Sandbox Reserved 921: Difference between revisions
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'''Fatty Acid Amide Hydrolase''' | '''Fatty Acid Amide Hydrolase''' | ||
[[Image:CatalyticTriadProteopedia.png|100 px|left|thumb|Figure | [[Image:CatalyticTriadProteopedia.png|100 px|left|thumb|Figure 1: Ser, Ser, Lys Catalytic Triad in FAAH. [http://www.sciencemag.org/content/298/5599/1793 1MT5]]] | ||
== Introduction == | == Introduction == | ||
Fatty acid | [http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase Fatty acid amide hydrolase] (FAAH) is the primary catabolic enzyme for the degradation of [http://en.wikipedia.org/wiki/Fatty_acid_amide fatty acid amides]. FAAH primarily degrades [http://en.wikipedia.org/wiki/Anandamide anandamide], which is an endocannabinoid that activates the CB1 and CB2 [http://en.wikipedia.org/wiki/Cannabinoid_receptor 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. | ||
<StructureSection load='4J5P' size='340' side='right' caption='FAAH' scene='57/573135/Ser241_4j5p/1'> | 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. | ||
<scene name='57/ | |||
<scene name='57/ | A recent study on FAAH inhibitors combined an irreversible bond at Cys269 and a reversible bond at Ser241 of the active site.<ref name="Most Recent Study">PMID:23581831</ref> 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.<ref name="Most Recent Study">PMID:23581831</ref> This is the first step towards developing a long lasting pain relief medication by inhibiting FAAH. | ||
<StructureSection load='4J5P' size='340' side='right' caption='4J5P; K and L of 1MT5' scene='57/573135/4j5p_dimer/3'> | |||
== Function == | |||
The fatty acid amide hydrolase <scene name='57/573135/4j5p_dimer/3'>dimer</scene> is an integral membrane protein that cleaves fatty acid amides at the carbon-oxygen double bond in the amide functional group.<ref name="Wiki FAAH">http://en.wikipedia.org/wiki/FAAH</ref> | |||
[[Image:Anandamide.png|150 px|left|thumb|Figure 2: Anadamide, hydrolysis substrate of FAAH]] | |||
The lipid-degrading activity of FAAH derives from its unusual <scene name='57/573135/Catalytic_triad/2'>catalytic triad</scene>, consisting of Ser241, Ser217, and Lys142. The hydrogen bonding between the three amino acid residues allows for a partial negative charge at <scene name='57/573135/Ser241_4j5p/1'>Ser241</scene>, 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 [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] active site and inactivating the [http://en.wikipedia.org/wiki/Hydrolase hydrolase].<ref name= "4HBP">PMID:23218778</ref> 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 <scene name='57/573136/Starting_view/1'>surface</scene> of FAAH reveals two equivalent openings (<scene name='57/573136/Starting_view/4'>Opening 1</scene>, <scene name='57/573136/Starting_view/5'>Opening 2</scene>) directly accessible by the inner layer of the [http://en.wikipedia.org/wiki/Lipid_bilayer lipid bilayer].<ref name= "1MT5">PMID:12459591</ref> These <scene name='57/573136/Membrane_access_channel/8'>Membrane Access Channels</scene> (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 <scene name='57/573136/Membrane_access_channel/9'>salt bridge</scene> between Arg486 and Asp403. Flap 2 contains a very <scene name='57/573136/Membrane_access_channel/12'>hydrophobic membrane binding cap</scene> that partially covers the opening with Phe432. This binding cap clings to the cell's hydrophobic inner membrane and uses a multitude of <scene name='57/573136/Membrane_access_channel/13'>positively charged residues</scene> to lure out partitioned anandamide by its narrow partial negative charge. The catalytic site is defined by the catalytic triad: the <scene name='57/573136/Membrane_access_channel/14'>238-241 anionic hole loop</scene> contributes the nucleophilic S241, loop 3 contributes the neighboring <scene name='57/573136/Membrane_access_channel/15'>S217</scene> upon forming the very top of the membrane access channel, and a fourth loop contributes the deprotonating <scene name='57/573136/Membrane_access_channel/16'>K142</scene>. The membrane access channel leads to the active site, which is flanked by both the <scene name='57/573136/Membrane_access_channel/16'>cytosolic port</scene> and the acyl chain binding pocket. The cytosolic port is a lengthy, flexible loop that leads directly into the [http://en.wikipedia.org/wiki/Cytoplasm 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. | |||
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== References == | == References == | ||
<references/> | <references/> | ||