Sandbox Reserved 921

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.

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Fatty Acid Amide Hydrolase

IntroductionIntroduction

Fatty acid amide hydrolase (FAAH) is the primary catabolic enzyme for the degradation of fatty acid amides. FAAH is most commonly known for the degradation of anandamide, which is an endocannabinoid that activates the CB1 and CB2 cannabinoid receptors. When CB1 and CB2 cannabinoid receptors are active the receptors affect appetite, sleep, and relief of pain. The ability to inhibit FAAH has been widely investigated for possible pain relief medication. A recent study on FAAH inhibitors combined an irreversible bond at Cys269 and a reversible bond at Ser241 of the active site.^[1] A humanized rat variant of FAAH was inhibited and the mice displayed an increase in endogenous brain levels of FAAH substrates for over six hours. This is the first step towards developing a long lasting pain relief medication by inhibiting FAAH.

Function

The fatty acid amide hydrolase is an integral protein that cleaves fatty acid amides at the carbon-oxygen double bond in the amide functional group. The lipid-degrading activity of FAAH derives from its unusual , consisting of Ser241, Ser217, and Lys142. The hydrogen bonding between the three amino acid residues allows for a partial negative charge at , which acts as a nucleophile in the enzymatic reaction. The Ser241 residue binds with the carbon in the amide group, cleaves the fatty acid amide, and is protonated by water. The inhibitor used covalently binds to Ser241 disrupting the catalytic triad active site and leaving the hydrolase inactive.^[2] Without the enzyme FAAH active, anandamide accumulates, resulting in pain relief due to its interaction with the CB1 and CB2 cannabinoid receptors.

Structure

The of FAAH reveals two openings directly accessible by the inner layer of the lipid bilayer.^[3] These (MAC) are each proceed by a respective membrane binding cap. This sturdy flap appears to be loosened by the presence of five positively charged residues, and each MAC remains conformation-stable by a salt bridge. The membrane access channel leads to the active site, which is flanked by both the (ABP and CP).^[4] The cytosolic port is a lengthy, flexible loop that leads directly into the cytoplasm, allowing the deacylated amine to enter the cell.

ReferencesReferences

↑ Otrubova K, Brown M, McCormick MS, Han GW, O'Neal ST, Cravatt BF, Stevens RC, Lichtman AH, Boger DL. Rational design of Fatty Acid amide hydrolase inhibitors that act by covalently bonding to two active site residues. J Am Chem Soc. 2013 Apr 24;135(16):6289-99. doi: 10.1021/ja4014997. Epub 2013 Apr, 12. PMID:23581831 doi:http://dx.doi.org/10.1021/ja4014997
↑ Kono M, Matsumoto T, Kawamura T, Nishimura A, Kiyota Y, Oki H, Miyazaki J, Igaki S, Behnke CA, Shimojo M, Kori M. Synthesis, SAR study, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase (FAAH) inhibitors. Bioorg Med Chem. 2013 Jan 1;21(1):28-41. doi: 10.1016/j.bmc.2012.11.006. Epub, 2012 Nov 15. PMID:23218778 doi:http://dx.doi.org/10.1016/j.bmc.2012.11.006
↑ Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 2002 Nov 29;298(5599):1793-6. PMID:12459591 doi:10.1126/science.1076535
↑ Mileni M, Kamtekar S, Wood DC, Benson TE, Cravatt BF, Stevens RC. Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. J Mol Biol. 2010 Jul 23;400(4):743-54. Epub 2010 May 21. PMID:20493882 doi:10.1016/j.jmb.2010.05.034

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, R. Jeremy Johnson, Carter Sharp, Daniel B. Lange

[Most_Recent_Study-1] Otrubova K, Brown M, McCormick MS, Han GW, O'Neal ST, Cravatt BF, Stevens RC, Lichtman AH, Boger DL. Rational design of Fatty Acid amide hydrolase inhibitors that act by covalently bonding to two active site residues. J Am Chem Soc. 2013 Apr 24;135(16):6289-99. doi: 10.1021/ja4014997. Epub 2013 Apr, 12. PMID:23581831 doi:http://dx.doi.org/10.1021/ja4014997

[4HBP-2] Kono M, Matsumoto T, Kawamura T, Nishimura A, Kiyota Y, Oki H, Miyazaki J, Igaki S, Behnke CA, Shimojo M, Kori M. Synthesis, SAR study, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase (FAAH) inhibitors. Bioorg Med Chem. 2013 Jan 1;21(1):28-41. doi: 10.1016/j.bmc.2012.11.006. Epub, 2012 Nov 15. PMID:23218778 doi:http://dx.doi.org/10.1016/j.bmc.2012.11.006

[1MT5-3] Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 2002 Nov 29;298(5599):1793-6. PMID:12459591 doi:10.1126/science.1076535

[3LJ7-4] Mileni M, Kamtekar S, Wood DC, Benson TE, Cravatt BF, Stevens RC. Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. J Mol Biol. 2010 Jul 23;400(4):743-54. Epub 2010 May 21. PMID:20493882 doi:10.1016/j.jmb.2010.05.034

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