Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present

Abstract

This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events. Moreover, mitochondrial function is severely impaired when the PE content of mitochondria is reduced below a threshold level. The discovery and implications of the existence of membrane contact sites between the endoplasmic reticulum and mitochondria and their relevance for PS and PE metabolism, as well as for mitochondrial function, are also discussed. Many of the recent advances in these fields are due to the use of isotope labeling for tracing biochemical pathways. In addition, techniques for disruption of specific genes in mice are now widely used and have provided major breakthroughs in understanding the roles and metabolism of PS and PE in vivo.

Keywords: ether lipids; membranes; mitochondria; phosphoglycerolipids; phospholipid trafficking.

Fig. 1.

Chemical structures of PS, PE, and PC.

Fig. 2.

Harry Deuel, Jr. (1897–1956). Left: taken from (10). Right: the three volumes of H. J. Deuel’s treatise (10); from the author’s personal file.

Fig. 3.

Eugene P. Kennedy. Top: From the author’s personal file. Bottom: Results from an experiment showing that CTP, not ATP, is the nucleotide cofactor for PC biosynthesis [modified from (43)].

Fig. 4.

Base-exchange reactions for PS synthesis: from PC and PE, catalyzed by PS synthase-1 and PS synthase-2, respectively.

Fig. 5.

PE biosynthetic pathways. The enzyme catalyzing each reaction is indicated by the numbers 1–9. #1, ETNK; #2, ET; #3, CDP-ethanolamine:1,2-diacylglycerol ethanolaminephosphotransferase; #4, PSD; #5, PS synthase-2; #6, PS synthase-1; #7, lyso-PE acyltransferase; #8, PE N-methyltransferase; #9, release of ethanolamine from PE. Etn, ethanolamine.

Fig. 6.

MAMs. Left: Percoll gradient isolation of MAMs and mitochondria from rat liver (from the author’s personal file). Right: Electron microscopic visualization of MAMs, shown as contacts/close proximity between ER and mitochondria (M) [From (95)].

Fig. 7.

Synthesis, translocation, and decarboxylation of PS. PS is synthesized in MAMs by serine-exchange via PS synthase (PSS) with either PC or PE. The newly made PS is subsequently imported via MAMs into mitochondria (MITO) and decarboxylated to PE therein via PSD.

Fig. 8.

Origin of mitochondrial PE. Incorporation of [³H]ethanolamine (Etn) (left) and [³H]serine (Ser) (right) into PE from subcellular fractions of rat hepatocytes [from (92)]. MIC, microsomes; MIT, mitochondria.

Fig. 9.

Structures of the ether lipids: plasmenylethanolamine (top) and plasmanylethanolamine (bottom).

Fig. 10.

Enzymes and their subcellular locations for plasmenylethanolamine biosynthesis. #1, Dihydroxyacetone-3-P acyltransferase (peroxisomes); #2, ether bond formation by 1-alkylglycerone-3-P synthase (peroxisomes); #3, 1-alkylglycerone-3-P reductase (ER); #4, acyl-CoA-1-alkyl-2-acylglycerol-3-P acyltransferase (ER); #5, 1-alkyl-2-acylglycerol-3-phosphate phosphohydrolase (ER); #6, CDP-ethanolamine 1-alkyl-2-acylglycerol ethanolaminephosphotransferase (ER); #7, plasmanylethanolamine 1-alkyldesaturase (ER).