Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.

Metabolic and molecular aspects of ethanolamine phospholipid biosynthesis: the role of CTP:phosphoethanolamine cytidylyltransferase (Pcyt2)

The CDP-ethanolamine branch of the Kennedy pathway is the major route for the formation of ethanolamine-derived phospholipids, including diacyl phosphatidylethanolamine and alkenylacyl phosphatidylethanolamine derivatives, known as plasmalogens. Ethanolamine phospholipids are essential structural components of the cell membranes and play regulatory roles in cell division, cell signaling, activation, autophagy, and phagocytosis. The physiological importance of plasmalogens has not been not fully elucidated, although they are known for their antioxidant properties and deficiencies in a number of inherited peroxisomal disorders. This review highlights important aspects of ethanolamine phospholipid metabolism and reports current molecular information on 1 of the regulatory enzymes in their synthesis, CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Pcyt2 is encoded by a single, nonredundant gene in animal species that could be alternatively spliced into 2 potential protein products. We describe properties of the mouse and human Pcyt2 genes and their regulatory promoters and provide molecular evidence for the existence of 2 distinct Pcyt2 proteins. The goal is to obtain more insight into Pcyt2 catalytic function and regulation to facilitate a better understanding of the production of ethanolamine phospholipids via the CDP-ethanolamine branch of the Kennedy pathway.

Incorporation of serine into Paramecium ethanolamine phospholipid and phosphonolipid head groups

Ethanolamine phospholipid head groups in Paramecium were synthesized directly from ethanolamine. As in other cell types, radioactivity from ethanolamine failed to incorporate significantly into head groups of ethanolamine phosphonolipids, indicating that the phosphonolipids are not derived from their phospholipid analogues. Unlike other systems previously examined, radioactivity from serine is incorporated into both ethanolamine phospholipid and phosphonolipid head groups of glycerolipids and sphingolipids in this ciliate. These observations suggest that synthesis of ethanolamine phosphonolipids involves synthesis de novo of free phosphonoserine, which is then incorporated into lipids, and then lipid-bound phosphonoserine intermediates (glycerolipids or sphingolipids) undergo decarboxylation, forming lipidbound phosphonoethanolamine compounds.