Figure 5. Mechanistic Hypotheses for Endogenous Substrate Processing.

A) The crystal structures of the hCE1-taurocholate complex, the bovine salt-activated lipase (bCE)-taurocholate complex, and the rabbit liver carboxylesterase (rCE)-4-piperidinopiperidine (4PP) complex are shown. The three domains of hCE1 and rCE (catalytic, αβ , and regulatory) are rendered in cornflower blue, green, and red, respectively, while the lipase is shown in magenta. Note that the taurocholate surface binding sites of hCE1 (the Z-site) and the lipase are distinct

B) The active site and side door regions of hCE1, rCE and the bovine salt-activated lipase (bBAL). Note that the ligands, palmitate (in cyan) for hCE1, 4PP (in purple) for rCE, and taurocholate (in orange) for bBAL, are located at an equivalent side door region in each enzyme located in proximity to the active site.

C) Schematic models of fatty acyl CoA hydrolysis and fatty acyl ethyl ester synthesis by the hCE1 hexamer. When the fatty acyl CoA is abundant, it is possible that the hexameric hCE1 would allow the acyl CoA substrate to enter the active site through the side door. See Figure 5D for a definition of the schematic regions of hCE1.

D) Schematic models of cholesteryl ester hydrolysis, fatty acyl CoA hydrolysis, and acyl CoA cholesterol acyl transferase by the hCE1 trimer. First, excess cholesterol could bind the Z-site and shift the trimer-hexamer equilibrium towards trimer. Second, the substrates fatty acyl CoA or a cholesteryl ester could enter the active site through the main substrate binding gorge. For hydrolysis reactions, products (e.g., CoA, cholesterol and fatty acids) could leave through the main substrate binding gorge and the side door. For a transesterification, cholesterol may enter the active site via the substrate binding gorge, producing a cholesteryl ester.