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Review
, 111 (10), 6387-422

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

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Review

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Alfred H Merrill Jr. Chem Rev.

Figures

Figure 1
Figure 1
Basic structures of mammalian sphingolipids. The upper left panel summarizes the categories of complex sphingolipids, and the upper right panel displays the root structures of the glycosphingolipid families using the glycan symbols defined by the key in the lower panel (the letter and number within the symbols convey the nature of the glycosidic linkage between that carbohydrate and the species to its right, for example: “β4” represents a β1–4 linkage). The abbreviations are: Glc, glucose; GlcNAc, N-acetylglucosamine; Gal, galactose; GalNAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid; Fuc, fucose. The lower panel displays the structure of ganglioside GM1a using both ChemDraw and glycan symbols, the Roman numbering system for the positions of the glucans (i.e., beginning with the first carbohydrate attached to ceramide), and a comparison with two other gangliosides (GM1b and fucosyl-GM1a) using the glycan symbol system.
Figure 2
Figure 2
Representative structures of Lewis epitopes. The key for the glycan symbols is the same as for Figure 1.
Figure 3
Figure 3
Schematic representation of sphingolipid functions. This diagram depicts a hypothetical plasma membrane with representative categories of sphingolipids with the black headgroup representing sphingomyelin, the colored headgroups the glycosphingolipids as in Figure 1, and the lipid backbones with the sphingoid base in blue and the amide-linked fatty acid in gray; phosphoglycerolipids and cholesterol are depicted in gray. The diagram illustrates the clustering of a portion of the sphingolipids (and cholesterol) in membrane “rafts,” the binding of ganglioside GM3 (left) and GM1 (right) to proteins, and the metabolic interconversions of some of the sphingolipids (shown in the box, in the order ceramide 1-phosphate, ceramide, sphingosine, and sphingosine 1-phosphate, S1P), which alters both the biophysical properties of the membrane and generates signaling molecules, such as S1P, which is involved in both intracellular signaling and extracellular signaling (represented by the green arrow).
Figure 4
Figure 4
De novo sphingolipid biosynthesis through lactosylceramide and sulfatide. Starting at top left, serine and palmitoyl-CoA are condensed by serine palmitoyltransferase (SPT) to form 3-ketosphinganine that is reduced to sphinganine, which is N-acylated by ceramide synthases (CerS) with the shown fatty acyl-CoA preferences, or phosphorylated by sphingosine kinase (SphK). The N-acylsphinganines (dihydroceramides, DHCer) can be incorporated into more complex dihydro-sphingomyelins, SM, from sphingomyelin synthases, SMS; -ceramide 1-phosphates, CerP, from ceramide kinase, CERK; -glucosylceramides, GlcCer, from GlcCer synthase; and -galactosylceramides, GalCer, from GalCer synthase). DHCer is also oxidized to Cer by dihydroceramide desaturase (DES1 and DES2; DES2 is also capable of hydroxylating the 4-position to form 4-hydroxydihydroceramides, t18:0) and incorporated into more complex sphingolipids as shown. The diagram also displays the formation of lactosylceramide (LacCer) from GlcCer and sulfatides (ST) from GalCer, and the turnover of DHCer to sphinganine (and Cer to sphingosine), which can be recycled or phosphorylated and cleaved to fatty aldehydes and ethanolamine phosphate. Not shown is ceramide phosphoethanolamine, which is present in mammalian cells in nearly trace amounts. The key is shown at the bottom, and is the same as for Figure 1 except that heavy black boxes represent SM, thin black for Cer1P, and (DH)Cer are represented by the green octagon.
Figure 5
Figure 5
Proposed reaction mechanism for serine palmitoyltransferase (modified from D. J. Campopiano and colleagues, see text). Starting with the enzyme with pyridoxal 5′-phosphate (PLP) bound as a Schiff’s base with an active site Lys (upper left), Ser is bound to make the external aldimine 24 then palmitoyl-CoA is bound and the reaction proceeds as shown until 3-ketosphinganine 30 is released.
Figure 6
Figure 6
Comparison of the structures of the “typical” and “atypical” sphingoid bases and the interrelationships between intermediary metabolism and the precursor substrates for them. The interconversion of Ser and Gly are catalyzed by serine hydroxymethyltransferase, and Ser is converted to pyruvate by serine dehydratase. Ser, Ala, and Gly are related to other metabolic pathways as illustrated, and produce the shown sphingoid bases when utilized by serine palmitoyltransferase.
Figure 7
Figure 7
A scheme depicting the major headgroup additions to (dihydro)ceramides and subsequent metabolites that define the different categories (including root structure series) of more complex sphingolipids. Ceramides and dihydroceramides (one of which is depicted in the octagon at one o’clock in this diagram) are converted into sphingomyelin (SM), ceramide 1-phosphate (CerP), glucosylceramide (GlcCer), and galactosylceramide (GalCer), then to downstream metabolites as shown (see text). Ceramide phosphoethanolamine and 1-O-acyl-ceramides are not shown because they appear in mammalian cells in trace amounts. Each enclosed section represents a subcategory of glycosphingolipid, such as ST for sulfatides (red circles, as in Figure 4) (note that some of the sulfated glycosphingolipids fall into both the GalCer, that is, Gala, subcategory and others are derivatives of GlcCer). The arrow to the isoglobo family is less bold because that enzyme is not thought to be active in humans. The key for the symbols and coloring scheme is the same as in Figure 1 the earlier figures.
Figure 8
Figure 8
Representative reactions of ganglioside biosynthesis. An illustration of the “combinatorial” nature of ganglioside biosynthesis by the indicated glycosyltransferases (note alternatives names for each enzyme). The key is the same as in Figure 1.
Figure 9
Figure 9
Backbone and headgroup relational depiction of mammalian sphingolipid biosynthesis. This alternative depiction of de novo sphingolipid biosynthesis displays how the pathway can be envisioned to start with a fatty acyl-CoA (palmitoyl-CoA in lower portion of panel A) that is condensed with Ser to form 3-ketosphinganine then sphinganine (at the center of the fan), which is N-acylated to produce different chain-length dihydroceramides (represented by the ring, with examples of chain lengths labeled in blue). Each dihydroceramide subspecies can be converted into families of dihydro-complex sphingolipids, which are symbolized by the blades. The upper portion of panel A shows some of the complex sphingolipids within each wedge (which are only a fraction of the actual number of compounds that can be made, as illustrated by Figures 7 and 8, and the discussion in the text). Panel B displays further complexities related to the lipid backbones. The upper portion of panel B illustrates how the dihydroceramides from each sphingoid base backbone (in this case, d18:0 from palmitoyl-CoA) can be hydroxylated to phytoceramides (t18:0) and/or desaturated to ceramides (d18:1) (c.f., Figure 4); the latter is also presumed to undergo further desaturation to form N-acyl-sphingadienes (d18:2). The blades radiating from each N-acyl-chain subspecies represents the complex sphingolipids, as explained for panel A. The lower portion of panel B shows that Ala or Gly are alternatively used by serine palmitoyltransferase to form m18:0 and m17:0 which are N-acylated and, to some degree, desaturated to N-acyl-m18:1’s and N-acyl-m17:1 (to date, backbone hydroxylation has not been noted). Note that these do not radiate into larger blades because headgroups cannot be added. Not shown are the utilization of other fatty acyl-CoAs, which would constitute parallel schemes like these, nor pathways where sphingolipids are turned over to generate intermediates that are recycled or turned over (although one can envision this occurring within the blades to return to the hub, with the apex of the hub representing the free sphingoid base). The symbols and abbreviations are the same as have been used in the other figures in this Review.
Figure 10
Figure 10
Sphingolipid turnover and catabolism. Representative enzymes and intermediates are shown for the turnover of each complex sphingolipid family to the lipid moiety (Cer), and the insert displays the degradation of the sphingoid base by phosphorylation and lytic cleavage to a fatty aldehyde and ethanolamine phosphate. The symbols and abbreviations are the same as have been used in the other figures in this Review.
Figure 11
Figure 11
Schematic representation of the locations in and outside of the cell where sphingolipids are metabolized and trafficked. The black dashed lines show the traditional biosynthetic pathway beginning with biosynthesis of the lipid backbone in the ER and subsequent trafficking through the Golgi for further metabolism, leading ultimately to movement to the plasma membrane and other parts of the cell via vesicles and transport proteins (e.g., GLTP) or across the membrane via pumps (ABC, etc.). The green arrows reflect inward movement of sphingolipids destined to lysosomes or to the ER via retrograde motion. The red lines represent additional trafficking of sphingolipids; for examples, for autophagosome formation, formation of multivesicular endosomes and multivesicular bodies, and fusion with the plasma membrane as shown.

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