SPHINGOLIPIDS: CHARACTERISTICS, FUNCTIONS, GROUPS, SYNTHESIS - BIOLOGY - 2025

The sphingolipids are one of the three major families of lipids in biological membranes. Like glycerophospholipids and sterols, they are amphipathic molecules with a hydrophilic polar region and a hydrophobic apolar region.

They were first described in 1884 by Johann LW Thudichum, who described three sphingolipids (sphingomyelin, cerebrosides, and cerebrosulfatide) that belong to the three different classes that are known: phosphoesphingolipids, neutral and acidic glycosphingolipids.

Alejandro Porto, via Wikimedia Commons

Unlike glycerophospholipids, sphingolipids are not built on a glycerol 3-phosphate molecule as the main backbone, but are compounds derived from sphingosine, an amino alcohol with a long hydrocarbon chain linked by an amide bond.

In terms of complexity and diversity, at least 5 different types of bases are known for sphingolipids in mammals. These bases can be joined by more than 20 different types of fatty acids, with varying lengths and degrees of saturation, in addition to the many variations in the polar groups that can occur.

Biological membranes have about 20% sphingolipids. These have varied and important functions in cells, from structural to signal transduction, and control of different cellular communication processes.

The distribution of these molecules varies depending on the function of the organelle where they are found, but normally the concentration of sphingolipids is much higher in the outer monolayer of the plasma membrane than in the inner monolayer and other compartments.

In humans there are at least 60 species of sphingolipids. Many of them are important components of the membranes of nerve cells, while others play important structural roles or participate in signal transduction, recognition, cell differentiation, pathogenesis, programmed cell death, among others.

E structura

General structure of sphingolipids. LHcheM, from Wikimedia Commons

All sphingolipids are derived from an L-serine, which is condensed with a long-chain fatty acid to form the sphingoid base, also known as the long-chain base (LCB).

The most common bases are sphinganine and sphingosine, which differ from each other only in the presence of a trans double bond between carbons 4 and 5 of the sphingosine fatty acid.

The carbons 1, 2, and 3 of sphingosine are structurally analogous to the glycerol carbons of glycerophospholipids. When a fatty acid is attached to carbon 2 of sphingosine through amide bonds, a ceramide is produced, which is a molecule very similar to diacylglycerol and represents the simplest sphingolipid.

The long-chain fatty acids that make up the hydrophobic regions of these lipids can be very diverse. The lengths vary from 14 to 22 carbon atoms that can have different degrees of saturation, usually between carbons 4 and 5.

In positions 4 or 6 they can have hydroxyl groups and double bonds in other positions or even branches such as methyl groups.

characteristics

The fatty acid chains linked by amide bonds to ceramides are commonly saturated, and tend to be longer than those found in glycerophospholipids, which appears to be crucial for their biological activity.

A distinctive characteristic of the sphingolipid skeleton is that they can have a net positive charge at neutral pH, rare among lipid molecules.

However, the pK a of the amino group is low compared to a simple amine, between 7 and 8, so that a portion of the molecule is not charged at physiological pH, which could explain the "free" movement of these between the bilayers.

The traditional classification of sphingolipids arises from the multiple modifications that the ceramide molecule can undergo, especially in terms of substitutions of the polar head groups.

Features

Sphingolipids are essential in animals, plants, and fungi, as well as in some prokaryotic organisms and viruses.

-Structural functions

Sphingolipids modulate the physical properties of membranes, including their fluidity, thickness, and curvature. Modulating these properties also gives them direct influence on the spatial organization of membrane proteins.

In lipid "rafts"

In biological membranes, dynamic micro domains with less fluidity can be detected, made up of cholesterol and sphingolipid molecules called lipid rafts.

These structures occur naturally and are closely related to integral proteins, cell surface receptors and signaling proteins, transporters, and other proteins with glycosylphosphatidylinositol (GPI) anchors.

-Signage functions

They have functions as signaling molecules that act as second messengers or as secreted ligands for cell surface receptors.

As secondary messengers they can participate in the regulation of calcium homeostasis, cell growth, tumorigenesis, and suppression of apoptosis. Furthermore, the activity of many integral and peripheral membrane proteins depends on their association with sphingolipids.

Many interactions between cells and the cell with its environment depend on the exposure of the different polar groups of sphingolipids to the outer face of the plasma membrane.

The binding of glycosphingolipids and lectins is crucial for the association of myelin with axons, the adhesion of neutrophils to the endothelium, etc.

Byproducts of your metabolism

The most important signaling sphingolipids are the long-chain bases or sphingosines and ceramides, as well as their phosphorylated derivatives, such as sphingosine 1-phosphate.

The metabolism products of many sphingolipids activate or inhibit multiple downstream targets (protein kinases, phosphoprotein phosphatases, and others), which control complex cellular behaviors such as growth, differentiation, and apoptosis.

-As receptors in the membrane

Some pathogens use glycosphingolipids as receptors to mediate their entry into host cells or to deliver virulence factors to them.

Sphingolipids have been shown to participate in multiple cellular events such as secretion, endocytosis, chemotaxis, neurotransmission, angiogenesis, and inflammation.

They are also involved in membrane trafficking, thus influencing receptor internalization, ordering, movement and fusion of secretory vesicles in response to different stimuli.

Sphingolipid groups

There are three subclasses of sphingolipids, all derived from ceramide and differing from each other by polar groups, namely: sphingomyelins, glycolipids, and gangliosides.

Sphingomyelins

Sphingomilein. Black: sphingosine. Red: phosphocholine. Blue: fatty acid.

These contain phosphocholine or phosphoethanolamine as a polar head group, so they are classified as phospholipids along with glycerophospholipids. They resemble, of course, phosphatidylcholines in three-dimensional structure and general properties since they have no charge on their polar heads.

They are present in the plasma membranes of animal cells and are especially abundant in myelin, a sheath that surrounds and insulates the axons of some neurons.

Neutral glycolipids or glycosphingolipids (no charge)

Glycolipid Wpcrosson, from Wikimedia Commons

They are found primarily on the outer face of the plasma membrane and have one or more sugars as a polar head group attached directly to the hydroxyl of carbon 1 of the ceramide portion. They do not have phosphate groups. Since at pH 7 they have no charge, they are called neutral glycolipids.

Cerebrosides have a single sugar molecule attached to ceramide. Those containing galactose are found in plasma membranes of non-nerve tissue cells. Globosides are glycosphingolipids with two or more sugars, usually D-glucose, D-galactose, or N-acetyl-D-galactosamine.

Acidic gangliosides or glycosphingolipids

Structure of ganglioside GM1

These are the most complex sphingolipids. They have oligosaccharides as a polar head group and one or more terminal N-acetylmuramic acid residues, also called sialic acid. Sialic acid gives gangliosides the negative charge at pH 7, which distinguishes them from neutral glycosphingolipids.

The nomenclature of this class of sphingolipids depends on the amount of sialic acid residues present in the oligosaccharide portion of the polar head.

Synthesis

The long-chain base molecule, or sphingosine, is synthesized in the endoplasmic reticulum (ER) and the addition of the polar group to the head of these lipids occurs later in the Golgi complex. In mammals, some synthesis of sphingolipids can also occur in the mitochondria.

After completing their synthesis in the Golgi complex, sphingolipids are transported to other cellular compartments through vesicle-mediated mechanisms.

The biosynthesis of sphingolipids consists of three fundamental events: the synthesis of long-chain bases, the biosynthesis of ceramides by the union of a fatty acid through an amide bond, and finally, the formation of complex sphingolipids through of the union of the polar groups on carbon 1 of the sphingoid base.

In addition to de novo synthesis, sphingolipids can also be formed by the turnover or recycling of long-chain bases and ceramides, which can feed the pool of sphingolipids.

Synthesis of the ceramide skeleton

The biosynthesis of ceramide, the backbone of sphingolipids, begins with the decarboxylative condensation of a palmitoyl-CoA molecule and an L-serine. The reaction is catalyzed by a heterodimeric serine palmitoyl transferase (SPT), dependent on pyridoxal phosphate and the product is 3-keto dihydrosphingosine.

This enzyme is inhibited by β-halo-L-alanines and L-cycloserines. In yeast it is encoded by two genes, while in mammals there are three genes for this enzyme. The active site is located on the cytoplasmic side of the endoplasmic reticulum.

The role of this first enzyme is conserved in all the organisms studied. However, there are some differences between the taxa that have to do with the subcellular location of the enzyme: that of bacteria is cytoplasmic, that of yeasts, plants and animals is in the endoplasmic reticulum.

3-ketosphinganine is subsequently reduced by NADPH-dependent 3-ketosphinganine reductase to produce sphinganine. Dihydroceramide synthase (sphinganine N-acyl transferase) then acetylates sphinganine to produce dihydroceramide. The ceramide is then formed by dihydroceramide desaturase / reductase, which inserts a trans double bond at position 4-5.

In mammals there are numerous isoforms of ceramide synthases, each binding a specific chain of fatty acids to long-chain bases. Therefore, ceramide synthases and other enzymes, elongases, provide the main source of diversity for fatty acids in sphingolipids.

Specific sphingolipid formation

Sphingomyelin is synthesized by the transfer of a phosphocholine from phosphatidylcholine to ceramide, releasing diacylglycerol. The reaction links the sphingolipid and glycerophospholipid signaling pathways.

Phosphoethanolamine ceramide is synthesized from phosphatidylethanolamine and ceramide in a reaction analogous to that of sphingomyelin synthesis, and once formed it can be methylated to sphingomyelin. Inositol phosphate ceramides are formed by transesterification from phosphatidylinositol.

Glycosphingolipids are modified mainly in the Golgi complex, where specific glycosyltransferase enzymes participate in the addition of oligosaccharide chains in the hydrophilic region of the ceramide skeleton.

Metabolism

The degradation of sphingolipids is carried out by the enzymes glucohydrolases and sphingomyelinases, which are responsible for removing the modifications of the polar groups. On the other hand, ceramidases regenerate long chain bases from ceramides.

Gangliosides are degraded by a set of lysosomal enzymes that catalyze the step-by-step removal of sugar units, eventually producing a ceramide.

Another degradation pathway consists of the internalization of sphingolipids in endocytic vesicles that are sent back to the plasma membrane or transported to lysosomes where they are degraded by specific acid hydrolases.

Not all long-chain bases are recycled, the endoplasmic reticulum has a route for their terminal degradation. This degradation mechanism consists of a phosphorylation instead of acylation of LCBs, giving rise to signaling molecules that can be soluble substrates for lyase enzymes that cleave the LCBs-phosphate to generate acyloaldehydes and phosphoethanolamine.

Regulation

The metabolism of these lipids is regulated at various levels, one of them is that of the enzymes in charge of synthesis, their post-translational modifications, and their allosteric mechanisms.

Some regulatory mechanisms are cell-specific, either to control the moment of cell development in which they are produced or in response to specific signals.

References

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