Monoglyceride lipase: Difference between revisions

MGL’s serine hydrolase chemistry is executed by a <scene name='57/573134/Catalytic_triad/4'>Catalytic Triad</scene> (Ser132-His279-Asp249) and seems to utilize the same mechanism as the much-studied [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin]. In this mechanism, an activated serine nucleophile cleaves the ester bond of the substrate.<ref name="labar" /><ref name="bert" /><ref name="shalk" /> The subsequent tetrahedral intermediate is stabilized by the <scene name='57/573134/Oxyanion_hole/3'>Oxyanion Hole</scene>, formed by the main-chain nitrogens of Ala61 and Met (or Se-Met) 133.<ref name="bert" /> The triad was found using site-directed mutagenesis of each individual residue and each of these amino acid residues are catalytically essential to MGL <ref name="Bertrand" />. The catalytic triad is located in the [[:Category:Ligand binding pocket| Binding Pocket]] buried at the bottom of it in the oxyanion hole connected by a water molecule.'''Figure 4''' [[Image:Catalytic_triad_binding_pocket.png|300px|thumb|'''Figure 4:''' The binding pocket of MGL with the catalytic triad (shown in red) buried in it.]]

[[Image:Overall_ligand.png|left|200px|thumb|'''Figure 6:''' Ligand within the Overall Structure of MGL]] [[Image:Ligand_tunnel.png|right|200px|thumb|'''Figure 7:''' Ligand binding pocket showing the hydrophobic and polar regions]]

The <scene name='58/580298/Ligand/1'>ligand binding pocket</scene> of MGL has a large hydrophobic region with a polar bottom.  The entrance of the binding pocket for MGL contains a lid, which is very flexible <ref name="Bertrand" />.  The binding pocket or tunnel within MGL matches with the overall structure of 2-AG, with 2-AG's polar head being cleaved by the catalytic triad '''Figure 7'''. The binding pocket is not being adjusted to the ligand's shape.  However, the main movements of MGL involve the lid region of the ligand binding pocket upon the ligand binding. When 2-AG and its isomer 1(3)-AG bind to MGL, the hydrophobic chain is first aligned with the left part of the binding pocket. The carbonyl on 2-AG and 1(3)-AG is then hydrogen bonded to <scene name='58/580298/Ala61/1'>Ala61</scene>. The polar head group of the ligand is then fixed by three hydrogen bonds.  The large lipophilic portion of the binding pocket is being used to design more selectivie inhibitors <ref name="Bertrand" />.  

Three general MGL [http://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitor] classes have been observed: noncompetitive, partially irreversible inhibitors such as [http://en.wikipedia.org/wiki/URB602 URB602]; cysteine-reactive inhibitors such as [http://www.chemspider.com/Chemical-Structure.24774833.html N-arachidonoylmaleimide] (NAM); and irreversible serine-reactive inhibitors such as [http://en.wikipedia.org/wiki/JZL184 JZL184] and <scene name='57/573134/Sar629/3'>SAR 629</scene>.<ref name="bert" /> SAR629 covalently binds to the catalytic Serine-132; the oxygen of the nucleophilic serene residue attacks the carbonyl carbon of SAR629, forming a [http://en.wikipedia.org/wiki/Carbamate carbamate]. This covalent bond is believed to be reversible via hydrolysis, albeit slowly.<ref name="bert" />SAR629 adopts a Y shape and interacts with the MGL by hydrophobic interactions, with a few polar interactions as well. '''Figure 3''' [[Image:SAR.png|left|thumb|'''Figure 3:''' The structure and shape of SAR629.]] Due to JZL184's similar structure to SAR629, it may undergo a similar reaction with MGL.<ref name="bert" /> Despite the existence of multiple lead compounds, there is a strong demand for the creation of more highly-specific and more potent inhibitors that could be used as anti-pain drugs for their ability to keep 2-AG active in the neuronal synapses. <ref name="labar" />

N-arachidonyl maleimide (NAM) is another inhibitor of MGL. NAM reacts with the amino acid <scene name='58/580298/Cys252/1'>Cys252</scene>. '''Figure 2''' [[Image:NAM.png|thumb|'''Figure 2:''' The structure of N-arachidonyl maleimide (NAM)that interacts with Cys252.]] Cys252 is buried in the active site near the catalytic serine and functions by sterically clashing with the natural ligand. A possible conformational change to Cys252 upon the binding of NAM could also lead to an inactive form of MGL.