have been associated with inflammation thought to exacerbate asthma and ocular surface inflammation (dry eye). Increased sPLA2 activity is observed in the cerebrospinal fluid of humans with Alzheimer's disease and multiple sclerosis, and may serve as a marker of increases in permeability of the blood-cerebrospinal fluid barrier. There are atypical members of the phospholipase A2 family, such as PLA2G12B, that have no phospholipase activity with typical phospholipase substrate. The lack of enzymatic activity of PLA2G12B indicates that it may have unique function distinctive from other sPLA2s. It has been shown that in PLA2G12B null mice VLDL levels were greatly reduced, suggesting it could have an effect in lipoprotein secretion Cytosolic phospholipases A2 (cPLA2) The intracellular, group IV PLA2 are also Ca-dependent, but they have a different 3D structure and are significantly larger than secreted PLA2 (more than 700 residues). They include a C2 domain and a large catalytic domain. These phospholipases are involved in cell signaling processes, such as inflammatory response. They release arachidonic acid from membrane phospholipids. Arachidonic acid is both a signaling molecule and the precursor for the synthesis of other signaling molecules termed eicosanoids. These include leukotrienes and prostaglandins. Some eicosanoids are synthesized from diacylglycerol, released from the lipid bilayer by phospholipase C (see below). Phospholipases A2 can be classified based on sequence homology. Lipoprotein-associated PLA2s (lp-PLA2) Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis. Although, the role of LP-PLA2 in atherosclerosis may depend on its carrier in plasma, and several lines of evidence suggest that HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activities. Mechanism The suggested catalytic mechanism of pancreatic sPLA2 is initiated by a His-48/Asp-99/calcium complex within the active site. The calcium ion polarizes the sn-2 carbonyl oxygen while also coordinating with a catalytic water molecule, w5. His-48 improves the nucleophilicity of the catalytic water via a bridging second water molecule, w6. It has been suggested that two water molecules are necessary to traverse the distance between the catalytic histidine and the ester. The basicity of His-48 is thought to be enhanced through hydrogen bonding with Asp-99. An asparagine substitution for His-48 maintains wild-type activity, as the amide functional group on asparagine can also function to lower the pKa, or acid dissociation constant, of the bridging water molecule. The rate limiting state is characterized as the degradation of the tetrahedral intermediate composed of a calcium coordinated oxyanion.