Current Knowledge on Mammalian Phospholipase A₁, Brief History, Structures, Biochemical and Pathophysiological Roles

Phospholipase A₁ (PLA₁) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA₁ activities have been detected both extracellularly and intracellularly, which are well conserved in higher eukaryotes, including fish and mammals. All extracellular PLA₁s belong to the lipase family. In addition to PLA₁ activity, most mammalian extracellular PLA₁s exhibit lipase activity to hydrolyze triacylglycerol, cleaving the fatty acid and contributing to its absorption into the intestinal tract and tissues. Some extracellular PLA₁s exhibit PLA₁ activities specific to phosphatidic acid (PA) or phosphatidylserine (PS) and serve to produce lysophospholipid mediators such as lysophosphatidic acid (LPA) and lysophosphatidylserine (LysoPS). A high level of PLA₁ activity has been detected in the cytosol fractions, where PA-PLA₁/DDHD1/iPLA₁ was responsible for the activity. Many homologs of PA-PLA₁ and PLA₂ have been shown to exhibit PLA₁ activity. Although much has been learned about the pathophysiological roles of PLA₁ molecules through studies of knockout mice and human genetic diseases, many questions regarding their biochemical properties, including their genuine in vivo substrate, remain elusive.