Sphingolipid
Encyclopedia
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
. They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx
Sphinx
A sphinx is a mythical creature with a lion's body and a human head or a cat head.The sphinx, in Greek tradition, has the haunches of a lion, the wings of a great bird, and the face of a woman. She is mythicised as treacherous and merciless...
because of their enigmatic nature. These compounds play important roles in signal transmission and cell recognition. Sphingolipidoses
Sphingolipidoses
-Accumulated products:* Gangliosides: Gangliosidosis** GM1 gangliosidoses** GM2 gangliosidoses*** Tay-Sachs disease*** Sandhoff disease* Glycolipids** Fabry's disease** Krabbe disease** Metachromatic leukodystrophy*Glucocerebrosides**Gaucher's disease...
, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with an R group consisting of a hydrogen atom only is a ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
. Other common R groups include phosphocholine
Phosphocholine
Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
, yielding a sphingomyelin
Sphingomyelin
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphorylcholine and ceramide...
, and various sugar monomers or dimers, yielding cerebroside
Cerebroside
Cerebrosides is the common name for a group of glycosphingolipids called monoglycosylceramides which are important components in animal muscle and nerve cell membranes.They consist of a ceramide with a single sugar residue at the 1-hydroxyl moiety...
s and globoside
Globoside
A globoside is a type of glycosphingolipid with more than one sugars as the side chain . The sugars are usually a combination of N-Acetylgalactosamine, D-glucose or D-galactose. A glycosphingolipid that has only one sugar as the side chain is called a cerebroside.The side chain can be cleaved by...
s, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
Structure
The long-chain bases, sometimes simply known as sphingoid bases, are the first non-transient products of de novo sphingolipid synthesis in both yeast and mammals. These compounds, specifically known as phytosphingosine and dihydrosphingosine (also known as sphinganine, although this term is less common), are mainly C18 compounds, with somewhat lower levels of C20 bases. Ceramides and glycosphingolipids are N-acyl derivatives of these compounds.The sphingosine backbone is O-linked to a (usually) charged head group such as ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
, serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, or choline
Choline
Choline is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
.
The backbone is also amide-linked to an acyl group, such as a fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
.
Types
- CeramideCeramideCeramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
is the fundamental structural unit common to all sphingolipids. They consist simply of a fatty acid chain attached through an amideAmideIn chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
linkage to sphingosine.
There are three main types of sphingolipids, differing in their head groups:
- SphingomyelinSphingomyelinSphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphorylcholine and ceramide...
s have a phosphocholinePhosphocholinePhosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
or phosphoethanolamine molecule with an ester linkageEsterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
to the 1-hydroxy group of a ceramide. - Glycosphingolipids, which differ in the substituents on their head group (see image). Glycosphingolipids are ceramides with one or more sugarSugarSugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
residues joined in a β-glycosidic linkage at the 1-hydroxyl position.- CerebrosideCerebrosideCerebrosides is the common name for a group of glycosphingolipids called monoglycosylceramides which are important components in animal muscle and nerve cell membranes.They consist of a ceramide with a single sugar residue at the 1-hydroxyl moiety...
s have a single glucoseGlucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
or galactoseGalactoseGalactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
at the 1-hydroxy position.- SulfatideSulfatideSulfatides are a class of sulfated galactosylceramides synthesized primarily in the oligodendrocytes in the central nervous system. Sulfatides are a type of sulfolipid.-Clinical significance:...
s are sulfated cerebrosides.
- Sulfatide
- Cerebroside
- Gangliosides have at least three sugars, one of which must be sialic acidSialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
.
Mammalian sphingolipid metabolism
De novo sphingolipid synthesis begins with formation of 3-keto-dihydrosphingosine by serine palmitoyltransferase. The preferred substrates for this reaction are palmitoyl-CoA and serineSerine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
. However, studies have demonstrated that serine palmitoyltransferase has some activity toward other species of fatty acyl-CoA and alternative amino acids, and the diversity of sphingoid bases has recently been reviewed. Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine. Dihydrosphingosine is acylated by a (dihydro)-ceramide synthase, such as Lass1
LASS1
LAG1 longevity assurance homolog 1 is a protein that in humans is encoded by the LASS1 gene.-Further reading:...
p or Lass2
LASS2
LAG1 longevity assurance homolog 2 is a protein that in humans is encoded by the LASS2 gene.-Further reading:...
p (also termed as CerS), to form dihydroceramide. This is desaturated to form ceramide.
Ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
may subsequently have several fates. It may be phosphorylated by ceramide kinase
Ceramide kinase
In enzymology, a ceramide kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and ceramide, whereas its two products are ADP and ceramide 1-phosphate....
to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase or galactosylceramide synthase. Additionally, it can be converted to sphingomyelin
Sphingomyelin
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphorylcholine and ceramide...
by the addition of a phosphorylcholine
Phosphorylcholine
Phosphorylcholine is a zwitterionic phospholipid found on the outer surface of red blood cell membranes. It is created by CD5+/B-1 B cells and is referred to as a non-pathogenic autoantibody.-Thrombus Resistant Stents:...
headgroup by sphingomyelin synthase
Sphingomyelin synthase
In enzymology, a sphingomyelin synthase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ceramide and phosphatidylcholine, whereas its two products are sphingomyelin and 1,2-diacyl-sn-glycerol....
. Diacylglycerol is generated by this process. Finally, ceramide may be broken down by a ceramidase
Ceramidase
Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate .- Function :...
to form sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
. Sphingosine may be phosphorylated to form sphingosine-1-phosphate. This may be dephosphorylated to reform sphingosine.
Breakdown pathways allow the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelin may be broken down by sphingomyelinase to form ceramide.
The only route by which sphingolipids are converted to non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.
Functions of mammalian sphingolipids
Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayerLipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
. Certain complex glycosphingolipids
Glycosphingolipids
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They include:* Cerebrosides* Gangliosides* Globosides...
were found to be involved in specific functions, such as cell recognition and signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
. Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or with protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s.
Recently, relatively simple sphingolipid metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s, such as ceramide and sphingosine-1-phosphate
Sphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...
, have been shown to be important mediators in the signaling cascades involved in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, and stress responses. Ceramide-based lipids self-aggregate in cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s and form separate phase
Phase (matter)
In the physical sciences, a phase is a region of space , throughout which all physical properties of a material are essentially uniform. Examples of physical properties include density, index of refraction, and chemical composition...
s less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or "lipid raft
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
s" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport. At present, most research focuses on the organizing function during signal transduction.
Sphingolipids are synthesized in a pathway that begins in the ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
and is completed in the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
, but these lipids are enriched in the plasma membrane and in endosomes, where they perform many of their functions. Transport occurs via vesicles and monomeric transport in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. Sphingolipids are virtually absent from mitochondria and the ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, but constitute a 20-35 molar fraction of plasma membrane lipids.
Yeast sphingolipids
Because of the incredible complexity of mammalian systems, yeast are sometimes used as a model organismModel organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
for working out new pathways. These single-celled organisms are often more genetically tractable than mammalian cells, and strain libraries are available to supply strains harboring almost any non-lethal open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
single deletion. The two most commonly used yeasts are Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
and Schizosaccharomyces pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
, although research is also done in the pathological yeast Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
.
In addition to the important structural functions of complex sphingolipids (inositol phosphorylceramide and its mannosylated derivatives), the sphingoid bases phytosphingosine and dihydrosphingosine (sphinganine) play vital signaling roles in S. cerevisiae. These effects include regulation of endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, ubiquitin-dependent proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
(and, thus, regulation of nutrient uptake ), cytoskeletal dynamics, the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
, translation
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
, posttranslational protein modification, and the heat stress response. Additionally, modulation of sphingolipid metabolism by phosphatidylinositol (4,5)-bisphosphate
Phosphatidylinositol (4,5)-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
signaling via Slm1p and Slm2p and calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
has recently been described. Additionally, a substrate-level interaction has been shown between complex sphingolipid synthesis and cycling of phosphatidylinositol 4-phosphate
Phosphatidylinositol 4-phosphate
Phosphatidylinositol 4-phosphate is a precursor of Phosphatidylinositol -bisphosphate. PtdIns4P is prevalent in the membrane of the Golgi apparatus....
by the phosphatidylinositol kinase Stt4p and the lipid phosphatase Sac1p.
Plant sphingolipids
Higher plants contain a wider variety of sphingolipids than animals and fungi.Disorders
There are several disorders of sphingolipid metabolism, known as sphingolipidosesSphingolipidoses
-Accumulated products:* Gangliosides: Gangliosidosis** GM1 gangliosidoses** GM2 gangliosidoses*** Tay-Sachs disease*** Sandhoff disease* Glycolipids** Fabry's disease** Krabbe disease** Metachromatic leukodystrophy*Glucocerebrosides**Gaucher's disease...
. The most common is Gaucher's disease
Gaucher's disease
Gaucher's disease is a genetic disease in which a fatty substance accumulates in cells and certain organs.Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a hereditary deficiency of the enzyme glucosylceramidase. The enzyme acts on the fatty acid...
.
Also of note is Fabry's disease
Fabry's disease
Fabry disease is a rare X-linked recessive lysosomal storage disease, which can cause a wide range of systemic symptoms...
, an X-linked recessive condition wherein a buildup of glycosphingolipids in lysosomes of various tissues is due to alpha-galactosidase deficiency. These patients tend to present with peripheral neuropathies and develop chronic renal conditions.