Sandbox Reserved 911

This Sandbox is Reserved from Jan 06, 2014, through Aug 22, 2014 for use by the Biochemistry II class at the Butler University at Indianapolis, IN USA taught by R. Jeremy Johnson. This reservation includes Sandbox Reserved 911 through Sandbox Reserved 922.

To get started: Click the edit this page tab at the top. Save the page after each step, then edit it again. Click the 3D button (when editing, above the wikitext box) to insert a 3D applet Jmol scene window. show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page. Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc. More help: Help:Editing

spinqualitylabelsall models Fatty Acid Amide Hydrolase 1 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Introduction Fatty acid amide hydrolase (FAAH) degrades fatty acid amides to terminate their signaling activity.(IMT5) A serine hydrolase from the Amidase signature superfamily of enzymes (other amidases), FAAH degrades endocannabinoid signaling lipids, molecules associated with pain relief.(2VYA) Because 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 integral membrane protein that degrades FAAs as they enter the membrane bilayer. (IMT5) Current research about FAAH aims to find inhibitors for the enzyme, which would prolong the pain alleviation provided by endocannabinoid molecules. (2VYA) FAAH Subunit Hydrolase Information Crystal structures of FAAH show that the enzyme is a homodimer in solution, with each subunit having a mass of 63 kD. The protein's twisted Beta sheet core of 11 strands is surrounded by 24 alpha helices. The enzyme is embedded in the cell membrane 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. 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. (IMT5) This hydrolase has a membrane binding cap, a helix-turn-helix motif consisting of alpha helices 18 and 19. These helices present hydrophobic amino acid residues that likely help FAAH interact with the hydrophobic region of the lipid bilayer. (IMT5) humanized rat FAAH dimer with PF-750 inhibitor Catalytic Triad Mutagenesis and inhibitor studies have shown that FAAH has a Ser-Ser-Lys catalytic triad, consisting of S241, S217, and K142. Ser-Ser-Lys catalytic triads are not often seen in hydrolases, making FAAH an enzyme of interest for additional research. S241 acts as the catalytic nucleophile for the cleavage of amide bonds. (IMT5) FAAH requires two water molecules in its active site to properly cleave amide bonds. One water molecule (W1) deacylates the substrate, and the other (W2) helps coordinate W1 through the catalytic K142. (3LJ6) File:Water image.png FAAH catalytic site with water molecules bound

Applications

The human nervous system has several types of chemical messengers, including amino acids, lipids, peptide hormones, and monoamines. (IMT5) FAAH primarily degrades 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. (2YVA)

Anandamide

References

1MT5

2VYA <ref>PMID:18753625

2WAP <ref>PMID:19389627

3LJ6 <ref>PMID:20493882

2WJ2 <ref>PMID:19722626