Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewFormation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells☆
Highlights
► The biosynthesis and functions of PS in mammalian cells are reviewed. ► The transport of PS to mitochondria via mitochondria-associated membranes is discussed. ► 4 Pathways for mammalian PE biosynthesis are reviewed.
Introduction
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are two metabolically related aminophospholipids (Fig. 1) that are present in membranes of all eukaryotic and prokaryotic cells (reviewed in Ref. [1]). In mammalian, plant and yeast cells phosphatidylcholine (PC) is the most abundant phospholipid whereas PE is the second most abundant. However, with a few exceptions, prokaryotes do not make PC so that in this class of organisms PE is usually the most abundant phospholipid. In eukaryotic cells, PE and PS account for approximately 20% and 3–15%, respectively, of total phospholipids. The majority of phospholipids in mammalian cells are made in the ER whereas mitochondria supply all of the cardiolipin and a significant fraction of PE. Since mitochondria are presumed to be derived from bacteria during the evolution of eukaryotic cells, it has been suggested that the lack of PC synthesis in mitochondria reflects the (general) inability of bacteria to synthesize PC. On the other hand, PE is the major bacterial phospholipid so that mammalian mitochondria have retained the capacity for synthesis of PE, as well as another abundant bacterial phospholipid cardiolipin. Intriguingly, however, mammalian mitochondria do not make PS whereas bacteria do, albeit by a pathway different from that in mammalian cells. Thus, not all of the phospholipid biosynthetic capacity of bacteria has been retained in mammalian mitochondria.
PE was first isolated from the brain as “cephalin” by Ludwig Thudichum in 1884. His research on this topic was for many years considered to be “relatively insignificant,” according to Thudichum's obituaries in Nature [volume 64, page 527 (1901)] and “The Times” of London (Sept. 10, 1901). The latter article stated that “the knowledge yielded by these researches was hardly commensurate with the time and cost at which it was obtained.” Unfortunately, similar sentiments are even today often applied to basic research. Almost 70 years later (1952) the structure of PE was deduced by Baer and colleagues [2]. In 1941 PS was identified as a secondary component of cephalin which was originally thought to be pure PE. The structure of PS was elucidated by Folch in 1941 [3] and was subsequently confirmed by chemical synthesis [4].
In this article we shall discuss the mechanisms of the biosynthesis and cellular functions of PS and PE, particularly in mammalian cells.
Section snippets
Functions of phosphatidylserine
PS is not equally abundant in membranes of all types of mammalian cells or tissues. Compared to other tissues, the brain, and particularly the retina, is enriched in PS and PE. Moreover, in the human brain > 36% of the acyl-chains of PS consist of docosahexanoyl residues [5], [6] and the presence of these acyl-chains appears to be essential for normal functioning of the nervous system [6], [7], [8], [9]. The concentration of PS also varies among different organelle membranes (reviewed in Ref.
The PS synthases
The pathway for PS biosynthesis depends upon the type of organism. In prokaryotes and the yeast Saccharomyces cerevisiae, all PS is synthesized by a PS synthase that uses CDP-diacylglycerol and l-serine (Fig. 1). In contrast, in mammalian cells PS is synthesized solely by calcium-dependent base-exchange reactions in which the polar head-group (choline or ethanolamine) of a pre-existing phospholipid (PC or PE, respectively) is exchanged for l-serine [57] (Fig. 1). Whereas Escherichia coli and
Mechanism of PS transport
A major use of PS is its conversion into PE by the mitochondrial enzyme PS decarboxylase (PSD) (Fig. 2). Although yeast contains two distinct proteins that catalyze PS decarboxylation (Psd1 in mitochondria and Psd2 in the Golgi/vacuole [88], [89]), mammalian cells contain only a single PSD that is located in mitochondria [90], [91]. Since PS is synthesized in elements of the ER, and since PSD activity is restricted to mitochondria in mammalian cells, the mechanism by which PS is imported into
Functions of PE
PE comprises ~ 25% of mammalian phospholipids and is particularly enriched in the brain where the PE content is ~ 45% of total phospholipids. PE appears to play an important role in the heart since a decreased PE content of cardiac myocytes causes cell damage after ischemia, and altered asymmetrical transbilayer distribution of PE in sarcolemmal membranes disrupts these membranes [132]. PE is the phospholipid substrate for the hepatic enzyme PE N-methyltransferase [133], [134] that provides
Ether-linked ethanolamine phospholipids
Approximately 20% of human phospholipids are ether-linked lipids (reviewed in Ref. [208]). Whereas the diacyl lipids, including PE, consist of glycerol-3-phosphate esterifed to acyl residues at the sn-1 and sn-2 positions, the ether lipids contain an ether linkage at the sn-1 position. In addition, the choline and ethanolamine plasmalogens (plasmenylcholine and plasmenylethanolamine, respectively) contain a cis double bond adjacent to the sn-1 ether linkage, whereas the 1-alkyl-2-acyl
Summary and future directions
In addition to contributing to membrane structure, the metabolically-related aminophospholipids PS and PE participate in multiple facets of metabolism and cell biology that were, until recently, completely unanticipated. Many of the key experiments that revealed these functions were performed in genetically modified mice and in mammalian cell mutants, as well as in other eukaryotic organisms such as yeast and parasites. Recent studies have demonstrated the crucial requirement of PE in
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This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.