Sandbox Reserved 911: Difference between revisions

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"/>.

==Hydrolase Information==

Mutagenesis and inhibitor studies have shown that FAAH has a <scene name='57/573125/2vya/6'>Ser-Ser-Lys catalytic triad</scene>, consisting of Ser241, Ser217, and Lys142. Ser-Ser-Lys catalytic triads are not often seen in hydrolases, making FAAH an enzyme of interest for additional research to better determine how proteins with this catalytic triad function. Ser241 acts as the catalytic nucleophile for the cleavage of amide bonds <ref name="1MT5"/>. Inhibitors are able to inactivate the catalytic triad by providing a substrate containing a leaving group, such as aniline, that is a more favorable leaving group than the Ser241 hydroxyl group.  With the serine bound to the carbonyl carbon, FAAH is no longer able to accommodate any more substrates <ref name="2VYA"/>. FAAH also requires two water molecules in its active site to properly position and cleave amide bonds. One water molecule (W1) deacylates the substrate, and the other (W2) helps coordinate W1 through the catalytic K142 <ref name="3LJ6">PMID:20493882</ref> .

==Relationship to other proteins==

The hydrolytic water molecules important to FAAH's function suggest an evolutionary relationship of this hydrolase to other enzymes. The structures of other [http://en.wikipedia.org/wiki/Serine_hydrolase serine hydrolases] also display a catalytic water molecule in their active sites. Because hydrolases that are non-homologous to FAAH also require a water molecule to cleave bonds, researchers have inferred that a functional convergance has developed between amidase signature enzymes (such as FAAH) and other classes of serine proteases <ref name="3LJ6"/>.

This evidence of convergent evolution between FAAH and other amidase signature enzymes supports the [http://euch6f.chem.emory.edu/burgidunitz.html Bürgi-Dunitz theory]. This concept 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. Research showing water molecules in the active sites of enzymes suggests that these water molecules 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==

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="2WAP"/>.

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="2WAP"/>.