Lysosomal phospholipase A2 (LPLA2/PLA2G15) is a key enzyme involved in lipid homeostasis and is characterized by both phospholipase A2 and transacylase activity and by an acidic pH optimum. Divalent cations such as Ca(2+) and Mg(2+) have previously been shown to have little effect on the activity of LPLA2, but the discovery of a novel crystal form of LPLA2 with Zn(2+) bound in the active site suggested a role for this divalent cation in regulating enzyme activity. In this complex, the cation directly coordinates the serine and histidine of the alpha/beta-hydrolase triad and stabilizes a closed conformation. This closed conformation is characterized by an inward shift of the lid loop, which extends over the active site and effectively blocks access to one of its lipid acyl chain binding tracks. Therefore, we hypothesized that Zn(2+) would inhibit LPLA2 activity at a neutral but not acidic pH because histidine would be positively charged at lower pH. Indeed, Zn(2+) was found to inhibit the esterase activity of LPLA2 in a noncompetitive manner exclusively at a neutral pH (between 6.5 and 8.0). Because lysosomes are reservoirs of Zn(2+) in cells, the pH optimum of LPLA2 might allow it to catalyze acyl transfer unimpeded within the organelle. We conjecture that Zn(2+) inhibition of LPLA2 at higher pH maintains a lower activity of the esterase in environments where its activity is not typically required.
Representative scheme of PC-sterol_acyltransferase structure and an image from PDBsum server
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