por What are the sphingolipids?
Sphingolipids represent one of the three large families of lipids present in biological membranes. Like glycerophospholipids and sterols, they are amphipathic molecules with a hydrophilic polar region and a hydrophobic nonpolar 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 known: phosphosphingolipids, neutral, and acidic glycosphingolipids.
Unlike glycerophospholipids, sphingolipids are not built on a glycerol 3-phosphate molecule as their backbone, but instead are compounds derived from sphingosine, an amino alcohol with a long hydrocarbon chain linked by an amide bond.
ANDsphingolipid structure
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.
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 by 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 constitute 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 skeletal feature of sphingolipids is that they can have a net positive charge at neutral pH, rare among lipid molecules.
However, the pKa of the amino group is low compared to a simple amine, between 7 and 8, so a portion of the molecule is not charged at physiological pH, which could explain their «free» movement 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.
functions
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»
Less fluid dynamic microdomains made up of cholesterol and sphingolipid molecules called lipid rafts can be detected in biological membranes.
These structures are naturally occurring and are closely associated with integral proteins, cell surface receptors and signaling proteins, transporters, and other proteins with glycosylphosphatidylinositol (GPI) anchors.
-Signaling functions
They have functions as signaling molecules acting 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 intercellular and cell-environment interactions 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) that control such complex cell behaviors as growth, differentiation, and apoptosis.
-As membrane receptors
Some pathogens use glycosphingolipids as receptors to mediate their entry into host cells or to deliver virulence factors to host cells.
Sphingolipids have been shown to be involved in multiple cellular events such as secretion, endocytosis, chemotaxis, neurotransmission, angiogenesis, and inflammation.
They are also involved in membrane trafficking, which is why they influence the internalization of receptors, the 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 their polar groups, namely the sphingomyelins, the glycolipids, and the gangliosides.
sphingomyelin
These contain phosphocholine or phosphoethanolamine as the polar head group, so they are classified as phospholipids along with glycerophospholipids. They resemble, of course, the phosphatidylcholines in three-dimensional structure and in 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 (uncharged) glycolipids or glycosphingolipids
They are found primarily on the outer face of the plasma membrane and have one or more polar headgroup sugars attached directly to the 1-carbon hydroxyl of the ceramide moiety. They do not have phosphate groups. Since they are uncharged at pH 7, they are called neutral glycolipids.
Cerebrosides have a single sugar molecule attached to the ceramide. Those that contain galactose are found in plasma membranes of cells of non-nerve tissues. Globosides are glycosphingolipids with two or more sugars, usually D-glucose, D-galactose, or N-acetyl-D-galactosamine.
Gangliosides or acidic glycosphingolipids
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 their 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 sphingolipid synthesis may 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 attachment of a fatty acid through an amide bond, and finally, the formation of complex sphingolipids by from 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 sphingolipid pool.
Synthesis of the ceramide backbone
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, pyridoxal phosphate-dependent serine palmitoyl transferase (SPT) 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 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 yeast, 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 linking a specific chain of fatty acids to the long-chain bases. Therefore, ceramide synthases and another enzyme, elongases, provide the main source of fatty acid diversity in sphingolipids.
Metabolism
The degradation of sphingolipids is carried out by the enzymes glucohydrolases and sphingomyelinases, which are in charge of removing the modifications of the polar groups. On the other hand, ceramidases regenerate long-chain bases from ceramides.
Gangliosides are broken down by a set of lysosomal enzymes that catalyze the stepwise removal of sugar units, ultimately producing a ceramide.
Another route of degradation 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 phosphorylation rather than acylation of LCBs, giving rise to signaling molecules that can be soluble substrates for lyase enzymes that cleave LCBs-phosphate to generate acylaldehydes and phosphoethanolamine.
Regulation
The metabolism of these…