Sandbox Reserved 911: Difference between revisions

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, a functional convergance has inferred between amidase signature enzymes (such as FAAH) and other classes of [http://en.wikipedia.org/wiki/Serine_protease 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]. 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"/>.  

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 [http://www.scripps.edu/cravatt/images/faah_cartoon.gif 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 [http://www.painresearchforum.org/news/11548-flat-tening-pain 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. 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"/>.