Sphingolipid metabolism

Stable Identifier
Homo sapiens
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Sphingolipids are derivatives of long chain sphingoid bases such as sphingosine (trans-1,3-dihydroxy 2-amino-4-octadecene), an 18-carbon unsaturated amino alcohol which is the most abundant sphingoid base in mammals. Amide linkage of a fatty acid to sphingosine yields ceramides. Esterification of phosphocholine to ceramides yields sphingomyelin, and ceramide glycosylation yields glycosylceramides. Introduction of sialic acid residues yields gangliosides. These molecules appear to be essential components of cell membranes, and intermediates in the pathways of sphingolipid synthesis and breakdown modulate processes including apoptosis and T cell trafficking.

While sphingolipids are abundant in a wide variety of foodstuffs, these dietary molecules are mostly degraded by the intestinal flora and intestinal enzymes. The body primarily depends on de novo synthesis for its sphingolipid supply (Hannun and Obeid 2008; Merrill 2002). De novo synthesis proceeds in four steps: the condensation of palmitoyl-CoA and serine to form 3-ketosphinganine, the reduction of 3-ketosphinganine to sphinganine, the acylation of sphinganine with a long-chain fatty acyl CoA to form dihydroceramide, and the desaturation of dihydroceramide to form ceramide.

Other sphingolipids involved in signaling are derived from ceramide and its biosynthetic intermediates. These include sphinganine (dihydrosphingosine) 1-phosphate, phytoceramide, sphingosine, and sphingosine 1-phosphate.

Sphingomyelin is synthesized in a single step in the membrane of the Golgi apparatus from ceramides generated in the endoplasmic reticulum (ER) membrane and transferred to the Golgi by CERT (ceramide transfer protein), an isoform of COL4A3BP that is associated with the ER membrane as a complex with PPM1L (protein phosphatase 1-like) and VAPA or VAPB (VAMP-associated proteins A or B). Sphingomyelin synthesis appears to be regulated primarily at the level of this transport process through the reversible phosphorylation of CERT (Saito et al. 2008).

Literature References
PubMed ID Title Journal Year
18165232 Protein phosphatase 2Cepsilon is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes

Tamura, S, Saito, S, Kobayashi, T, Echigo, S, Kawano, M, Matsui, H, Hanada, K, Tomishige, N, Kumagai, K

J Biol Chem 2008
12011104 De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway

Merrill AH, Jr

J Biol Chem 2002
18216770 Principles of bioactive lipid signalling: lessons from sphingolipids

Hannun, YA, Obeid, LM

Nat Rev Mol Cell Biol 2008
28295942 Gangliosides: Structures, Biosynthesis, Analysis, and Roles in Cancer

Delannoy, P, Groux-Degroote, S, Guérardel, Y

Chembiochem 2017
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