Sandbox Reserved 911: Difference between revisions
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Mutagenesis and inhibitor studies have shown that FAAH has a <scene name='57/573125/2vya/15'>Ser-Ser-Lys catalytic triad</scene>, consisting of Ser241, Ser217, and Lys142 <ref name="1MT5"/>. Ser-Ser-Lys catalytic triads are not often seen in hydrolases, making FAAH an enzyme of interest for additional research to better determine how proteins with this catalytic triad function. Ser241 acts as the catalytic nucleophile for the cleavage of amide bonds (Figure 2) <ref name="1MT5"/>. [http://proteopedia.org/wiki/index.php/Fatty_acid_amide_hydrolase Inhibitors] are able to inactivate the catalytic triad by providing a substrate containing a leaving group, such as aniline, that is a more favorable leaving group than the Ser241 hydroxyl group. With the serine bound to the carbonyl carbon, FAAH is no longer able to accommodate any more substrates <ref name="2VYA"/>. FAAH also requires two water molecules in its active site to properly position and cleave amide bonds. One water molecule (W1) deacylates the substrate, and the other (W2) helps coordinate W1 through the catalytic K142 (Figure 3) <ref name="3LJ6">PMID:20493882</ref> . | Mutagenesis and inhibitor studies have shown that FAAH has a <scene name='57/573125/2vya/15'>Ser-Ser-Lys catalytic triad</scene>, consisting of Ser241, Ser217, and Lys142 <ref name="1MT5"/>. Ser-Ser-Lys catalytic triads are not often seen in hydrolases, making FAAH an enzyme of interest for additional research to better determine how proteins with this catalytic triad function. Ser241 acts as the catalytic nucleophile for the cleavage of amide bonds (Figure 2) <ref name="1MT5"/>. [http://proteopedia.org/wiki/index.php/Fatty_acid_amide_hydrolase Inhibitors] are able to inactivate the catalytic triad by providing a substrate containing a leaving group, such as aniline, that is a more favorable leaving group than the Ser241 hydroxyl group. With the serine bound to the carbonyl carbon, FAAH is no longer able to accommodate any more substrates <ref name="2VYA"/>. FAAH also requires two water molecules in its active site to properly position and cleave amide bonds. One water molecule (W1) deacylates the substrate, and the other (W2) helps coordinate W1 through the catalytic K142 (Figure 3) <ref name="3LJ6">PMID:20493882</ref> . | ||
[[Image:Catalytic_triad2.png|1000px|left|thumb|Figure 2: Catalytic Triad and PF-750 Inhibitor Mechanism; The combination of Ser241, Ser217, and | [[Image:Catalytic_triad2.png|1000px|left|thumb|Figure 2: Catalytic Triad and PF-750 Inhibitor Mechanism; The combination of Ser241, Ser217, and Lys142 provides a partial negative charge on the Ser241 hydroxyl group. The Ser241 oxygen attacks the carbonyl carbon of PF-750, resulting in a tetrahedral intermediate. Aniline is released as a leaving group, with the remaining portion of PF-750 still covalently bound to Ser241. FAAH is now inactivated, unable to accommodate any new ligands <ref name="2VYA"/>. ]] | ||
==Relationship to other proteins== | ==Relationship to other proteins== | ||