Molecular Cloning of Two New Human Paralogs of 85-kDa Cytosolic Phospholipase A2 *

Two new cloned human cDNAs encode paralogs of the 85-kDa cytosolic phospholipase A2(cPLA2). We propose to call these cPLA2β (114 kDa) and cPLA2γ (61 kDa), giving the name cPLA2α to the well known 85-kDa enzyme. cPLA2β mRNA is expressed more highly in cerebellum and pancreas and cPLA2γ more highly in cardiac and skeletal muscle. Sequence-tagged site mapping places cPLA2β on chromosome 15 in a region near a phosphoinositol bisphosphate phosphatase. The mRNA for cPLA2β is spliced only at a very low level, and Northern blots in 24 tissues show exclusively the unspliced form. cPLA2β has much lower activity on 2-arachidonoyl-phosphatidylcholine liposomes than either of the other two enzymes. Its sequence contains a histidine motif characteristic of the catalytic center of caspase proteases of the apoptotic cascade but no region characteristic of the catalytic cysteine. Sequence-tagged site mapping places cPLA2γ on chromosome 19 near calmodulin. cPLA2γ lacks the C2 domain, which gives cPLA2α its Ca2+ sensitivity, and accordingly cPLA2γ has no dependence upon calcium, although cPLA2β does. cPLA2γ contains a prenyl group-binding site motif and appears to be largely membrane-bound. cPLA2α residues activated by phosphorylation do not appear to be well conserved in either new enzyme. In contrast, all three previously known catalytic residues, as well as one additional essential arginine, Arg-566 in cPLA2α, are conserved in both new enzyme sequences. Mutagenesis shows strong dependence on these residues for catalytic activity of all three enzymes.