The ins and outs of sphingolipid synthesis

https://doi.org/10.1016/j.tcb.2005.04.006Get rights and content

Sphingolipids are ubiquitous components of eukaryotic cell membranes, where they play important roles in intracellular signaling and in membrane structure. Even though the biochemical pathway of sphingolipid synthesis and its compartmentalization between the endoplasmic reticulum and Golgi apparatus have been known for many years, the molecular identity of the enzymes in this pathway has only recently been elucidated. Here, we summarize progress in the identification and characterization of the enzymes, the transport of ceramide from the endoplasmic reticulum to the Golgi apparatus, and discuss how regulating the synthesis of sphingolipids might impact upon their functions.

Introduction

The past few years have seen an upsurge of interest in sphingolipids (SLs) – membrane lipids containing a ceramide backbone – resulting in a vast increase in our understanding of the roles that they play in signaling events and in membrane lipid rafts. In addition, there has been remarkable progress recently in identifying the enzymes involved in the de novo synthesis of SLs, and a more-or-less comprehensive picture of the route taken by a SL can now be delineated from initiation of its biosynthesis on the cytosolic leaflet of the endoplasmic reticulum (ER), through its transport from the ER to the Golgi apparatus, and its metabolism in the Golgi apparatus.

Previous reviews have focused on a particular enzyme [1], transport step 2, 3, or a particular aspect of SL function 4, 5, whereas the current review presents an overview of all steps of SL synthesis and transport through the early compartments of the secretory pathway. To this end, we systematically discuss the enzymes of the SL synthetic pathway (Figure 1), what is known about the topology of the reactions, and the mechanisms of transport of ceramide from the ER to the Golgi apparatus.

Section snippets

Sphingolipid structure, synthesis and transport

SLs consist of three main structural elements (see insert of Figure 2). The basic building block of a SL is the sphingoid long-chain base (lcb), normally sphingosine, sphinganine (dihydrosphingosine) or 4-hydroxysphinganine (phytosphingosine). A fatty acid is attached to carbon-2 (C-2) of the lcb via an amide bond, yielding ceramide, and attachment of hydrophilic head groups to the OH-group at C-1 yields complex SLs. The head group can be a sugar, in the case of glycosphingolipids (GSLs), or

Moving forward

The molecular identification of most of the components in the SL synthetic pathway is a major achievement and illustrates that the description of a biochemical pathway by itself (as in Figure 1) is not sufficient to understand, or even to ask the correct questions, about how a pathway is regulated; for this, the cellular context must also be known (as in Figure 2). With these tools in hand, it is now possible to turn to questions that, to date, have been inaccessible. Central among these is why

Concluding remarks

In summary, the molecular identification of the enzymes involved in SL synthesis allows both the formulation of relevant questions, mainly concerning regulation, and will also provide the tools to answer them. The availability of yeast mutants and the possibility of up- or down-regulating expression of mammalian homologs of the enzymes will permit new approaches to study the function of SLs. Thus, this is the beginning of an exciting new era in the study and discovery of the intricacies of SL

Acknowledgements

Tony Futerman is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science, and his work was supported by the Israel Science Foundation. Howard Riezman's work was supported by grants from the Swiss National Science Foundation. A.H.F. and H.R. were supported by an EC network grant HPRN-2000-00077.

References (59)

  • A. Kihara et al.

    FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane

    J. Biol. Chem.

    (2004)
  • E.C. Mandon

    Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver

    J. Biol. Chem.

    (1992)
  • M.M. Nagiec

    The LCB4 (YOR171c) and LCB5 (YLR260w) genes of Saccharomyces encode sphingoid long chain base kinases

    J. Biol. Chem.

    (1998)
  • K. Funato

    Lcb4p is a key regulator of ceramide synthesis from exogenous long chain sphingoid base in Saccharomyces cerevisiae

    J. Biol. Chem.

    (2003)
  • N.C. Hait

    Lcb4p sphingoid base kinase localizes to the Golgi and late endosomes

    FEBS Lett.

    (2002)
  • A. Billich

    Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases

    J. Biol. Chem.

    (2003)
  • C. Delon

    Sphingosine kinase 1 is an intracellular effector of phosphatidic acid

    J. Biol. Chem.

    (2004)
  • N. Igarashi

    Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis

    J. Biol. Chem.

    (2003)
  • M. Ikeda

    Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol

    Biochem. Biophys. Res. Commun.

    (2004)
  • A.H. Merrill

    De novo sphingolipid biosynthesis. A necessary, but dangerous, pathway

    J. Biol. Chem.

    (2002)
  • K. Venkataraman

    Upstream of Growth and Differentiation Factor 1 (uog1), a mammalian homolog of the yeast Longevity Assurance Gene 1 (LAG1), regulates N-Stearoyl-sphinganine (C18-(Dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells

    J. Biol. Chem.

    (2002)
  • K. Venkataraman et al.

    Do longevity assurance genes containing Hox domains regulate cell development via ceramide synthesis?

    FEBS Lett.

    (2002)
  • E. Winter et al.

    TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains?

    Trends Biochem. Sci.

    (2002)
  • C. Riebeling

    Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors

    J. Biol. Chem.

    (2003)
  • I. Guillas

    Human homologues of LAG1 reconstitute Acyl-CoA-dependent ceramide synthesis in yeast

    J. Biol. Chem.

    (2003)
  • L. Qie

    Identification of a Saccharomyces gene, LCB3, necessary for incorporation of exogenous long chain bases into sphingolipids

    J. Biol. Chem.

    (1997)
  • N.L. Alderson

    The human FA2H gene encodes a fatty acid 2-hydroxylase

    J. Biol. Chem.

    (2004)
  • P. Ternes

    Identification and characterization of a sphingolipid delta 4-desaturase family

    J. Biol. Chem.

    (2002)
  • C. Michel et al.

    Conversion of dihydroceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum

    FEBS Lett.

    (1997)
  • Cited by (274)

    • The Sphinx and the egg: Evolutionary enigmas of the (glyco)sphingolipid biosynthetic pathway

      2024, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
    • Impact of sphingolipids on protein membrane trafficking

      2023, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
    View all citing articles on Scopus
    View full text