Structural Basis for Human Monoglyceride Lipase Inhibition

Specific Inter-residue Interactions as Determinants of Human Monoacylglycerol Lipase Catalytic Competency

“…With this interpretation, our data suggest the existence of a His-54 -Asp-197 hydrogen bond in the open state, as indicated by the presence of the His-54 resonance, whereas it is broken in the closed state, as indicated by the absence of the His-54 resonance. This differs from x-ray structures of the open form where His-54 is shown as the N ␦1 -H tautomer and does not display this hydrogen-bonding (4,5), whereas the structure of the closed form indicated His-54 is in the more common N ⑀2 OH tautomer and is hydrogen-bonded to (Fig. 2C) (6).…”

“…1) with a significant loss of catalytic efficiency ( Table 1). The His-54 residue of hMGL is located at a substantial distance from the catalytic triad (4,6) such that this mutation could not have had a direct effect on His-269. Among the His-272 mutants, the H272S mutation in sol-hMGL most compromised the enzyme's catalytic efficiency, consistent with the conformational transition to the inactive form reflected by the absence of the His-269 and His-54 resonances in the down- field region (Fig.…”

“…Published crystal structures of modified/ liganded forms of hMGL (4 -6) indicate that the enzyme has a typical lipase structure that includes a lid subdomain (residues 151-225) that can assume open or closed states and control, through its gating dynamics, substrate access to the active site (7)(8)(9)(10)(11)(12)(13). The open state has been observed in the absence and presence of bound ligand (4,5), whereas the hMGL closed conformation has only been reported in complex with a reversible inhibitor (6). Interspecies conservation of the overall hMGL lid architecture and dynamics has been suggested from x-ray studies and molecular dynamics simulations of bacterial MGL (14 -16).…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…44,45 The residues Leu174 and Leu176 form the entrance to the catalytic site, whereas Phe93 and Phe209 display "gate"-like functions ( Figure 8). 34,43 Interestingly, three cysteines (Cys201, Cys208, Cys242), which are close to the catalytic triad, were hypothesized to stabilize MAGL conformation and additionally interact with some substrates (such as maleimides).…”

“…34,43 Interestingly, three cysteines (Cys201, Cys208, Cys242), which are close to the catalytic triad, were hypothesized to stabilize MAGL conformation and additionally interact with some substrates (such as maleimides). 44,46,47 These cysteines were once considered as beneficial targets for the development of selective MAGL inhibitors over other serine hydrolases. 45 The functional site of MAGL comprises the ABP, the alcohol-binding channel and the glycerol exit channel, which serve to accommodate the acyl chain, the glycerol moiety, and the leaving group, respectively ( Figure 8).…”