Molecular and Cell Biology of Phosphatidylserine and Phosphatidylethanolamine Metabolism

Abstract

In this review, the pathways for phosphatidylserine (PS) and phosphatidylethanolamine (PE) biosynthesis, as well as the genes and proteins involved in these pathways, are described in mammalian cells, yeast, and prokaryotes. In mammalian cells, PS is synthesized by a base-exchange reaction in which phosphatidylcholine or PE is substrate for PS synthase-1 or PS synthase-2, respectively. Isolation of Chinese hamster ovary cell mutants led to the cloning of cDNAs and genes encoding these two PS synthases. In yeast and prokaryotes PS is produced by a biosynthetic pathway completely different from that in mammals: from a reaction between CDP-diacylglycerol and serine. The major route for PE synthesis in cultured cells is from the mitochondrial decarboxylation of PS. Alternatively, PE can be synthesized in the endoplasmic reticulum (ER) from the CDP-ethanolamine pathway. Genes and/or cDNAs encoding all the enzymes in these two pathways for PE synthesis have been isolated and characterized. In mammalian cells, PS is synthesized on the ER and/or mitochondria-associated membranes (MAM). PS synthase-1 and -2 are highly enriched in MAM compared to the bulk of ER. Since MAM are a region of the ER that appears to be in close juxtaposition to the mitochondrial outer membrane, it has been proposed that MAM act as a conduit for the transfer of newly synthesized PS into mitochondria. A similar pathway appears to operate in yeast. The use of yeast mutants has led to identification of genes involved in the interorganelle transport of PS and PE in yeast, but so far none of the corresponding genes in mammalian cells has been identified. PS and PE do not act solely as structural components of membranes. Several specific functions have been ascribed to these two aminophospholipids. For example, cell-surface exposure of PS during apoptosis is thought to be the signal by which apoptotic cells are recognized and phagocytosed. Translocation of PS from the inner to outer leaflet of the plasma membrane of platelets initiates the blood-clotting cascade, and PS is an important activator of several enzymes, including protein kinase C. Recently, exposure of PE on the cell surface was identified as a regulator of cytokinesis. In addition, in Escherichia coli, PE appears to be involved in the correct folding of membrane proteins; and in Drosophila, PE regulates lipid homeostasis via the sterol response element-binding protein.