The sn-2 acyl hydrolysis of phospholipids catalyzed by phospholipase A2 (PLA2) was investigated at the density functional B3LYP level. The PLA2 active site is represented by quantum-chemical models that are based on available X-ray crystal structures. The two still controversial catalytic triad and calcium-coordinated oxyanion reaction mechanisms were considered. Tetrahedral intermediate formation in the first mechanism and the cleavage of the C-O bond in the second one are the rate-determining steps. Both mechanisms, in the gas phase and in the protein-like environment, yielded potential energy profiles with low energy barriers and consequently the comparison did not indicate a clear preference for one or the other path. An alternative mechanism, based on some corrections to the previously suggested ones, provides for an optional pathway for the enzyme activity.
Favored Reaction Mechanism of Calcium-Dependent Phospholipase A2. Insights from Density Functional Exploration
RUSSO, Nino;TOSCANO, Marirosa
2010-01-01
Abstract
The sn-2 acyl hydrolysis of phospholipids catalyzed by phospholipase A2 (PLA2) was investigated at the density functional B3LYP level. The PLA2 active site is represented by quantum-chemical models that are based on available X-ray crystal structures. The two still controversial catalytic triad and calcium-coordinated oxyanion reaction mechanisms were considered. Tetrahedral intermediate formation in the first mechanism and the cleavage of the C-O bond in the second one are the rate-determining steps. Both mechanisms, in the gas phase and in the protein-like environment, yielded potential energy profiles with low energy barriers and consequently the comparison did not indicate a clear preference for one or the other path. An alternative mechanism, based on some corrections to the previously suggested ones, provides for an optional pathway for the enzyme activity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
