Trends in Cell Biology
The ins and outs of sphingolipid synthesis
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.
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