Review
Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells

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Abstract

Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are metabolically related membrane aminophospholipids. In mammalian cells, PS is required for targeting and function of several intracellular signaling proteins. Moreover, PS is asymmetrically distributed in the plasma membrane. Although PS is highly enriched in the cytoplasmic leaflet of plasma membranes, PS exposure on the cell surface initiates blood clotting and removal of apoptotic cells. PS is synthesized in mammalian cells by two distinct PS synthases that exchange serine for choline or ethanolamine in phosphatidylcholine (PC) or PE, respectively. Targeted disruption of each PS synthase individually in mice demonstrated that neither enzyme is required for viability whereas elimination of both synthases was embryonic lethal. Thus, mammalian cells require a threshold amount of PS. PE is synthesized in mammalian cells by four different pathways, the quantitatively most important of which are the CDP-ethanolamine pathway that produces PE in the ER, and PS decarboxylation that occurs in mitochondria. PS is made in ER membranes and is imported into mitochondria for decarboxylation to PE via a domain of the ER [mitochondria-associated membranes (MAM)] that transiently associates with mitochondria. Elimination of PS decarboxylase in mice caused mitochondrial defects and embryonic lethality. Global elimination of the CDP-ethanolamine pathway was also incompatible with mouse survival. Thus, PE made by each of these pathways has independent and necessary functions. In mammals PE is a substrate for methylation to PC in the liver, a substrate for anandamide synthesis, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Thus, PS and PE participate in many previously unanticipated facets of mammalian cell biology. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.

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

References (210)

  • D. Park et al.

    The phosphatidylserine receptor TIM-4 does not mediate direct signaling

    Curr. Biol.

    (2009)
  • A. Yu et al.

    Stimulation of phosphatidylserine biosynthesis and facilitation of UV-induced apoptosis in Chinese hamster ovary cells over-expressing phospholipid scramblase 1

    J. Biol. Chem.

    (2003)
  • K. Saito et al.

    Genetic evidence that phosphatidylserine synthase II catalyzes the conversion of phosphatidylethanolamine to phosphatidylserine in Chinese hamster ovary cells

    J. Biol. Chem.

    (1998)
  • P.A. Grandmaison et al.

    Externalization of phosphatidylserine during apoptosis does not specifically require either isoform of phosphatidylserine synthase

    Biochim. Biophys. Acta

    (2004)
  • S.C. Frasch et al.

    Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity

    J. Biol. Chem.

    (2011)
  • D.L. Bratton et al.

    Neutrophil clearance: when the party is over, clean-up begins

    Trends Immunol.

    (2011)
  • H. Hosono et al.

    Phosphatidylserine-specific phospholipase A1 stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine

    J. Biol. Chem.

    (2001)
  • J. Aoki et al.

    Structure and function of phosphatidylserine-specific phospholipase A1

    Biochim. Biophys. Acta

    (2002)
  • D.L. Daleke

    Phospholipid flippases

    J. Biol. Chem.

    (2007)
  • Q. Zhou et al.

    Molecular cloning of human plasma membrane phospholipid scramblase: a protein mediating transbilayer movement of plasma membrane phospholipids

    J. Biol. Chem.

    (1997)
  • Q. Zhou et al.

    Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1

    Blood

    (2002)
  • C.V. Finkielstein et al.

    Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1

    J. Biol. Chem.

    (2006)
  • K.A. Powell et al.

    Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids

    J. Biol. Chem.

    (2000)
  • N. Lucas et al.

    Phosphatidylserine binding is essential for plasma membrane recruitment and signaling function of 3-phosphoinositide-dependent kinase-1

    J. Biol. Chem.

    (2011)
  • D. Arikketh et al.

    Defining the importance of phosphatidylserine synthase-1 (PSS1): unexpected viability of PSS1-deficient mice

    J. Biol. Chem.

    (2008)
  • M.S. Bae-Lee et al.

    Phosphatidylserine synthesis in Saccharomyces cerevisiae. Purification and characterization of membrane-associated phosphatidylserine synthase

    J. Biol. Chem.

    (1984)
  • A. DeChavigny et al.

    Sequence and inactivation of the pss gene of Escherichia coli. Phosphatidylethanolamine may not be essential for cell viability

    J. Biol. Chem.

    (1991)
  • R.G. Gardner et al.

    A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eukaryotes

    J. Biol. Chem.

    (1999)
  • A. Signorell et al.

    Phosphatidylethanolamine is the precursor of the ethanolamine phosphoglycerol moiety bound to eukaryotic elongation factor 1A

    J. Biol. Chem.

    (2008)
  • D.R. Voelker et al.

    Isolation and characterization of a Chinese hamster ovary cell line requiring ethanolamine or phosphatidylserine for growth and exhibiting defective phosphatidylserine synthase activity

    J. Biol. Chem.

    (1986)
  • S.J. Stone et al.

    Cloning and expression of mouse liver phosphatidylserine synthase-1 cDNA: overexpression in rat hepatoma cells inhibits the CDP-ethanolamine pathway for phosphatidylethanolamine biosynthesis

    J. Biol. Chem.

    (1998)
  • T.T. Suzuki et al.

    Purification and properties of an ethanolamine-serine base exchange enzyme of rat brain microsomes

    J. Biol. Chem.

    (1985)
  • O. Kuge et al.

    Purification and characterization of Chinese hamster phosphatidylserine synthase 2

    J. Biol. Chem.

    (2003)
  • O. Kuge et al.

    Cloning of a Chinese hamster ovary (CHO) cDNA encoding phosphatidylserine synthase (PSS) II, overexpression of which suppresses the phosphatidylserine biosynthetic defect of a PSS I-lacking mutant of CHO-K1 cells

    J. Biol. Chem.

    (1997)
  • L.M.G. van Golde et al.

    Biosynthesis of lipids in Golgi complex and other subcellular fractions from rat liver

    Biochim. Biophys. Acta

    (1974)
  • C.J. Jelsema et al.

    Distribution of phospholipid biosynthetic enzymes among cell components of rat liver

    J. Biol. Chem.

    (1978)
  • J.E. Vance

    Phospholipid synthesis in a membrane fraction associated with mitochondria

    J. Biol. Chem.

    (1990)
  • K. Saito et al.

    Immunochemical identification of the pssA gene product as phosphatidylserine synthase I of Chinese hamster ovary cells

    FEBS Lett.

    (1996)
  • S.J. Stone et al.

    Phosphatidylserine synthase-1 and ‐2 are localized to mitochondria-associated membranes

    J. Biol. Chem.

    (2000)
  • J.N. Kanfer et al.

    Regulation of the choline, ethanolamine and serine base exchange enzyme activities of rat brain microsomes by phosphorylation and dephosphorylation

    FEBS Lett.

    (1988)
  • K. Hasegawa et al.

    Isolation and characterization of a Chinese hamster ovary cell mutant with altered regulation of phosphatidylserine biosynthesis

    J. Biol. Chem.

    (1989)
  • O. Kuge et al.

    Control of phosphatidylserine synthase II activity in Chinese hamster ovary cells

    J. Biol. Chem.

    (1999)
  • B. Sturbois-Balcerzak et al.

    Structure and expression of the murine phosphatidylserine synthase-1 gene

    J. Biol. Chem.

    (2001)
  • M.O. Bergo et al.

    Defining the importance of phosphatidylserine synthase 2 (Ptdss2) in Mice

    J. Biol. Chem.

    (2002)
  • G. Tasseva et al.

    N-Myc and SP regulate phosphatidylserine synthase-1 expression in brain and glial cells

    J. Biol. Chem.

    (2011)
  • R. Steenbergen et al.

    Phospholipid homeostasis in phosphatidylserine synthase-2-deficient mice

    Biochim. Biophys. Acta

    (2006)
  • O. Kuge et al.

    Phosphatidylserine biosynthesis in cultured Chinese hamster ovary cells. III. Genetic evidence for utilization of phosphatidylcholine and phosphatidylethanolamine as precursors

    J. Biol. Chem.

    (1986)
  • P.J. Trotter et al.

    Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae

    J. Biol. Chem.

    (1995)
  • P.J. Trotter et al.

    Phosphatidylserine decarboxylase 2 of Saccharomyces cerevisiae. Cloning and mapping of the gene, heterologous expression and creation of the null allele

    J. Biol. Chem.

    (1995)
  • A.K. Percy et al.

    Characterization of brain phosphatidylserine decarboxylase: localization in the mitochondrial inner membrane

    Arch. Biochem. Biophys.

    (1983)
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    This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.

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