Gérard Lambeau

Cloning, Chromosomal Mapping, and Expression of a Novel Human Secretory Phospholipase A2

Secretory phospholipases A2(sPLA2s) represent a rapidly expanding family of structurally related enzymes found in mammals as well as in insect and snake venoms. In this report, a cDNA coding for a novel sPLA2 has been isolated from human fetal lung, and its gene has been mapped to chromosome 16p13.1-p12. The mature sPLA2protein has a molecular mass of 13.6 kDa, is acidic (pI 5.3), and made up of 123 amino acids. Key structural features of the sPLA2include: (i) a long prepropeptide ending with an arginine doublet, (ii) 16 cysteines located at positions that are characteristic of both group I and group II sPLA2s, (iii) a C-terminal extension typical of group II sPLA2s, (iv) and the absence of elapid and pancreatic loops that are characteristic of group I sPLA2s. Based on these structural properties, this sPLA2 appears as a first member of a new group of sPLA2s, called group X. A 1.5-kilobase transcript coding for the human group X (hGX) sPLA2 was found in spleen, thymus, and peripheral blood leukocytes, while a less abundant 0.8-kilobase transcript was detected in the pancreas, lung, and colon. When the hGX sPLA2cDNA was expressed in COS cells, sPLA2 activity preferentially accumulated in the culture medium, indicating that hGX sPLA2 is an actively secreted enzyme. It is maximally active at physiological pH and with 10 mm Ca2+. hGX sPLA2 prefers phosphatidylethanolamine and phosphatidylcholine liposomes to those of phosphatidylserine.

On the Functional Diversity of Secreted Phospholipases A2: Cloning of Novel Mammalian Enzymes and HIV-1 Antiviral Properties

Over the past decade, it has become clear that mammalian cells not only express a variety of intracellular phospholipases A2 (PLA2), but also a diverse set of secreted phospholipases A2 (sPLA2s). While PLA2s are generally considered as key enzymes which control the production of lipid mediators, the function of the 10 distinct sPLA2s cloned so far remains ill-defined. Using venom sPLA2s, two types of specific membrane receptors (N and M) have been identified in various mammalian tissues. Of physiological relevance, the M-type receptor can bind with high affinities to several mammalian sPLA2s, making it likely that mammalian sPLA2s are endogenous ligands of the receptors initially identified with venom sPLA2s, and that the physiological function of the mammalian sPLA2s is not limited to their catalytic activity.