Glycerophospholipids are major components of cell membranes and consist of a
glycerol backbone esterified with one of over 30 unique
fatty acids at each of the sn-1 and sn-2 positions. In addition, in some human cells and tissues as much as 20% of the
glycerophospholipids contain a
fatty alcohol rather than an
ester in the sn-1 position, although it can also occur in the sn-2 position. The sn-3 position of the
glycerol backbone contains a phosphodiester bond linked to one of more than 10 unique polar head-groups. Hence, humans contain thousands of unique individual molecular species of
phospholipids given the heterogeneity of the sn-1 and sn-2 linkage and
carbon chains and the sn-3 polar groups.
Phospholipase A2 (PLA2) is a superfamily of
enzymes that hydrolyze the sn-2 fatty acyl chain resulting in lyso-
phospholipids and
free fatty acids that then undergo further metabolism. PLA2's play a critical role in
lipid-mediated biological responses and membrane
phospholipid remodeling. Among the PLA2
enzymes, the Group VIA
calcium-independent PLA2 (GVIA iPLA2), also referred to as PNPLA9, is a fascinating
enzyme with broad substrate specificity and it is implicated in a wide variety of diseases. Especially notable, the GVIA iPLA2 is implicated in the sequelae of several
neurodegenerative diseases termed "
phospholipase A2-associated neurodegeneration" (PLAN) diseases. Despite many reports on the physiological role of the GVIA iPLA2, the molecular basis of its enzymatic specificity was unclear. Recently, we employed state-of-the-art lipidomics and molecular dynamics techniques to elucidate the detailed molecular basis of its substrate specificity and regulation. In this review, we summarize the molecular basis of the enzymatic action of GVIA iPLA2 and provide a perspective on future therapeutic strategies for PLAN diseases targeting GVIA iPLA2.