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Thematic Review e Authorʼs Choice thematic review Thematic Review Series: Sphingolipids Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols † † † Sarah T. Pruett,1,* Anatoliy Bushnev,* Kerri Hagedorn, Madhura Adiga, Christopher A. Haynes, † M. Cameron Sullards, Dennis C. Liotta,* and Alfred H. Merrill, Jr.2,† Department of Chemistry,* Emory University, Atlanta, GA 30322; and Schools of Biology, Chemistry, and † Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0230 Downloaded from Abstract “Sphingosin” was first described by J. L. W. Thu- after the original designation of the first isolated com- dichum in 1884 and structurally characterized as 2S,3R,4E-2- pound from brain as “sphingosin” by J. L. W. Thudichum aminooctadec-4-ene-1,3-diol in 1947 by Herb Carter, who in 1884 (1). Today, the term “sphingosine” is usually “ also proposed the designation of lipides derived from reserved for (2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol sphingosine as sphingolipides.” This category of amino alco- (compound 6 in Fig. 1), which has important biological hols is now known to encompass hundreds of compounds www.jlr.org that are referred to as sphingoid bases and sphingoid base- functions in cell signaling per se (2, 3) as well as after de- like compounds, which vary in chain length, number, posi- rivatization to the 1-phosphate (compound 9 in Fig. 1) (2, tion, and stereochemistry of double bonds, hydroxyl groups, 4, 5), N-acylated metabolites (ceramides; compound 4 in and other functionalities. Some have especially intriguing Fig. 1) (2, 6, 7), and more complex phosphosphingolipids at Univ of IL Chicago, on January 30, 2014 features, such as the tail-to-tail combination of two sphin- and glycosphingolipids with head groups attached to the goid bases in the a,v-sphingoids produced by sponges. Most hydroxyl on carbon 1. The structural diversity of the latter of these compounds participate in cell structure and reg- compounds is widely appreciated, with hundreds of head ulation, and some (such as the fumonisins) disrupt normal group variants for mammals alone, as was reviewed re- sphingolipid metabolism and cause plant and animal dis- “ ” ease. Many of the naturally occurring and synthetic sphingoid cently (8, 9) and addressed at a number of omics web bases are cytotoxic for cancer cells and pathogenic microor- sites, such as SphinGOMAP (www.sphingomap.org), the ganisms or have other potentially useful bioactivities; hence, Japanese Lipid Bank (http://www.lipidbank.jp) and Glyco- they offer promise as pharmaceutical leads. This thematic forum (http://www.glycoforum.gr.jp/), the Lipid Maps review gives an overview of the biodiversity of the back- Consortium (www.lipidmaps.org), the Consortium for bones of sphingolipids and the broader field of naturally oc- Functional Glycomics (http://www.functionalglycomics. — curring and synthetic sphingoid base-like compounds. org/fg/), and the Complex Carbohydrate Research Cen- Pruett, S. T., A. Bushnev, K. Hagedorn, M. Adiga, C. A. ter at the University of Georgia (http://www.ccrc.uga.edu/ Haynes, M. C. Sullards, D. C. Liotta, and A. H. Merrill, Jr. ~moremen/glycomics/). Biodiversity of sphingoid bases (“sphingosines”)andre- lated amino alcohols. J. Lipid Res. 2008. 49: 1621–1639. Somewhat less well appreciated is that sphingoid bases also display considerable structural diversity, as was ele- gantly reviewed by K. A. Karlsson almost 40 years ago Supplementary key words sphinganine • phytosphingosine • fumonisin • myriocin • long-chain base • anti-tumor • anti-fungal (10, 11). In remembrance of Herbert E. Carter, who first elucidated the structure of sphingosine 6 and dihydro- sphingosine 2 (12) and “proposed to designate those lip- ” Sphingolipids are composed of a structurally related fam- ides derived from sphingosine as sphingolipides (13), this ily of backbones termed sphingoid bases, which are some- thematic review summarizes and updates points made pre- times referred to as “long-chain bases” or “sphingosines” viously regarding the structural diversity of sphingoid bases (10, 11) and expands the topic to include sphingoid bases and sphingoid base-like compounds that have been discov- The work from our laboratories on naturally occurring sphingolipids cited in this review was supported by National Institutes of Health Grants GM-076217 and GM-069338 (Lipid Maps Consortium), and work involving sphingolipid analogs was supported by funding from the National Cancer Institute (Grant CA-87525). e Authorʼs Choice — Final version full access. Abbreviations: SPT, serine palmitoyltransferase. 1 Present address of S. T. Pruett: Yerkes National Primate Research Manuscript received 15 May 2008. Center, Emory University, Atlanta, GA 30329. Published, JLR Papers in Press, May 21, 2008. 2 To whom correspondence should be addressed. DOI 10.1194/jlr.R800012-JLR200 e-mail: [email protected] Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 49, 2008 1621 Downloaded from www.jlr.org at Univ of IL Chicago, on January 30, 2014 Fig. 1. Biosynthesis and turnover of the three major categories of sphingoid bases in mammalian cells. DHR, dihydroceramide; SPT, ser- ine palmitoyltransferase. ered in intervening years. In addition to being fascinating mediate in the de novo biosynthesis of sphingosine via de- for their biodiversity, some of these naturally occurring saturation of dihydroceramides (3) to produce ceramides compounds (and synthetic analogs) are promising drug (4)(17)andfortheformationof“phytosphingosine” 7 leads, while others cause disease, as exemplified by the (2S,3S,4R-2-aminooctadecane-1,3,4-triol) and what is collo- fumonisins (14). quially referred to as “phytoceramide” (compound 5 in Fig. 1) via hydroxylation of sphinganine (18) or dihydrocer- amide (17). The alternative names (4E)-sphing-4-enine and DIVERSITY IN THE SPHINGOID BASE BACKBONES (4E)-sphingenine are sometimes used to designate the OF SPHINGOLIPIDS specific location of the double bond of sphingosine. The International Union of Pure and Applied Chemists- Within a few decades after the structure for sphingosine International Union of Biochemists Joint Commission 6 hadbeendetermined(12)andsensitivemethodsfor (16) and others (19) have recommended naming chain the analysis of sphingoid bases devised (15), there was evi- length homologs by the root chemical name of the parent dence for .60 structural variations (10, 11). The 1997 Inter- hydrocarbon (e.g., a 20 carbon sphinganine is called an national Union of Pure and Applied Chemists-International icosasphinganine and one with 14 carbon atoms is called Union of Biochemists Joint Commission on Biochemical No- tetradecasphinganine), and the position and stereochem- menclature (16) proposed that “Sphingoids are long-chain istry of substituents such as double bonds (with E/Z pre- aliphatic amino alcohols...represented by the compound ferred over trans/cis), hydroxyl groups, methyl groups, originally called ‘dihydrosphingosine’ [(2S,3R)-2-amino- etc., should be stated explicitly, if known. Examples of such octadecane-1,3-diol]…[and]… imply a chain length of 18 car- compounds are shown in Figs. 2 and 3. A useful short- bon atoms.” Dihydrosphingosine (compound 2 in Fig. 1; hand nomenclature is to give the number of hydroxyl also called “sphinganine”) is one of the major sphingoid groups [“d” for the two (di-) hydroxyls of sphingosine and bases found in many organisms as well as an early inter- sphinganine and “t” (tri-) for the additional hydroxyl in 4- 1622 Journal of Lipid Research Volume 49, 2008 Downloaded from www.jlr.org at Univ of IL Chicago, on January 30, 2014 Fig. 2. Sphingoid bases of mammalian tissues. hydroxysphinganine] followed by the number of carbon brosides in black epidermis from the Antarctic minke atoms in the backbone and the number of double bonds, whale also have a high proportion (?25%) of 16 carbon with the location and configuration given as a prefix or suf- sphingoid bases (30). fix. Therefore, sphingosine is designated 4E-d18:1 (and Variation in the number and position of double bonds D sometimes d18:1 4t), dihydrosphingosine is designated and hydroxyl groups also occurs. Plasma, brain, and human d18:0, and phytosphingosine (4-hydroxysphinganine) is aorta contain a 4E,14Z-diene 15 (31, 32), and 6-hydroxy- designated t18:0. sphingosine 16 is present in skin sphingolipids (23, 33, 34). An unusual sphingosine with the double bond between car- Mammalian sphingoid bases bons 3 and 4 (5-hydroxy,3E-sphingosine; compound 17 in The predominance of 18 carbon sphingoid bases (d18:0, Fig. 3) has been found in acid-hydrolyzed brain extracts d18:1, and t18:0) in most mammalian sphingolipids is con- (35). While it is possible that 17 is a by-product of the acid sistent with the preference of mammalian serine palmitoyl- hydrolysis (36, 37) (as will be discussed below for Fig. 8), it transferase (SPT) for saturated fatty acyl-CoAs with 16 6 is nonetheless interesting that the N-octanoyl derivatives of 1 carbon atoms, combined with the abundance of palmitoyl- both the 5R and 5S stereoisomers of 17 have been reported CoA (20, 21); nonetheless, small amounts of sphingoid to be more potent than ceramide in inhibition of the pro- bases with other chain lengths of 12 to 26 carbons have liferation of a human breast cancer cell line (MCF-7 cells) been reported (22, 23). The most
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