Modulation of arachidonic acid metabolism: focus on phospholipase A2(S).
New information has challenged our traditional concepts that the forms and functions of PLA(2) are highly homologous, suggesting now that distinct PLA(2)s may be assigned distinct functions in normal and pathological processes. The nonpancreatic type II 14-kDa PLA(2) and the recently identified type IV "cytosolic" 85-kDa PLA(2) are the two forms most studied in inflammation. Observations in the past suggested that the type II 14-kDa PLA2 is a secreted enzyme that functions extracellularly. Evidence is now emerging that the type II 14-kDa PLA(2) or its recently discovered low-molecular-weight isoforms may be localized and act intracellularly. In view of this, a more complex notion of distinctly functioning PLA(2)s in arachidonic acid release and/or eicosanoid generation can be envisioned. A comparison of the structural and biochemical features of the type II 14-kDa and the 85-kDa PLA(2)s reveals that the enzymes are more distinct than similar. These two enzymes would appear to have distinctly different genetic and biochemical regulatory mechanisms, suggesting that their functions could be quite distinct. Inhibitors of the 14-kDa PLA(2) and to a lesser extent the 85-kDa PLA(2) have been used to obtain a greater understanding of their cellular roles. The concept that the two distinct enzymes might hydrolyze arachidonic acid from different pools and/or supply distinct metabolizing systems in a single cell system has emerged. At this time an intriguing hypothesis can be formed suggesting distinct functional modalities for the two the PLA(2) enzymes in a single cell system. Evidence continues to build implicating the role of the type II 14-kDa PLA(2) in disease, providing a strong rationale for targeting this enzyme in designing novel antiinflammatory therapeutics.
Marshall
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LA
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Morgan
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