1.1. Discovery of the Phospholipase A2 Superfamily Phospholipases represent one of the earliest enzyme activities to be identified and studied, and the phospholipase A2 (PLA2) superfamily (see defining specificity1 in Figure 1) traces its roots to the identification of lytic actions of snake venom at the end of the 19th century. The enzyme was first purified and characterized from cobra venom and later from rattlesnake venom. As protein sequencing methodologies advanced in the 1970s, it became apparent that these enzymes had an unusually large number of cysteines (> 10% of the amino acids) and, as secreted enzymes, that they were all in the form of disulfide bonds. It was further recognized that, in the case of PLA2, cobras and rattlesnakes had six disulfides in common, but one disulfide bond is located in distinctly different locations. This led to the designation of Type 1 and Type 2 for cobras (old world snakes) and rattlesnakes (new world snakes), respectively. 2 During that same period, studies on the porcine pancreatic digestive enzyme that hydrolyzes phospholipids led to the determination that this mammalian enzyme (and also the human pancreatic enzyme) had the same disulfide bonding pattern as cobras and hence the designation as IB with the cobra enzyme as IA. A dramatic change in the phospholipase A2 field that attracted the attention of the broader scientific community occurred in July, 1988, when at the first FASEB Summer Conference on Phospholipases, Jeffery J. Seilhamer and Lorin K. Johnson from California Biotechnology Inc. 3 and Ruth M. Kramer from Biogen Research Corporation4 independently and with much fanfare and excitement reported the purification, sequencing, and cloning of the first human nonpancreatic secreted PLA2, which they each had isolated from the human synovial fluid of arthritic knee joints. Because the sequence revealed that the disulfide bond pattern was more like the rattlesnake than the human pancreatic enzyme, this new form of PLA2 was designated IIA. All of these enzymes then became known as secreted or sPLA2s. It was not until the late 1980s that PLA2-like activities were reported in mammalian cells in contrast to extracellular secreted activities from venom and pancreas. In July, 1992, at the second FASEB Summer Conference on Phospholipases, James D. Clark from the Genetics Institute5 and Ruth M. Kramer (who had moved to Lilly Research Laboratories) 6 independently reported the purification, sequencing, and cloning of the first human cytosolic PLA2 (cPLA2) from the U937 macrophage cell line. The sequence was unrelated to those of the secreted enzymes. To track this new enzyme and potentially additional PLA2s, a group numbering system7 was established utilizing the preexisting venom designation of I and II and expanding them to include subgroups IA, IB, and IIA (GIA, GIB, GIIA); adding group III (GIII) for the clearly different PLA2, which had been purified from bee venom; and establishing the group IV (GIV) designation for the new cytosolic PLA2 (cPLA2). This was fortuitous because soon thereafter a new form of secreted PLA2 was discovered. It was produced by macrophages and it had the same six disulfide bonds as group I and group II,