Structure and Catalytic Mechanism of Secretory Phospholipases A2

TL;DRAbstract

This chapter focuses on the aspects of phospholipases A2 (sPLA2) structure that are of particular relevance to catalysis. A formal reaction pathway based largely on high-resolution structure analysis of crystalline complexes of secretory phospholipids (sPLA2s) with a transition-state analog is proposed. This mechanism that is consistent with the available biochemical and genetic data, implies a highly specific interaction between the calcium cofactor, the glycerophospholipid substrate, and the active site residues. Conserved water molecules, associated with either the catalytic histidine or the primary calcium ion, are essential participants in the proposed chemistry. Catalysis by sPLA2s is conceptually divided into three phases: (1) general base-mediated attack on productively bound substrate, (2) formation and collapse of the tetrahedral intermediate, and (3) product release. Although the catalytic activity of sPLA2s is generally unaffected by small perturbations in phospholipid stru

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