Sphingolipids

=**Sphingolipids**=


 * Authors:** **Landon Herrera, Daniel Kim**

Sphingolipids represent another class of lipid that, like the phospholipids, are composed of a polar head and two non-polar tails and are frequently found in biological membranes. An 18-carbon amino alcohol, sphingosine, forms the backbone of these lipids rather than glycerol. The root term "sphingo-" was first coined b**y J.L.W. Thudi**chum in 1884 because the enigmatic nature of the molecules reminded him of the riddle of the sphinx. While they are most likely less enigmatic then there were in 1884, sphingolipids still are extremely versatile molecules that play an important role in signal transmission and cell recognition, especially in neural tissue.

toc =Structure=

In sphingolipids, the amino group of the sphingosine is linked to the acyl group of a fatty acid by amide bond. This combination of a sphingosine with a fatty acid is called the ceramide unit. Both asymmetric centers in the sphingosine have the S configuration. While all sphingolipids contain a ceramide unit, it is the head group that attaches to the sphingosine which differentiates them from each other. If the primary -OH on a sphingosine is bonded to a phosphocholine or phosphoethanolamine via ester linkage, then it becomes a sphingomyelin. On the other hand, if the primary -OH group of the sphingosine bonds with sugar residue by β-glycosodic linkage, then it becomes a glycosphingolipid. It's important to note that sphingomyelins can be classified as phospholipids while glycosphingolipids cannot. This is because sphingomyelins contain a phosphate group. =Types=

A.k.a. ceramide phosphorylcholine, sphingomyelin consists of a ceramide unit with a phosphorylcholine moiety attached to position 1 and is known as the sphingolipid analogue of phosphatidycholine. It is commonly composed of a phosphorylcholine and a ceramide. Found in animal cell membranes and being present in the myelin sheath of nerve cells in the brain, it does not appear in plants or microorganisms. Sphingomyelin makes up the majority of sphingolipids that are present in the human body. Besides forming a stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer, sphingomyelin can participate in hydrogen bonding at the amide bond on position 2 and at the hydroxyl on position 3 of the sphingoid base. Sphingomyelin also has the peculiar property of having a high affinity for cholesterol. Sphingomyelin and cholesterol have been known to congregate together in certain micro-domains of membranes known as lipid rafts. Because of this, it has been speculated that sphingomyelin may control cholesterol distribution in the cell.
 * Sphingomyelin:**

A.k.a. monoglycosylceramide, cerebrosides consist of a ceramide bonded to either a glucose or galactose molecule. Hence, the two main types of cerebrosides are glucocerebroside and galactocerebroside.While it can be found in all nerve cells, galactocerebroside is the principal glycosphingolipid found in brain tissue. Galactocerebrosides can make up to 2% of the mass of grey matter and 12 % of the mass of white matter. Glucocerebrosides can also be found in low-level nerve cells, but their major contribution comes from their presence in skin cells. Epidermal glucocerebrosides are essential for lamellar body formation in the stratum corneum and are responsible for maintaining the water permeability barrier of the skin. Glucocerebroside is the only glycosphingolipid that is commonly found in plant, animals, and fungi. Glucocerebrosides aide in defense against fungal attack and help the plasma membrane in plants withstand the stress brought about by cold or drought. In fungi, glucocerebrosides help in cell wall assembly, cell differentiation, cell division, and signaling.
 * Cerebrosides:**

Gangliosides consist of a ceramide bonded to an oligosaccharide with one or more sialic acids attached to its sugar chain. They are only found in animals and mostly occupy the neuronal membranes in the brain. In terms of function, gangliosides occupy the surface of oligosaccharides to provide cells with distinguishing surface markers that can serve in cellular recognition and cell-to-cell communication. Specifically, the sialoglycan components of gangliosides extend out from the cell surface, where they can participate in intermolecular interactions. Thus, functioning by recognizing specific molecules at the cell surface and by regulating the activities of proteins in the plasma membrane. Gangliosides also serve to promote the survival and regrowth of injured neurons. It is postulated that gangliosides are the body's natural counteragent towards neurodegenerative disorders.
 * Gangliosides:**

=Mammalian Sphingolipid Metabolism=

While sphingolipids themselves are not essential nutrients and are a poor source for calories, their metabolism plays a crucial role in the cell. Specifically, the metabolites of sphingolipids (particularly ceramide and sphingosine) are known to serve as signaling molecules that function to regulate cell growth, specialization of cell type (differentiation), and apoptosis. Additionally, the metabolism of sphingolipids prevents their over-accumulation in the cell. The sphingolipid metabolic pathway is a branching network with the central compound that connects everything together being ceramide. There are at least two discernible ways that ceramide can be produced when sphingolipids are broken down: The de novo ("from the beginning") pathway and the hydrolysis of of lipids.

Serine palmitoyl transferase (SPT) catalyzes the condensation of serine and palmitoyl-CoA to form 3-keto-dihydrosphingosine (KDS). KDS is then reduced into sphinganine. Sphinganine is then N-acylated with the help of dihydroceramide synthase and fatty acyl CoA to become dihydroceramide. Lastly, dihydroceramide is desaturated by dihydroceramide desaturase to generate the 4,5-trans-double bond to form ceramide.
 * 1. De novo pathway:**



Sphingomyelin is cleaved by sphingomyelinase to create phosphochoine and ceramide as products. There are different types of sphingomyelinase that can be used in the hydrolytic pathway to metabolize sphingomyelin: Lysosomal acid SMase (aSMase), zinc dependent secretory SMase (sSMase), neutral magnesium dependent SMase (nSMase), and alkaline SMase (bSMase).
 * 2. Hydrolytic pathway:**



glucosylceramide (GlcCer) and galactosylceramide (GalCer) can be hydrolyzed by β-glucosidases and galactosidases to release ceramide. Also, sphingosine-1-phosphate (S1P) can be dephosphorylated with S1P phosphatase to become sphingosine. Sphingosine can then bond to a fatty acid to become ceramide. Ceramide-1-phosphate can be reverted to a ceramide by simply removing the phosphate group with the help of ceramide kinase.
 * 3. Peripheral methods for retrieving ceramide:**



While ceramide is central to sphingolipid metabolism, it can be further broken down to create smaller metabolites. Ceramidases are able to metabolize ceramides by breaking the amide bond and turning them into sphingosines. The sphingosines can then be phosphorylated by sphingosine kinase to create S1P. With the phosphate group attached, S1P lyase can then metabolize S1P to produce ethanolamine-1-phosphate.

=Disorders=

Sphingolipid metabolism helps to maintain a good balance of enzymes and substrates that contribute to neuronal health. Defects or hindrances in metabolism can lead to a number of neurological disorders. In the medical field, disorders that relate to Sphingolipid metabolism are known as Sphingolipidoses: A heterogeneous group of inherited disorders of lipid metabolism that affect the central nervous system. They are generally characterized by diffuse and progressive involvement of neurons (gray matter) with psychomotor retardation and myoclonus or of fiber tracts (white matter) with weakness and spasticity. Generally, its the deficiency of an enzyme in sphingolipid metabolism that causes the disorder. Niemann-Pick disease stems from the lack of sphingomyelinase; Krabbe's disease comes from the inadequate supply of galactocerebrosidqse; Gaucher's disease is caused by the low amount of beta-D-glucosidase; metachromatic leukodystrophy is from sulfatase deficiency; Tay-Sachs disease generates from insufficient amounts of hexosaminidase A; and generalized gangliosidosis originates from the absence of an adequate reserve of beta-galactosidase.