Structure and function of extracellular phospholipase A₁ belonging to the pancreatic lipase gene family

Phospholipase A₁ (PLA₁) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids and is conserved in a wide range of organisms. Mammals have several enzymes that exhibit PLA₁ activity in vitro. The extracellular PLA₁s include phosphatidylserine (PS)-specific PLA₁ (PS-PLA₁), membrane-associated phosphatidic acid (PA)-selective PLA₁s (mPA-PLA₁α and mPA-PLA₁β), hepatic lipase (HL), endothelial lipase (EL) and pancreatic lipase-related protein 2 (PLRP2), all of which belong to the pancreatic lipase gene family. The former three PLA₁s differ from other members in their substrate specificities, structural features and gene organizations, and form a subfamily in the pancreatic lipase gene family. PS-PLA₁, mPA-PLA₁α and mPA-PLA₁β exhibit only PLA₁ activity, while HL, EL and PLRP2 show triacylglycerol-hydrolyzing activity in addition to PLA₁ activity. The tertiary structures of lipases have two surface loops, the lid and the β9 loop. The lid and the β9 loop cover the active site in its closed conformation. An alignment of amino acid sequences of the pancreatic lipase gene family members revealed two molecular characteristics of PLA₁s in the two surface loops. First, lipase members exhibiting PLA₁ activity (PS-PLA₁, mPA-PLA₁α and mPA-PLA₁β, EL, guinea pig PLRP2 and PLA₁ from hornet venom (DolmI)) have short lids. Second, PS-PLA₁, mPA-PLA₁α, mPA-PLA₁β and DolmI, which exhibit only PLA₁ activity, have short β9 loops. Thus, the two surface loops appear to be involved in the ligand recognition. PS-PLA₁ and mPA-PLA₁s specifically hydrolyze PS and PA, respectively, producing their corresponding lysophospholipids. Lysophosphatidylserine and lysophosphatidic acid have been defined as lipid mediators with multiple biological functions. Thus, these PLA₁s have a role in the production of these lysophospholipid mediators.