Sandbox Reserved 921

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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

Figure 1: Ser, Ser, Lys Catalytic Triad in FAAH. 1MT5
Figure 1: Ser, Ser, Lys Catalytic Triad in FAAH. 1MT5


Introduction

Fatty acid amide hydrolase (FAAH) is the primary catabolic enzyme for the degradation of fatty acid amides. FAAH primarily degrades 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.

An inhibitor binds to the active site of the enzyme lowering the rate at which the enzyme degrades substrate, thus enzyme inhibitors are often used as drugs. A FAAH inhibitor offers great potential as a pain relief drug because FAAH commonly degrades anandamide. If the enzymatic activity of FAAH was lowered there would be increased levels of anandamide causing increased appetite, sleep, and pain relief.

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 by BR1, CL, and PEG. The mice displayed an increase in endogenous brain levels of the FAAH substrate anandamide for over six hours.[1] This is the first step towards developing a long lasting pain relief medication by inhibiting FAAH.


Function

The fatty acid amide hydrolase dimer is an integral membrane protein that cleaves fatty acid amides at the carbon-oxygen double bond in the amide functional group.[2]

Figure 2: Anadamide, hydrolysis substrate of FAAH
Figure 2: Anadamide, hydrolysis substrate of FAAH

The lipid-degrading activity of FAAH derives from its unusual catalytic triad, consisting of Ser241, Ser217, and Lys142. The hydrogen bonding between the three amino acid residues allows for a partial negative charge at Ser241, 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 BR1 covalently binds to Ser241 disrupting the catalytic triad active site and inactivating the hydrolase.[3] Without the active FAAH, anandamide accumulates, resulting in pain relief due to its increased concentration and interaction with the CB1 and CB2 cannabinoid receptors.

Structure

The surface of FAAH reveals two equivalent openings (Opening 1, Opening 2) directly accessible by the inner layer of the lipid bilayer.[4] These Membrane Access Channels (MAC) are made up of three flaps and two intrusions which collectively form the entry way for the aliphatic binding of the amide lipid substrate. Flaps 1 and 2 envelope the middle and backside of the anandamide mimic, and are locked together by a salt bridge between Arg486 and Asp403. Flap 2 contains a very hydrophobic membrane binding cap that partially covers the opening with Phe432. This binding cap clings to the cell's hydrophobic inner membrane and uses a multitude of positively charged residues to lure out partitioned anandamide by its narrow partial negative charge. The catalytic site is defined by the catalytic triad: the 238-241 anionic hole loop contributes the nucleophilic S241, loop 3 contributes the neighboring S217 upon forming the very top of the membrane access channel, and a fourth loop contributes the deprotonating K142. The membrane access channel leads to the active site, which is flanked by both the cytosolic port and the acyl chain binding pocket. The cytosolic port is a lengthy, flexible loop that leads directly into the cytoplasm, allowing the deacylated amine to enter the cell, while the acyl chain binding pocket is a space formed by several of the loops that accommodates the substrates polar head.



4J5P; K and L of 1MT5

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References

  1. ↑ 1.0 1.1 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
  2. ↑ http://en.wikipedia.org/wiki/FAAH
  3. ↑ 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
  4. ↑ 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
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