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

Phospholipase A(1) (PLA(1)) 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 PLA(1) activity in vitro. The extracellular PLA(1)s include phosphatidylserine (PS)-specific PLA(1) (PS-PLA(1)), membrane-associatedphosphatidic acid (PA)-selectivePLA(1)s (mPA-PLA(1)alpha and mPA-PLA(1)beta), 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 PLA(1)s differ from other members in their substrate specificities, structural features and gene organizations, and form a subfamily in the pancreatic lipase gene family. PS-PLA(1), mPA-PLA(1)alpha and mPA-PLA(1)beta exhibit only PLA(1) activity, while HL, EL and PLRP2 show triacylglycerol-hydrolyzing activity in addition to PLA(1) activity. The tertiary structures of lipases have two surface loops, the lid and the beta 9 loop. The lid and the beta 9 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 PLAIs in the two surface loops. First, lipase members exhibiting PLA(1) activity (PS-PLA(1), mPA-PLA(1)alpha and mPA-PLA(1)beta, EL, guinea pig PLRP2 and PLA, from hornet venom (Dolml)) have short lids. Second, PS-PLA(1), mPA-PLA(1)alpha, mPA-PLA(1)beta and Dolml, which exhibit only PLA, activity, have short beta 9 loops. Thus, the two surface loops appear to be involved in the ligand recognition. PS-PLA(1) and mPA-PLA(1)s 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 PLAIs have a role in the production of these lysophospholipid mediators. (c) 2006 Elsevier Masson SAS. All rights reserved.