Phospholipase D (PLD) catalyzes the hydrolysis of the P-O bond of phosphatidylcholine to form phosphatidic acid (PA) and choline. PA is the essential precursor for the biosynthesis of many other lipids, plays a role in the modulation of membrane curvature, and acts as a signaling lipid with activity in cell survival and apoptosis. Previous experimental in vitro studies with a model substrate (1,2-dibutyrylphosphatidylcholine) found a short-lived five-coordinate phosphohistidine intermediate and a �dead-end� four-coordinate phosphohistidine species. In the current computational study, the mechanism of PLD is studied using a fully quantum mechanical, geometrically constrained enzyme model. Density Functional Theory (DFT) is used to acquire thermodynamic and kinetic data for 51 unique mechanisms along the catalytic pathway, including phosphoryl transfer, subsequent hydrolysis, and finally, the formation of the �dead-end� four-coordinate phosphohistidine species. The five-coordinate phosphohistidine intermediate is found to be integral to the mechanism, and the context of the �dead-end� four-coordinate phosphohistidine species is also discussed.

The many phosphoryl transfers of Phospholipase D: A quantum mechanical theoretical study

244th National Meeting (2012)

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