Structures, Enzymatic Properties, and Expression of Novel Human and Mouse Secretory Phospholipase A2s

Abstract Mammalian secretory phospholipase A2s (sPLA2s) form a family of structurally related enzymes that are involved in a variety of physiological and pathological processes via the release of arachidonic acid from membrane phospholipids or the binding to specific membrane receptors. Here, we report the cloning and characterization of a novel sPLA2 that is the sixth isoform of the sPLA2family found in humans. The novel human mature sPLA2consists of 123 amino acids (M r = 14,000) and is most similar to group IIA sPLA2 (sPLA2-IIA) with respect to the number and positions of cysteine residues as well as overall identity (51%). Therefore, this novel sPLA2should be categorized into group II and called group IIE (sPLA2-IIE) following the recently identified group IID sPLA2 (sPLA2-IID). The enzymatic properties of recombinant human sPLA2-IIE were almost identical to those of sPLA2-IIA and IID in terms of Ca2+requirement, optimal pH, substrate specificity, as well as high susceptibility to the sPLA2 inhibitor indoxam. Along with the biochemical properties of proteins, genetic and evolutional similarities were also observed among these three types of group II sPLA2s as to the chromosomal location of the human gene (1p36) and the exon/intron organization. The expression of sPLA2-IIE transcripts in humans was restricted to the brain, heart, lung, and placenta in contrast to broad expression profiles for sPLA2-IIA and -IID. In sPLA2-IIA-deficient mice, the expression of sPLA2-IIE was markedly enhanced in the lung and small intestine upon endotoxin challenge, which contrasted with the reduced expression of sPLA2-IID mRNA. In situhybridization analysis revealed elevation of sPLA2-IIE mRNA at alveolar macrophage-like cells in the lung of endotoxin-treated mice. These findings suggest a distinct functional role of novel sPLA2-IIE in the progression of inflammatory processes.