Catalytic residues of group VIB calcium-independent phospholipase A ₂ (iPLA₂γ)

Although human group VIB calcium-independent phospholipase A₂ (iPLA₂γ) contains the lipase-consensus sequence Gly-Xaa-Ser-Xaa-Gly in the C-terminal half, its overall sequence exhibits a week similarity to those of other PLA₂s, and thus no information on the catalytic site has been available. Here we show that the C-terminal region of human iPLA₂γ is responsible for the enzymatic activity. Comparison of this catalytic domain with those of the mouse homologue, human cytosolic PLA₂ (cPLA₂), and the plant PLA₂ patatin reveals that an amino acid sequence of a short segment around Asp-627 of iPLA₂γ is conserved among these PLA₂s, in addition to the Ser-483-containing lipase motif; the corresponding serine and aspartate in cPLA₂ and patatin are known to form a catalytic dyad. Since substitution of alanine for either Ser-483 or Asp-627 results in a loss of the PLA₂ activity, we propose that Ser-483 and Asp-627 of human iPLA ₂γ constitute an active site similar to the Ser-Asp dyad in cPLA₂ and patatin.