Sphingomyelin: Definition, Physical Characteristics, Metabolism, Function, Abnormalities and Associated Diseases

It is a type of sphingolipid found in the membranes of animals, particularly the myelin sheath.

It is composed of phosphatidylcholine or phosphatidylethanolamine , a group related to a ceramide (main chain of sphingosine and fatty acid).

It is synthesized in the endoplasmic reticulum and in the Golgi trans and is enriched in the plasma membrane with a higher concentration in the external leaflet.

In humans, sphingomyelins comprise almost 85% of all sphingolipids and 10-20% of the total lipids of the plasma membrane.

Sphingomyelins comprise 4 to 18% of all the lipids of the sarcolemmal membrane, with 93% present in the external leaflet.

The sphingomyelins are almost cylindrical, although their alkyl tails often differ in the number of carbons with a high degree of saturation.

Its high transition temperature and a greater tendency to form intermolecular hydrogen bonds compared to similar phospholipids can lead to lateral heterogeneity and the spontaneous formation of microdomains.

In addition, the intermolecular hydrogen bond between sphingomyelin and cholesterol can allow tight packaging in the liquid ordered phase of “rafts” and favor their formation.

Sphingomyelins contain phosphocholine or phosphoethanolamine as their polar group and are therefore classified together with glycerophospholipids as phospholipids.

Sphingomyelin was isolated for the first time by the German chemist Johann LW Thudicum in the 1880s. The structure of sphingomyelin was first reported in 1927 as N-acyl-sphingosine-1-phosphorylcholine.

The content of sphingomyelin in mammals ranges from 2 to 15% in most tissues, with higher concentrations found in nerve tissues, red blood cells and eye lenses.

Sphingomyelin has important structural and functional functions in the cell. It is a component of the plasma membrane and participates in many signaling pathways. The metabolism of sphingomyelin creates many products that play an important role in the cell.

Physical characteristics

Composition

Sphingomyelin consists of a group of phosphocholine, a sphingosine and a fatty acid. It is one of the few membrane phospholipids not synthesized from glycerol.

Sphingosine and fatty acid can be collectively classified as a ceramide.

This composition allows sphingomyelin to play an important role in the signaling pathways: the degradation and synthesis of sphingomyelin produce second important messengers for signal transduction.

Sphingomyelin obtained from natural sources, such as bovine eggs or brain, contains fatty acids of varying chain length.

Sphingomyelin with established chain length, such as palmitoylphingomyelin with a chain of 16 saturated acyl, is commercially available.

Properties

Ideally, the sphingomyelin molecules have the shape of a cylinder, however, many sphingomyelin molecules have a significant chain mismatch (the lengths of the two hydrophobic chains are significantly different).

The hydrophobic chains of sphingomyelin tend to be much more saturated than other phospholipids.

The temperature of the main transition phase of the sphingomyelins is also higher compared to the phase transition temperature of similar phospholipids, near 37 ° C. This can introduce lateral heterogeneity in the membrane, generating domains in the bilayer membrane.

Sphingomyelin undergoes significant interactions with cholesterol. Cholesterol has the ability to eliminate the transition from liquid to solid phase in phospholipids.

Because the transition temperature of sphingomyelin is within the physiological temperature ranges, cholesterol can play a significant role in the sphingomyelin phase. Sphingomyelins are also more prone to intermolecular hydrogen bonds than other phospholipids.

Location

Sphingomyelin is synthesized in the endoplasmic reticulum (ER), where it can be found in low amounts, and in the Golgi trans. It is enriched in the plasma membrane with a greater concentration in the external prospect than in the internal one.

The Golgi complex represents an intermediate between the endoplasmic reticulum and the plasma membrane, with slightly higher concentrations towards the trans side.

Metabolism

Synthesis

The synthesis of sphingomyelin involves the enzymatic transfer of a phosphocholine from phosphatidylcholine to a ceramide.

The first committed step in the synthesis of sphingomyelin involves the condensation of L-serine and palmitoyl-CoA. This reaction is catalyzed by serine palmitoyltransferase.

The product of this reaction is reduced, producing dihydrosphingosine. The dihydrosphingosine is subjected to N-acylation followed by desaturation to produce a ceramide . Each of these reactions occurs on the cytosolic surface of the endoplasmic reticulum.

The ceramide is transported to the Golgi apparatus where it can be converted into sphingomyelin. Sphingomyelin synthase is responsible for the production of sphingomyelin from ceramide. Diacylglycerol is produced as a by-product when phosphocholine is transferred.

Degradation

The decomposition of sphingomyelin is responsible for initiating many universal signaling pathways. It is hydrolyzed by sphingomyelinases (S-type phospholipases specific for sphingomyelin).

The phosphocholine group is released into the aqueous environment while the ceramide diffuses through the membrane.

Function

Membranes

The membranous myelin sheath that surrounds and electrically isolates many axons from nerve cells is particularly rich in sphingomyelin, suggesting its role as an insulator of nerve fibers.

The plasma membrane of other cells is also abundant in sphingomyelin, although it is found largely in the exoplasmic leaflet of the cell membrane.

However, there is some evidence that there may also be a set of sphingomyelin in the inner leaflet of the membrane.

In addition, it has been discovered that neutral sphingomyelinase-2, an enzyme that breaks down sphingomyelin in ceramide, is located exclusively in the internal leaflet, suggesting that sphingomyelin may be present there.

Signal transduction

The function of sphingomyelin was not clear until it was discovered that it had a role in signal transduction. It has been discovered that sphingomyelin plays an important role in cell signaling pathways.

The synthesis of sphingomyelin in the plasma membrane by sphingomyelin synthase 2 produces diacylglycerol, which is a second lipid-soluble messenger that can pass through a signal cascade.

In addition, the degradation of sphingomyelin can produce ceramide that is involved in the apoptotic signaling pathway.

Apoptosis

It has been found that sphingomyelin has a role in cellular apoptosis when hydrolyzed into ceramide. Studies conducted in the late 1990s found that ceramide was produced in a variety of conditions that lead to apoptosis.

The hypothesis was then raised that sphingomyelin hydrolysis and ceramide signaling were essential in deciding whether a cell dies.

In the early 2000s, new studies emerged that defined a new role for the hydrolysis of sphingomyelin in apoptosis, which determines not only when a cell dies but how.

After further experimentation, it has been shown that if the hydrolysis of sphingomyelin occurs at a sufficiently early point in the route, the production of ceramide can influence either the rate and manner of cell death or in releasing blocks in later events.

Lipid rafts

Sphingomyelin, as well as other sphingolipids, are associated with lipid microdomains in the plasma membrane known as lipid rafts.

The lipid rafts are characterized by the fact that the lipid molecules are in the orderly phase of lipids, offering more structure and rigidity compared to the rest of the plasma membrane.

In the rafts, the acyl chains have a low chain movement, but the molecules have great lateral mobility. This order is due in part to the higher transition temperature of the sphingolipids, as well as to the interactions of these lipids with cholesterol.

Cholesterol is a relatively small nonpolar molecule that can fill the space between sphingolipids that is the result of large acyl chains.

It is believed that lipid rafts participate in many cellular processes, such as membrane classification and trafficking, signal transduction and cell polarization. Excess sphingomyelin in lipid rafts can cause insulin resistance.

Due to the specific types of lipids in these microdomains, lipid rafts can accumulate certain types of proteins associated with them, thus increasing the special functions they possess. It has been speculated that lipid rafts are involved in the cascade of cellular apoptosis .

Abnormalities and associated diseases

The biosynthesis of de novo sphingolipids is related to metabolic diseases. However, the mechanism is not yet clear. Sphingolipids are ubiquitous and critical components of biological membranes.

Its biosynthesis begins with soluble precursors in the endoplasmic reticulum and culminates in the Golgi complex and the plasma membrane. The interaction of sphingomyelin, cholesterol and glycosphingolipid promotes the formation of plasma membrane rafts.

It has been shown that lipid rafts are involved in cell signaling, lipid and protein classification and membrane trafficking.

It is well known that toll-like receptors, class A and B scavenger receptors and the insulin receptor are found in lipid rafts.

Of the two types that involve sphingomyelinase, type A occurs in babies. It is characterized by jaundice, enlarged liver and deep brain damage. Children with this type rarely live beyond 18 months.

Type B involves an enlarged liver and spleen, which usually occurs in preadolescent years. The brain is unaffected Most patients have <1% normal levels of the enzyme compared to normal levels.

As a result of autoimmune disease multiple sclerosis (MS), the myelin sheath of neuronal cells in the brain and spinal cord is degraded, resulting in the loss of signal transduction capacity.

Patients with multiple sclerosis exhibit positive regulation of certain cytokines in the cerebrospinal fluid, particularly the tumor necrosis factor alpha.

This activates sphingomyelinase, an enzyme that catalyzes the hydrolysis of sphingomyelin in ceramide; sphingomyelinase activity has been observed together with cellular apoptosis.

An excess of sphingomyelin in the membrane of red blood cells (as in abetalipoproteinemia) causes an excess of lipid accumulation in the outer leaflet of the plasma membrane of red blood cells.

This results in abnormally shaped red blood cells called acanthocytes. Sphingomyelin is also a reservoir for other sphingolipids.

Therefore, sphingomyelin has an important impact on the signaling of cells through their structural function in lipid rafts or their catabolic intermediates, such as ceramide and glycoceramide.