faah-inhibitor/ PF-3845 inhibitor]of FAAH is extremely selective for the enzyme and raises AEA levels for a prolonged duration of time. Therefore, this inhibitor could be explored as a possible pharmaceutical product to target FAAH when extended pain relief is desired <ref name="2WAP"/>.  

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==References==

*Carter Sharp

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